The European Blood and Marrow Transplantation Textbook for Nurses

Michelle Kenyon · Aleksandra Babic Editors The European Blood and Marrow Transplantation Textbook for Nurses

Under the Auspices of EBMT The European Blood and Marrow Transplantation Textbook for Nurses Michelle Kenyon • Aleksandra Babic Editors

Under the Auspices of EBMT Editors Michelle Kenyon Aleksandra Babic Department of Haematological Medicine Istituto Oncologico della King’s College Hospital NHS Svizzera Italiana Foundation Trust Bellinzona, Switzerland London, UK

This book is open access. ISBN 978-3-319-50025-6 ISBN 978-3-319-50026-3 (eBook) https://doi.org/10.1007/978-3-319-50026-3

Library of Congress Control Number: 2018930542

© EBMT and the Author(s) 2018. This book is an open access publication. Open Access This book is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this book are included in the book’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the book’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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This Springer imprint is published by the registered company Springer International Publishing AG part of Springer Nature The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Foreword

Autologous and allogeneic haematopoietic stem cell transplantations (HSCT) are curative procedures for patients with haematological diseases and immune deficiencies. This textbook is an easy-to-read primer for all those involved in the care of HSCT patients. It offers a solid and comprehensive overview of different nursing methods and requirements and their applications towards improving HSCT patients’ outcome. The book is divided into several chapters which allow reviewing the most important components of nursing and caring after HSCT both in the adult and paediatric patients. It also relies on real-life clinical situations to illustrate the scientific principles and concepts. Cutting-edge and updated nursing techniques are presented, but the basic principles and general considerations are explained first. This textbook developed under the auspices of the European Society for Blood and Marrow Transplantation (EBMT) by highly skilled and experienced colleagues in this field represents an invaluable resource that will be highly useful to all professionals involved in the modern management of HSCT patients. EBMT is very proud of this unique achievement that has been long awaited because nursing science must be continually improved in order to provide the best patient care possible. It will contribute to better patient care and make it visible not only for nurses but also for all other stakeholders. Far from being all-inclusive, it will definitely serve as a catalyst for the interest of the readership.

Mohamad Mohty

v Preface

The EBMT Nurses Group: promoting excellence in patient care through international collaboration, education, research and science The EBMT Nurses Group (NG) plays an essential role in haematology and haematological stem cell transplantation nursing. The group was created 33 years ago and now has over 750 members in more than 60 countries worldwide with a principal nurse identified in almost each EBMT centre. The EBMT NG’s mission is to enhance and value the nurses’ role all over the world, supporting and sharing knowledge through communication, advocacy, research, training and education. The group is dedicated to improving the care of patients receiving SCT and works towards promoting excellence in care through recognizing, building upon and providing evidence-based practice. Over the last two decades, BMT nursing has grown rapidly and has acknowledged the need for care of the patients, their families and donors. Advanced practice nurses have been taking a leading role in the care of patients, providing in holistic care; BMT nurses are involved in the decision- making process about treatment options for their patients, and they evidently contribute to an enhancement in their patients’ quality of life. More and more, EBMT NG is conducting a research on topics based within clinical practice and is formulating their own research agenda. The EBMT NG consists of a board and five committees (paediatric, research, global educational, scientific and communication and networking) and links with national groups/forums. Recently, we enhanced our collaboration between EBMT and the Haematology Society of Australia and New Zealand (HSANZ) Nurses Group. http://www.ebmt.org/Contents/Nursing/WhoWeAre/TheBoard/Pages/ TheBoard.aspx

Bellinzona, Switzerland Aleksandra Babic

vii Contents

1 JACIE and Quality Management in HSCT: Implications for Nursing ��1 Carole Charley, Aleksandra Babic, Iris Bargalló Arraut, and Ivana Ferrero 2 HSCT: How Does It Work? ��23 Letizia Galgano and Daphna Hutt 3 Donor Selection ��37 Mairéad Níchonghaile 4 Transplant Preparation ��45 Caroline Bompoint, Alberto Castagna, Daphna Hutt, Angela Leather, Merja Stenvall, Teija Schröder, Eugenia Trigoso Arjona, and Ton Van Boxtel 5 Cell Source and Apheresis ��71 Aleksandra Babic and Eugenia Trigoso 6 Principles of Conditioning Therapy and Cell Infusion ��89 Sara Zulu and Michelle Kenyon 7 BMT Settings, Infection and Infection Control ��97 John Murray, Iris Agreiter, Laura Orlando, and Daphna Hutt 8 Transplantation Through the Generations ��135 Alberto Castagna, Lisa Mcmonagle, Corien Eeltink, and Sarah Liptrott 9 Early and Acute Complications and the Principles of HSCT Nursing Care ��163 Elisabeth Wallhult and Barry Quinn 10 Supportive Care ��197 S. J. van der Linden, M. E. G. Harinck, H. T. Speksnijder, Teija Schröder, Ien Schlösser, Vera Verkerk, Micheala van Bohemen, A. M. Rusman-Vergunst, J. C. Veldhuijzen, and W. J. A. Quak 11 Graft-Versus-Host Disease (GvHD) ��221 John Murray, Jacqui Stringer, and Daphna Hutt

ix x Contents

12 Graft Versus Tumour Effect ��253 Mairéad NíChonghaile 13 Engraftment, Graft Failure, and Rejection ��259 Daphna Hutt 14 Late Effects and Long-Term Follow-Up ��271 Michelle Kenyon, John Murray, Barry Quinn, Diana Greenfield, and Eugenia Trigoso 15 Nursing Research and Audit in the Transplant Setting ��301 Corien Eeltink, Sarah Liptrott, and Jacqui Stringer About the Author

Michelle Kenyon works as Consultant Nurse (BMT Care and Survivorship) at King’s College Hospital, London. She has worked for more than 25 years in the field of haemato-oncology and stem cell transplantation. Her interest in improving the patient experience of haematopoietic stem cell transplantation (HSCT) led her to write The Seven Steps, a patient information book (2002) and subsequently the Next Steps (2012). Around 50,000 copies of these titles have been distributed and are now used as the basis of informed consent for transplant recipients throughout the UK. She studied her BSc in Cancer Nursing and MSc in Advancing Cancer Nursing Practice at King’s College London, and undertook an empirical research study exploring the use of life-coaching in stem cell transplant survivors for her dissertation. She supports patients throughout their post-transplant recovery and has a particular interest in survivorship issues and the effects of treatment. She launched the HSCT long-term follow-up clinic at King’s College Hospital in 2014 and has found the patient insights inspiring and the overall experience highly rewarding. She is the nurse representative on the BSBMT executive, Vice Chair EBMT (UK) NAP group and is Secretary of the EBMT NG.

Aleksandra Babic is a Nurse Manager, affiliate to Oncology Institute of Southern Switzerland (IOSI), in Bellinzona, as Transplant Unit Coordinator and Quality Manager. She received her nurse diploma from the College Center of Professional Formation in Dubrovnik, Croatia, in 1988, and was

xi xii About the Author awarded a Master’s degree in Nurse Management in 2006. Until 2016 she worked as a nurse manager in apheresis unit at IEO, European Institute of Oncology in Milan, and has published papers on peripheral blood stem cell collection and mobilisation (i.e. R-ESHAP Plus Pegfilgrastim as an Effective Peripheral Stem Cell Mobilization Regimen for Autologous Stem-Cell Transplantation in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma, Transfus Apher Sci. 2013; Successful Mobilisation of Peripheral Blood Stem Cells in Children Using Plerixafor: A Case Report and Review of the Literature, Blood Transfus. 2013; Who Should Be Really Considered as a Poor Mobilizer in the Plerixafor Era? Transfus Apher Sci. 2012) and photopheresis (i.e. Efficacy of Photopheresis Extracorporeal Procedure as Single Treatment for Severe Chronic GVHD: A Case Report, Transfus Apher Sci. 2013). In addition, Aleksandra has presented at a number of conferences worldwide, most recently including the GIIMA 3rd National Conference, GITMO and the EBMT 2015 conference: Validation of PBSC collection within JACIE program – A multicenter evaluation. From 2016 she is also a JACIE Quality Manager Inspector. Aleksandra is the former EBMT NG President (European Blood and Marrow Transplant Society) Nurses Group, which includes more than 800 nurses in 64 countries worldwide. She is a former President of GIIMA, the Italian Nurses Group in Mobilisation and Aphaeresis, and the founder and a board member of the not-for-profit association, Nurses No Frontiers. Brief History of HSCT Nursing: HSCT Nursing Through the Ages and Its Evolution

Since the beginning and progress of stem cell transplantations in the late 1950s/early 1960s, it was clear that nurses play a crucial role within the mul- tiprofessional team caring for patients and their families undergoing this treatment. Nurses as core professionals along physicians and other healthcare workers care for patients and their families around the clock. Continuity of care is vital to patients’ satisfaction as well as trust. In the beginning, care was considerably cumbersome with HSCT patients who needed to be treated in a sterile environment such as germ-free tents or bubbles. Being one of the nurses who still remembers how that had to be handled, it is clear that this work was very time consuming and specific material was needed because everything – from the linen and clothes of patients up to every single book, toy or newspaper – is all needed to be wrapped up and sterilized before given to the patient. Next to helping patients deal with the time in the germ-free environment, talking to their beloved ones through a plastic curtain or wearing a mask covering emotions on the face, nurses of course also needed to take care for the physical and psychological challenges patients faced.

• Nurses Field of Competences

To be able to care for patients and families, nurses need to perform duties and responsibilities that often comprise more tasks than the ones taught in nursing schools. Experience and long-term commitment to the care of HSCT patients can be a challenge but also very rewarding. Novices to the field will need to be supervised and supported by expert nurses from the beginning to be able to endure also burdensome situations in a very person-centred care.

–– Coordinator, Communicator and Translator

Nurses play an important role as coordinator of all issues including coordinating procedures and care activities within the interprofessional context before, during and after transplantation. This includes organizing all necessary diagnostic tests and checkups prior to transplantation. Sometimes they are responsible also for the donor and his/her health including questions concerning the donation of stem cells and its consequences. The process of transplantation involves many professionals and specialties – therefore, all results need to come back to one single point of coordination. It is important to communicate all diagnostic tests, their results, and what they mean in the situation

xiii xiv Brief History of HSCT Nursing: HSCT Nursing Through the Ages and Its Evolution of the patient in a language that the patient understands. Often the medical language is difficult to understand by lay people, and therefore nurses play an important role in translating the meaning and consequences to patients and their families.

–– Preparer and Educator of Patients for Transplantation and the Period After HSCT

Over the years, every centre developed modules, booklets or information brochures for patients which always supported the educational activities to prepare patients prior transplantation, help them through the phases of transplantation and make them ready for discharge and the time at home when no professional is around, and they have to make important decisions and cope with the situation in their own home environment. Specific attention has developed towards educating the long-term survivors and their next of kin in which nurses can play a prominent role because medical treatment activities are more in the background and day-to-day questions have to be dealt with. Some centres developed classes in which patients and families get together, gain the needed information and share concerns and discuss ways of coping. All this is often done under the auspice of nurses experienced not only in transplant nursing but also in principles of patient education.

–– Carer, Administrator and Technician

The administration of chemotherapeutic, immunosuppressive and symptom-control drugs; blood products; and parenteral nutrition through a central venous access device has developed over the years. The accurate handling and care of the central venous catheter and infusion pump systems is vital in the process because the catheter is related to the highest risk of infections. In addition, nurses often need to make important decision when no physician is around to prescribe medication (such as during the night shift) to ease suffering such as pain, mucositis, diarrhoea or nausea.

–– Social Supporter and Motivator

The distress during the time prior to undergoing HSCT, during isolation, in the recovery phase and the time after (long-term recovery) is not to be underestimated. Nurses play an important role as part of the interprofessional team in communicating, motivating and supporting patients throughout the entire process including the follow-up time. Connecting patients and family members with other professionals such as social worker, psychologist or spiritual carer whenever emotional distress is overwhelming, other questions arise and encouragement is needed is often considered very helpful. Being culturally sensitive and meeting the spiritual needs of patients has become a recognized challenge in our often multicultural societies. Because of the 24/7 availability of nurses, they often detect these needs and are able to call for the necessary support that patients and families need. Brief History of HSCT Nursing: HSCT Nursing Through the Ages and Its Evolution xv

Although over the years there were tremendous improvements in outcomes, namely, better survival rates, some patients and families need to face limited life expectancy. In this phase, the early support of palliative care in managing symptoms, helping patients in their often difficult and complex decision-making and discussing who of the family can be involved to take care and how to back up the family and look for additional offers to relieve and unburden family members is vital. Advance care planning should be integrated early into the care of stem cell recipients (Button et al. 2014), and nurses can address the above-mentioned topics and help patients and families to find a way in the often overwhelming and complex situation. An interprofessional palliative care service, supposedly even offered pre-transplantation (Loggers et al. 2016), could provide support in helping throughout often complex and instable situations which could lead to a better understanding of the situation, lessen distress and increase hope and quality of life (El-Jawahri et al. 2016) in the unit of care.

• Extended Practice Roles

In the late 1990s during the EBMT conference in Aix-les-Bain (France), nurses performing diagnostic and therapeutic interventions such as bone marrow or lumbar punctures – up to that time executed only by physicians – were strongly discussed and also criticized by the nursing audience. That can probably be considered as the beginning of the development of extended roles that nurses nowadays perform on a regular basis. Importantly, throughout the discussion, the core tasks of nurses remain in the hands of nurses and are not delegated to other professions. Probably a suitable mix of skills and grades of nurses is the foundation of professional nursing within the interprofessional team. Nurses trained on an academic level and performing tasks as a nurse practitioner or clinical nurse specialist are considered as advanced practice nurses. Several role models exist throughout the European countries. Learning from the highly qualified nurses in the USA and their approach of nursing inspired many European nurses to go beyond what was up to then traditional in their own country. Being academically trained often enabled nurses to argue more based on evidence-reflected practice and led to being accepted by other academic professionals. Being part of the interprofessional team with a strong shoulder-to-shoulder workforce together with physicians, physiotherapist, dietitians, social workers or chaplains, nurses found their unique role in being present with the patients 24/7 during the treatment but also in the time before and after the treatment. Nurses took over the responsibility to educate patients before the treatment about any aspects that are important to successfully undergo the procedure. Over the past decades, many nurses not only developed clinical skills but are also excellent researchers looking deeper into the phenomena of patients, family members and measuring outcomes based on a reflective way of practising nursing. The field of nursing research in HSCT has evolved from reflecting on symptom management and service development to quality of life and long-term survival topics. xvi Brief History of HSCT Nursing: HSCT Nursing Through the Ages and Its Evolution

Outcomes of research form the basis of standard operating procedures (SOPs) developed to support clinical practice, guarantee a high level of practice, and audit and accredit the transplant centres on evidence-based practice guidelines. The translation of evidence into clinical practice and taking into consideration the local circumstances is challenging. Still there are varieties among the nursing care in different transplant settings (Bevans et al. 2009). Therefore, networks of nurses in the field in which nurses discuss patient- centred outcomes are vital – not only to prevent the reinvention of the wheel but mainly to establish high-quality standards and data that are comparable in research. Nurses collaborate in local, national and international networks such as the EBMT Nurses Group, the American Society for Blood and Marrow Transplantation (ASBMT), the Special Interest Group of the American Oncology Nursing Society or the Haematology Nurses and Healthcare Allied Professionals Group (HNHCP). Also nurses reach out to cancer nursing organizations such as the European Oncology Nursing Society (EONS) because issues of haematological patients are not always specific to the stem cell transplant patient population but knowledge from the care for patients with other malignant diseases can be useful in the care. The shift of the focus towards more educational tasks – especially since the emergence of oral drugs developed to cure haematological malignancies without the necessity of a stem cell transplantation such as tyrosine kinase inhibitors – changed the work of nurses tremendously. Unexpectedly – despite the anticipation that patients with cancer will always take their medication as prescribed by their physician – nurses needed to develop skills and knowledge of adherence. By collaborating together with the industry and patients, educational initiatives were developed to support patients in adhering to the prescribed regimen often over a very long disease and therefore symptom-free time.

• Importance of HSCT Nursing

The best compliment towards nursing was done by Prof. Edward Donnall Thomas (1920–2012), founding medical director of the Fred Hutchinson Cancer Research Center’s Transplant Program who shared the 1990 Noble Prize in Physiology or Medicine with Dr. Joseph E. Murray: he stated that nurses and nursing was his secret weapon without whom he could not have achieved his goals. This acknowledges that nurses play a vital role as part of the interprofessional team in caring for the transplant recipients and their families. The statement of Prof. Thomas should be the basis on which nurses should develop the skills, knowledge and expertise to enhance a reflected care and be alert for any changes in treatments which might influence care. Picking up changes and supporting the developments will become a challenge in the often complex healthcare environment. Nurses will need to understand the challenges and shape the future care for any person trusting in what the interprofessional team has to offer – and maybe unravel the “secrets” of nursing and make it more visible of what nursing has to offer.

Bern, Switzerland Monica C. Fliedner Brief History of HSCT Nursing: HSCT Nursing Through the Ages and Its Evolution xvii

Literature

Bevans M, Tierney DK, Bruch C, Burgunder M, Castro K, Ford R, et al. Hematopoietic stem cell transplantation nursing: a practice variation study. Oncol Nurs Forum. 2009; 36(6):E317–25. doi:10.1188/09.ONF.E317-E325. Button EB, Gavin NC, Keogh SJ. Exploring palliative care provision for recipients of allogeneic hematopoietic stem cell transplantation who relapsed. Oncol Nurs Forum. 2014;41(4):370–81. doi:10.1188/14.ONF.370-381. El-Jawahri A, LeBlanc T, VanDusen H, Traeger L, Greer JA, Pirl WF, et al. Effect of inpatient palliative care on quality of life 2 weeks after hematopoietic stem cell transplantation: a randomized clinical trial. JAMA. 2016;316(20):2094–103. doi:10.1001/jama.2016.16786. Loggers ET, LeBlanc TW, El-Jawahri A, Fihn J, Bumpus M, David J, et al. Pretransplantation supportive and palliative care consultation for high-risk hematopoietic cell transplantation patients. Biol Blood Marrow Transplant. 2016;22(7):1299–305. doi:10.1016/j.bbmt.2016.03.006. JACIE and Quality Management in HSCT: Implications for Nursing 1

Carole Charley, Aleksandra Babic, Iris Bargalló Arraut, and Ivana Ferrero

Abstract Laboratory medicine, along with the airline industry, has a long history of utilising quality management systems. It took until 1999 for The Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT) and the European Group for Blood and Marrow Transplantation (EBMT), known as JACIE, to be established as an accreditation system in the field of haematopoietic stem cell transplantation (HSCT). The aim was to create a standardised system of accreditation to be officially recognised across Europe and was based on the accreditation standards established by the US-based Foundation for the Accreditation of Cellular Therapy (FACT). Since the concept of JACIE was originally launched, many European centres have applied for initial accreditation with other centres gaining reaccreditation for the 2nd or 3rd time. Transplant units, outside of Europe, have accepted the importance of the JACIE Standards, with units in South Africa, Singapore and Saudi Arabia also gaining accreditation. There is evidence that both donor and patient care have improved within the accredited centres (Passweg et al., Bone Marrow Transpl, 47:906–923, 2012; Demiriz IS, Tekgunduz E, Altuntas F (2012) What is the most appropriate source for hematopoietic stem cell transplantation?

C. Charley (*) • I.B. Arraut JACIE Accreditation Office, Barcelona, Spain e-mail: [email protected] A. Babic Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland I. Ferrero Stem Cell Transplantation and Cellular Therapy Laboratory, City of Health and Science of Turin, University of Turin, Italy/JACIE Accreditation Office, Barcelona, Spain

Peripheral Stem Cell/Bone Marrow/Cord Blood Bone Marrow Res. (2012):Article ID 834040 (online)). However, there is a lack of published evidence demonstrating that this improvement directly results from better nursing care. Therefore, the authors conducted a survey of nursing members of the European Blood and Marrow Transplantation Nurses Group (EBMT (NG)) to identify how nurses working in the area of HSCT felt that JACIE impacted in the care they delivered and the general implications of JACIE for nurses.

Keywords FACT-JACIE International Standards • Nurses implications • Quality management • Standard operating procedures

1.1 Background to JACIE dards that gave rise to common difficulty experienced by the transplant teams and to assess what The 1990s saw an increase in the number of assistance, if any, would be required by the cen- transplant teams performing haematopoietic stem tres for them to obtain accreditation. The results cell transplantation (HSCT) (Passweg et al. of this pilot study underlined the need to imple- 2012). The procedure that was initially consid- ment national and international regulations ered experimental during the 1960s/1970s was (Pamphilon et al. 2008) within each European becoming an established treatment for many country. In January 2004, with the support from blood cancers, solid tumours and acquired or the European Union under the Public Health congenital disorders of the haematopoietic sys- Programme (2003–2008), the JACIE accredita- tem within adult and paediatric populations. tion process was launched (Pamphilon et al. Towards the end of the 1990s, the source of hae- 2008). matopoietic stem cells was collectable from the To enable a set of international standards for the marrow, peripheral blood and cord blood and provision of quality medical, nursing and laboratory from autologous, sibling and unrelated donations practice in HSCT transplantation to be developed (Demiriz et al. 2012). and recognised, JACIE collaborated with their In 1998 two leading European scientific American counterparts, the Foundation for the organisations, The International Society for Accreditation of Cellular Therapy (FACT) (JACIE). Cellular Therapy (ISCT) Europe and the The “FACT-JACIE International Standards for European Group for Blood and Marrow Hematopoietic Cellular Therapy Product Collection, Transplantation (EBMT), formed a joint commit- Processing, and Administration” are revised on a tee to be known as the Joint Accreditation regular basis. Committee for ISCT and EBMT (JACIE) (JACIE JACIE remains a non-profit organisation with n.d.; Cornish 2008). The purpose of this new all members being an expert within their spe- committee was to establish a system to allow cialty: clinical, collection or processing transplant teams to self-assess against a group of procedures of HSCT. Clinicians, nurses and qual- standards (Cornish 2008), provide an inspection ity managers who are experts in their field can process and recognise compliance with the stan- volunteer to become JACIE inspectors, if they dards by awarding accreditation to those teams meet the criteria set. Potential inspectors must who worked within the field of HSCT. A pilot attend a training programme, pass the inspector’s study of the JACIE inspection and accreditation exam and act as an observer within the inspection process was carried out in Spain 2000–2002. team as a trainee before their first official JACIE This enabled JACIE to assess sections of the stan- inspection. As the JACIE accreditation process 1 JACIE and Quality Management in HSCT: Implications for Nursing 3 has evolved, the inspection team membership has Anthias et al. 2015, 2016). Nurses have suc- extended to include apheresis nurses and more cessfully taking on the role of improving com- recently experienced quality managers recognis- munications for donor mobilisation, ing the multi-professional components of our collections and liaising with the staff of the HSCT programmes. The accreditation process is processing facility. continuous reflecting an established quality man- • Track and monitor collected cell products for agement system (QMS); therefore accredited safety and viability from the time of donation centres are required to apply for reaccreditation to the administration procedure. Patients’ every 4 years. In 2016, many transplant teams medical records must include not only the were achieving reaccreditation for the 2nd or 3rd information of date and time of the collection time, whilst other centres are applying for their but should include volume of collected prod- initial application. At the beginning of December uct, type and volume of citrate and the product 2016, the JACIE website (www.jacie.org) (2016) identification. A transport log will be required cited 334 successful initial accreditations; 197 to ensure traceability of all products from col- successful reaccreditations from 26 countries had lection to processing and then to clinical for been granted since 2000. Although the initial aim administration. of the accreditation scheme was a voluntary pro- • Identify errors and incidents that can be cess, in many countries, health-care systems/ reviewed and corrective actions be imple- commissioners or health insurance providers and mented and allow a plan of action to be put tissue banking authorities increasingly view into place to minimise the error reoccurring. JACIE accreditation as important and demand • Formalise training and competencies. accreditation to allow the procedure of HSCT to • Clearly identify the roles and responsibilities be performed. of all staff working within the transplant team Accreditation is the means by which a centre or with outside agencies (clinical, collection, can demonstrate that it is performing to a required processing and support services; intensive level of practice in accordance with agreed stan- care, radiotherapy, cleaning and transport ser- dards of excellence. Essentially it allows a centre vices, laboratories and donor panels). to certify that it operates an effective • Review documentation for evidence that stan- QMS. Furthermore, due to the increased use of dards have achieved compliance on a regular unrelated donors from different countries, inter- basis. action and collaboration between units are key elements for the success of stem cell transplantation. JACIE accreditation is a guarantee that the 1.2 Preparing for JACIE donor and the cellular product have been handled Accreditation according to specific safety criteria. A QMS is a mechanism to: 1.2.1 Considerations

• Ensure that procedures are being performed in In the early stages of preparing for accreditation, line with agreed standards, with full participa- extra resources may be required: a dedicated tion by all staff members. In a HSCT pro- quality manager, data collection manager and gramme, this ensures that the clinical, support staff (pharmacist, dietician, social collection and laboratory facilities are all worker) to fulfil the standards and prepare for the working together to achieve excellent commu- inspection. Formalisation of the QMS and nication, effective common work practices, accreditation will depend on structures already in shared policies where appropriate and place. increases guarantees for improved patient out- There will be many processing facilities that comes and the use of international donor crite- are independent from the clinical transplant ria for related donors (Gratwohl et al. 2014; teams and may also be responsible for collections 4 C. Charley et al. of apheresis products. In this situation, the pro- administration, use of stem cell mobilisation cessing facility and clinical facility have a choice agents and collection of cellular material. of accreditation. They may decide to apply for The implementation of a QMS arises from separate or combined accreditation. However, in the need to develop an appropriate system to order to obtain JACIE accreditation, it is impor- optimise the quality of the service offered by a tant that the QMS describes the communication stem cell transplantation unit, in a general con- processes between all facilities involved and text of health-care quality improvement. A provides the evidence that communications QMS is a tool that can be used to rapidly iden- exist, e.g. minutes of weekly, monthly and tify errors or accidents and resolve them to min- annual meetings must include the names of the imise the risk of repetition. A QMS assists in attendees, sharing evidence of engraftment and training and clearly identifies the roles and adverse events. It is important to remember a responsibilities of all staff (Cornish 2008; clinical facility must use an apheresis and pro- Caunday et al. 2009). cessing facility that are JACIE accredited. In 1966, Avedis Donabedian wrote a paper Similarly, an apheresis facility must use a pro- entitled “Evaluating the Quality of Medical cessing facility that is accredited before clinical Care”, where the concepts of structure, process and apheresis facilities can be awarded JACIE and outcome in health care were introduced. The accreditation. structure includes not only the physical aspects in which care is given but also the resources and tools available to the health-care team, the lead- 1.2.2 Implementing a Quality ership and the staff. The process is how the Management System health-care system and the patient interact. The outcome includes the effect of care on diseases HSCT is a procedure with a high technological and their prevention, such as the mortality rate, content, which requires extensive attention the error rate and the quality of life (Samson towards patients/donors who might introduce et al. 2007). important problematic clinical factors and also During the 1950s, Edwards Deming intro- towards sophisticated laboratory procedures duced the plan-do-check-act (PDCA) cycle, an related to the collection, manipulation, cryo- iterative four-step management method used for preservation and transplantation of haematopoi- the implementation and improvements of pro- etic stem cells (HSCs). The continuous cesses and products, also known as plan-do- improvement of stem cell technology requires study-act (PDSA). He also stressed the that all procedures regarding HSCT be guaran- importance of viewing problems in the context of teed through the definition of qualitative stan- a system and that most mistakes were not the dards recognised by scientific associations and fault of the worker (Samson et al. 2007). international organisations. For the collection, The major objective of the JACIE Standards is processing and transplantation of HSCs, there are to promote quality medical and laboratory prac- standardised procedures, which require specific tice in HSCT and other therapies using cellular clinical, haematological and laboratory knowl- products; therefore dedicated quality manage- edge and strict quality controls concerning all ment standards are found within the FACT-JACIE processes from cellular collection and manipula- manual (clinical facility B04, marrow collection tion to the administration of the collected prod- facility CM04, apheresis collection facility C04, uct. Stem cell collection, processing, storage and processing facility D04). transplantation must be carried out in a highly Quality management is the management of regulated manner to guarantee both safety and activities involved in quality assessment, assur- clinical efficacy. Therefore, quality assurance is a ance and control that try to improve the quality of very important topic at all levels of HSCT, includ- patient care, products and services in cellular ing robust nursing procedures, e.g. chemotherapy therapy activities. 1 JACIE and Quality Management in HSCT: Implications for Nursing 5

A QMS could be implemented applying the In the 6th edition of the FACT-JACIE PDCA cycle for the management and continuous Standards, more specific requirements for valida- improvement of processes and products. tion and qualification studies have been delin- eated, and the concept of risk assessment has • PLAN means to establish the objectives and been implemented. processes necessary to the centre. This means define the scope of the QMS and identify which • Validation is documented evidence that the processes within the scope are most important, performance of a specific process meets the those staff who are involved in the important requirements for the intended application. For processes and involve them in defining the tar- example, the procedure for thawing frozen gets to be used to measure the quality of the cells should be evaluated, as there is a risk of process. Ensure all staff knows how they can contamination and loss of cells during the contribute to achieve the performance required. thawing process. A thawing control, on three procedures, could be performed to assess One important aspect to consider when imple- these criteria would validate the process. menting a QMS is the organisation and interac- • Qualification is documented evidence that the tion between the different facilities (clinical, equipment/facility/utility is meeting the user collection and processing). The plan shall include requirement specification, working correctly an organisational chart of functions, considering and leading to the expected results. For exam- clinical, collection and processing staff, in par- ple, “the dry shipper used for the transporta- ticular for those tasks that are critical to assuring tion of frozen haematopoietic stem cells product or service quality. Training plans should should be validated for temperature control”. be defined and put in place. Documentation may be displayed in a variety of formats (job descrip- During the implementation phase, risk man- tions, training records, qualifications certificates, agement should be an ongoing part of the quality retraining). management process, to minimise hazards for A document system should be implemented processes, patients and staff. There are several serving multiple purposes for the QM pro- methods for the assessment of the risk, such as gramme. They provide instructions on: Failure Mode and Effects Analysis (FMEA) or Failure Modes, Effects and Criticality Analysis • Activities, policies and processes controlling (FMECA), methods of assessing potential failure various steps within the activities mechanisms and their impact on system, identi- • Quality control and traceability of products, fying single failure points. donor and patients • DO means to implement the plan, execute the The Quality Management Plan (QMP) (or process and carry on the activities. Once the Quality Management Manual) should be one of programme has been established and staff the first documents developed when preparing for trained, the activities and the quality plan JACIE accreditation. The centre must have a should be maintained, through the document standard operating procedure (SOP) outlining the system and the available resources. Policies method by which to create, approve, implement and procedures could be revised, training pro- and update SOPs (known as the “SOP for SOPs”). grammes implemented and the outcome Clinical and collection protocols or laboratory analysis of cellular therapy product efficacy methods must be translated into written proce- reviewed to verify that the processes in use dures, in paper form or an electronic version, and provide a safe and effective product. readily available to staff. The purpose of docu- • CHECK is to measure the results and compare ment control is to ensure the correct approved them against the expected results or goals documents are in use. defined by the plan. Audits represent one of 6 C. Charley et al.

the principal activities in this step and should as a self-evaluation tool. This document contains be documented, independent inspection and all the JACIE Standards and will help the centre retrospective review of activities to determine establish their level of compliance against each if they are performed according to written pro- standard and identify further work required to cedure and specified endpoints. They should achieve accreditation. Furthermore, the checklist be conducted to ensure that the QMS is oper- is the pivotal tool used continually throughout the ating effectively and to identify trends and JACIE accreditation process, until JACIE accredi- recurring problems in all aspects of the pro- tation has been awarded. gramme. Moreover, the transplant programme should manage errors, accidents, deviations, adverse reactions and complaints and monitor 1.3.2 Application for JACIE activities, processes and products using mea- Accreditation surable indicators (Harolds 2015). • Finally, ACT is to improve the QMS based on When the applicant has established a mature the results of the previous steps. Investigation QMS, i.e. has been in place and operational for at of errors and indicators and the implementa- least a year, a self-assessment of the standards tion of corrective or improvement strategies has been performed and shows a high percentage are undertaken and monitored with follow-up of compliance the centre can formally apply for assessment to determine the effectiveness of JACIE accreditation. The completed application the change. form and inspection checklist should be submitted to the JACIE Office where the JACIE team Data shown by Gratwohl and colleagues will review and approve the application form, (Gratwohl et al. 2014) demonstrates the use of a finalising this part of the process by signing the clinical quality management system is associated accreditation agreement with the centre. with improved survival of patients undergoing Within 30 days of the application being allogeneic HSCT. approved, the applicant will be required to provide the preaudit documentation to the JACIE Office. The JACIE team and the inspectors will 1.3 The JACIE Accreditation determine that all required documentation has Process been correctly submitted. The documents can be provided in the language of the centre/applicant; 1.3.1 Start Working however in some exceptional cases, a translation with the Standards in English of some key documents can be requested. The preaudit documentation should be The JACIE accreditation process begins when the submitted using the predefined folder structure transplant centre, with the support of the hospital described on the JACIE website, which includes management team (a key element in order to relevant documentation for all areas of the Stem assure the required resources to successfully Cell Transplant Programme such as personnel implement the JACIE accreditation process), documentation, donor consent information, agrees to start working according to the JACIE labels and summary of QMS activities (Quality Standards. Management Plan, audit report, policies). It is important to gather all the necessary information before commencing the JACIE accreditation pathway. First read the JACIE Standards, 1.3.3 Arranging the Inspection Date access the guides, manuals and supporting documentation from the JACIE website (www.jacie. The JACIE Office will begin the process to assign an org). Then utilise the JACIE Inspection Checklist inspection date and the inspection team. However, 1 JACIE and Quality Management in HSCT: Implications for Nursing 7 this part of the process can take approximately 6 • Closing meeting summarising the inspection months from the approval of the application. The results with the transplant team inspection team will consist of one inspector per facility to be inspected. For example, if the applicant has applied for adult clinical and bone marrow, 1.3.5 The Inspection Report apheresis and processing accreditation, the inspection team will consist of the following: clinical, Following inspection, the inspectors submit their apheresis and a processing inspector (The clinical completed written report and inspection checklist inspector will be responsible for clinical and marrow to the JACIE Office. The inspection report is a collection facilities). The inspectors are selected fundamental part of the accreditation process. The according to their area of expertise: clinical, aphere- report will be prepared and presented to the JACIE sis and processing. For instance, a clinician will Accreditation Committee by the JACIE Report inspect the clinical facility. If a paediatric unit is part Assessors after their review and confirmation of the inspection, a paediatrician will be assigned. with the inspectors over any issues, if necessary. When there is more than one facility per area, for The Accreditation Committee is a group of instance, two apheresis units, an extra collection experts from all areas of Stem Cell Transplantation inspector will be included in the inspection team. (Clinical, Collection and Processing) that dis- The applicant will be invited to view the list of cusses each individual report and determines cor- JACIE inspectors, found on the JACIE website, rective actions the centre is required to implement and inform the JACIE Office if there are any in order to achieve the JACIE accreditation. inspectors that they prefer not to participate in Please bear in mind that although the inspectors their inspection, due to conflict of interest. The identify areas of non-compliance, it is the JACIE inspection will be performed in the language of Accreditation Committee who decide the correc- the centre unless there are no JACIE inspectors tive actions, not the inspectors. that speak the language of the applicant centre; in these cases, the inspection will be performed in English with language support. 1.3.6 Corrections and Accreditation Award

1.3.4 The Inspection A high percentage of all inspections reveal deficiencies and the degree of deficiency identified The inspection will take place over a period of will vary in seriousness. In most cases, evidence of 1–2 days and is a thorough examination of all corrections can be submitted electronically. aspects of the programme. The inspector will use However, if the deficiencies are considered a risk the inspection checklist previously completed by for patients, donors or personnel, a focussed re- the applicant to evaluate the centre’s compliance inspection will be required before JACIE accredi- with the standards. tation can be finalised. The inspection is usually divided in the fol- Centres are allowed a period between 6 and 9 lowing parts: months to implement and submit the corrections to the JACIE Office. The same team of inspectors • Introductory meeting by the programme direc- will review and assess the adequacy of the cor- tor and the inspection team with all the pro- rections provided by the centre. Once the inspec- gramme personnel tors are satisfied that all points have been resolved • MEDA/B data audit and review of and with the approval of the JACIE Accreditation documentation Committee, the applicant will be awarded the • Interviews with personnel JACIE accreditation for a 4-year period, subject • Closing meeting with programme director to an interim audit at the end of the second year. 8 C. Charley et al.

1.3.7 Post JACIE Accreditation 1.4 JACIE Standards that Affect Nursing: Clinical The inspection is the most visible part of the and Collection JACIE accreditation process. The most challenging part, once the JACIE accreditation has been The JACIE Standards are divided into sections: awarded, is maintaining accreditation. At the sec- clinical and donor (B), collection of marrow ond year of accreditation, the interim audit will be (CM), apheresis products(C) and laboratory (D). due, and if the system has not been maintained, the Many of these standards are shared across each hard work invested in achieving accreditation will facility as appropriate (Table 1.1). become void and centres return to the beginning of It is not possible to describe, within this the process when applying for reaccreditation. chapter, all the actions and evidence required to The JACIE Committee warns against failing fulfil a full compliance for all the standards pub- to uphold standards or maintain the QMS between lished in the latest edition of the JACIE inspections. Those centres that fail to maintain Standards; therefore in Tables 1.2, 1.3 and 1.4, their QMS due to lack of commitment or allow there are examples of appropriate standards, their system to devolve may discover standards compliance and comments that have implica- that were compliant at the initial inspection may tions for nurses. become partially or noncompliant during the It is important that the nursing team takes inspection required for reaccreditation. Inspectors ownership of the relevant standards and works will identify failures to review documentation, towards achieving full compliance whilst being perform audits and maintain competencies due to aware of the other standards that have implica- the lack of available evidence during the accredi- tions on nurses or nursing (Table 1.5). tation cycle.

Table 1.1 FACT-JACIE Hematopoietic Cellular Therapy Accreditation Standards (6th edition)

QUALITY MANAGEMENT

CLINICAL PROGRAM STANDARDS COLLECTION FACILITY STANDARDS PROCESSING FACILITY STANDARDS PART B PART C PART D

B1 General C1 General D1 General B2 Clinical Unit C2 Apheresis Collection Facility D2 Processing Facility B3 Personnel C3 Personnel D3 Personnel

B4 Quality Management C4 Quality Management D4 Quality Management

B5 Policies and Procedures C5 Policies and Procedures D5 Policies and Procedures B6 Allogeneic and Autologous C6 Allogeneic and Autologous Donor D6 Equipment, Supplies, and Reagents Donor Selection, Evaluation, and Evaluation and Management D7 Coding and Labeling of Cellular Management C7 Coding and Labeling of Cellular Therapy Products B7 Recipient Care Therapy Products D8 Process Controls B8 Clinical Research C8 Process Controls D9 Cellular Therapy Product Storage B9 Data Management C9 Cellular Therapy Product Storage D10 Cellular Therapy Product B10 Records C10 Cellular Therapy Product Transportation and Shipping Transportation and Shipping D11 Distribution and Receipt C11 Records D12 Disposal C12 Direct Distribution to Clinical D13 Records Program 1 JACIE and Quality Management in HSCT: Implications for Nursing 9

Table 1.2 Examples of “non compliant” clinical standards (FACT-JACIE Hematopoietic Cellular Therapy Accreditation Standards: 6th edition)

B.03.07 NURSES

B.03.07.01 The Clinical Program shall have nurses Partially No evidence of formal formally trained and experienced in the Compliant training in the transplant management of patients receiving cellular setting therapy.

B.03.07.02 Clinical Programs treating pediatric Partially Nurses are paediatric patients shall have nurses formally trained Compliant qualified but lack and experienced in the management of evidence of formal pediatric patients receiving cellular training in the transplant therapy. setting

B.03.07.03 Training and competency shall include:

B.03.07.03.03 Administration of blood products, growth Partially Hospital policy does not factors, cellular therapy products, and other Compliant include the administration supportive therapies. of cellular products; therefore a policy for the administration of cellular products is required. This policy can then be used for training and competency testing

B.03.07.03.06 Palliative and end of life care. Non Compliant No training

B.03.07.04 There shall be written policies for all relevant nursing procedures, including, but not limited to:

B.03.07.04.01 Care of immunocompromised patients. Partially Hospital policy used does Compliant not include the severely compromised transplant patient, therefore a policy or SOP required

B.03.07.04.03 Administration of cellular therapy Partially Policy/SOP does not products. compliant include administration of donor lymphocytes

B.03.07.06 There shall be a nurse/patient ratio Partially During the discussions satisfactory to manage the severity of the compliant with nursing staff there patients’ clinical status. appears to be an informal policy in place to increase the number of nursing staff when required. A formal policy should be written 10 C. Charley et al.

Table 1.3 Examples of “non compliant” quality management standards for clinical and apheresis facilties (FACTJACIE Hematopoietic Cellular Therapy Accreditation Standards: 6th edition)

B.04 QUALITY MANAGEMENT COMPLIANCE COMMENT

B.04.04 The Quality Management Plan shall include, or summarize and reference, policies and Standard Operating Procedures addressing personnel requirements for each key position in the Clinical Program. Personnel requirements shall include at a minimum:

B.04.04.01 A current job description for all staff. Partially Job Description not C.04.04.01 Compliant available for all nursing grades/roles

B.04.04.02 A system to document the following for all C.04.04.02 staff:

B.04.04.02.02 New employee orientation. Partially Orientation program in C.04.04.02.02 Compliant place but no evidence that nurse Smyth (only worked on the ward for 3 months) has participated in the orientation program

B.04.04.02.03 Initial training and retraining when appropriate Partially No evidence of re- C.04.04.02.03 for all procedures performed. compliant training for Nurse X who has returned from long-term absence.

B.04.04.02.05 Continued competency at least annually. Partially Not all nursing staff C.04.04.02.05 compliant have evidence that competencies are performed annually

B.04.04.02.06 Continuing education. Partially Education program in C.04.04.02.06 Compliant place but no attendance list for each education activity

B.04.08.03 Audits shall include, at a minimum:

B.04.08.03.03 Annual audit of verification of chemotherapy Non compliant Not performed drug and dose against the prescription ordering system and the protocol.

B.04.11 The Quality Management Plan shall include, Partially Policies and SOP are C.04.11 or summarize and reference, policies and compliant included with the QMP. procedures for cellular therapy product Staffs do not complete tracking and tracing that allow tracking from the tracking forms. the donor to the recipient or final disposition and tracing from the recipient or final disposition to the donor. 1 JACIE and Quality Management in HSCT: Implications for Nursing 11

Table 1.4 Examples of “non compliant” policy and procedure standards for clincial and apheresis facilties (FACTJACIE Hematopoietic Cellular Therapy Accreditation Standards: 6th edition)

B.05 POLICIES AND PROCEDURES COMPLIANCE COMMENT

B.05.01 The Clinical Program shall establish and C.05.01 maintain policies and/or procedures addressing critical aspects of operations and management in addition to those required in B4. These documents shall include all elements required by these Standards and shall address at a minimum:

B.05.01.08 Administration of HPC and other cellular Partially The policy has not been therapy products, including products under Compliant updated to include Cord exceptional release blood

C06.01.07 Labeling (including associated forms and Partially Labeling procedure samples) Compliant should show more details regarding roles of physician and nurse involved in labeling operations

C.05.01.14 Equipment operation, maintenance, and Partially No evidence of monitoring including corrective actions in the Compliant maintenance reports event of failure.

B.07.04.04 Prior to administration of the preparative Non Compliant No evidence of two regimen, one (1) qualified person using a persons verifying the validated process or two (2) qualified people drug. shall verify and document the drug and dose in the bag or pill against the orders and the protocol, and the identity of the patient to receive the therapy.

B.07.06 There shall be a policy addressing safe Partially The policy has not been administration of cellular therapy products. Compliant updated to include Cord blood

B.07.06.04 Two (2) qualified persons shall verify the Non Compliant No evidence of two identity of the recipient and the product and the person verify the drug order for administration prior to the administration of the cellular therapy product.

B.07.06.06 There shall be documentation in the recipient’s Partially No evidence of start and medical record of the administered cellular compliant completion times of the therapy product unique identifier, initiation and infused product written in completion times of administration, and any the recipient’s medical adverse events related to administration. notes 12 C. Charley et al.

Table 1.5 Examples of “non compliant” process control standards for apheresis facilities (FACT-JACIE Hematopoietic Cellular Therapy Accreditation Standards: 6th edition)

C.08 PROCESS CONTROLS COMPLIANCE COMMENT

C.08.10.01 Adequacy of central line placement shall be Partially No evidence that this verified by the Apheresis Collection Facility Complaint standard is performed prior to initiating the collection procedure.

C.08.11 Administration of mobilization agents shall be Partially The responsibilities of under the supervision of a licensed health care Compliant administration of growth professional experienced in their factors should be clearly administration and management of defined in the complications in persons receiving these appropriate policies agents. especially for those donors where shared care is in place

C.08.12.01 Methods for collection shall include a process Partially Criteria for HPC-A for controlling and monitoring the collection Compliant collection should be of cellular therapy products to confirm defined together with products meet predetermined release ranges of expected specifications. results concerning HPC product characteristics

1.4.1 Staffing and Nursing action to be taken for small teams, apheresis, (Table 1.2) quality management and data collection teams, in case of planned or unplanned long-term absence Senior staff should be aware that the patient’s from work, therefore allowing the patient’s or pathway, during the transplant process, can be donor’s pathway to continue without affecting unpredictable. There are episodes when the the nursing or medical care given. patient will experience complications of the treat- Not only should there be adequate nursing ment required for HSCT that will require a higher staff, the nurses should be qualified, trained and intensity of nursing care. During such episodes, competent in the roles they perform. the nursing management should have an estab- JACIE can be a challenge and an opportunity lished contingency plan to provide adequate for nurses in: nursing care for these patients. Possible options could be: • Reviewing existing procedures –– Especially those that have been performed • Nursing staff within the team allowed to work automatically in the same way despite extra shifts being inefficient • The employment of additional nursing staff • In adopting measures for clinical risk with relevant experience from the hospital management pool of nurses or from nursing agencies –– Paying more attention to long-term plan- • Transfer of the patient to a high dependency or ning for continuing education of personnel, intensive care setting procedures and tools for monitoring, verifying and in achieving competence Whatever the contingency plan, there should maintenance be evidence in place, such as a written policy for • Development and implementation of internal staffing. This policy should describe the plan of audits and quality indicators 1 JACIE and Quality Management in HSCT: Implications for Nursing 13

Furthermore, JACIE is an opportunity for can be difficult to show (Table 1.3). Ongoing nurse recognition within the organisation they training for clinical personnel should reflect: work, in terms of contribution to the overall results achieved. • Their experience • Individual competencies and proficiencies • Orientation for new staff 1.4.2 Training and Competencies • Preceptorship (Tables 1.2 and 1.3) Training needs to be flexible to reflect staff All hospitals should have their own programme requirements and should be performed in a timely for training, annual review/appraisal and compe- manner to demonstrate annual updating. tencies. The structure already in place for record- When staff cannot attend a particular training ing the individual staff members training can also session due to staffing issues, holidays or sick- be used to record the JACIE Standards’ require- ness, a self-teaching system, e.g. an electronic ments. A new system for training records for system that includes the presentation and self- JACIE is not required if the following is assessment tool, may be an option to consider. undertaken. For those centres that apply for a combined adult and paediatric JACIE accreditation, it is • Basic training: important that training sessions should include –– A route that leads to the skills acquisition relevant age-specific issues for each topic, espe- in order to obtain new or improved cially if the two age group populations are nursed “performance” within the same ward environment. Where adult • Educational training: and paediatric patients are nursed on separate –– The set of activities, including basic train- wards, training sessions may be separate for cer- ing, aimed to develop and enrich the staff tain topics, but it is also important to share ses- on the technical, special, managerial and sions, where appropriate, to provide evidence cultural side aspects of their role that both population groups are an integrated part • Competence: of a combined transplant facility. –– The proven ability to use knowledge and The FACT-JACIE International Standards skills Accreditation requires that the clinical pro- • Competency maintenance: gramme have access to personnel who are for- –– The minimum activity that is required to be mally trained, experienced and competent in the performed by each operator in order to management of patients receiving cellular ther- retain the assessments defined in the spe- apy. Core competencies are specified within the cific job description. standards, and evidence of training in these com- • Competency matrix: petencies must be documented. This may be –– The activities performed must be recorded achieved by evidence of in-service training, in order to perform an annual assessment attendance at conferences, etc. (quantitative and qualitative) for the activi- During September 2016, the EBMT (NG) in ties that can be recognised. collaboration with JACIE and the EOC (Ente Ospedaliero Cantonale - multicentre Swiss hos- It is important that training and competency pital name, www.eoc.ch) launched the first video programmes are structured and ongoing, with recorded course, aimed at physicians, nurses and documented evidence of training topics and technicians working within JACIE-accredited dates. Most importantly, an attendance register centres. The course focused on competency for training and competency sessions is required. maintenance and could be accessed in person, on Whilst initial supervised training is more easily the day, or through online conferencing and is documented, annual competency maintenance now a source of video recorded e-sessions, 14 C. Charley et al.

lectures and questionnaires, available online free mined period of time, it is necessary to reassess of charge. Upon correct answering of question- the changes made to measure any improvements naires on every topic, participants to the in-site or resulting from those changes. This is referred to online conference are able to obtain a Certificate as “closing the audit loop”. A nursing audit sched- of Competence that is validated by EBMT and ule works best when the nursing teams initiate the JACIE that can be used as evidence towards the audit topics. It is important to include the audits JACIE inspection. In addition, the activities were required by JACIE, e.g. (1) the verification of the granted a CME certification by EBMT/EBAH chemotherapy drug and dose against the prescrip- and Swiss CME credits (The course is available tion and the protocol and (2) the verification of the at http://www.dsit.it/prj/ebmt2016/inex2.php). haematopoietic stem cell infusion. This initiative was based on an online test system It is important that the audit is performed by using a SharePoint internal hospital standard personnel that are not directly involved within the operating procedures compliant with FACT- activity to be audited. JACIE standards, developed by the Bellinzona transplant centre (Babic et. al. 2015). 1.4.5 Reporting Adverse Events (Table 1.3) 1.4.3 Benefits of Quality Management (Table 1.3) To enable adverse events to be fully reported, it is important that a culture of “no blame” is present. The key aim of the JACIE process is to implement The hospital should have an established reporting a QMS into clinical practice. Despite the difficul- system in place, and it is important that the ties that maybe encountered, the process can be adverse events for transplantation and collection useful for integration of staff from all disciplines of cellular products including apheresis and mar- and professional collaboration. Staff education row can be coded separately to other departmen- plays a key role in the implementation of the tal adverse events. This allows for clarity and a whole system and in particular for the quality true record of the number of events recorded for management system (Piras and Aresi 2015). The the transplant programme. Each episode is majority of the quality standards are aimed at pro- reviewed and changes made if required. This is viding evidence that there are systematic pro- then followed by an audit of the changes made to cesses in place. Furthermore, several of the minimise a reoccurrence. Nurses working with standards relate to having systems in place to patients and donors have a very important role in record initial qualification, training and compe- reporting adverse events. tencies and minimal qualifications for the trainer. It is important that all adverse events are The hospital system can be utilised for these stan- recorded in the quality meeting minutes, quarterly dards, and this evidence can be shown to the and annual reports and most importantly shared inspectors. However, not all hospital record sys- with all the sections involved in delivery of the tems register the training qualification required by transplant programme (clinical, collection and pro- a member of staff who has a training role. cessing), as appropriate. For example, if a recipient has a reaction to a stem cell infusion or there is a deviation from the time specified for each infusion 1.4.4 Audits (Table 1.3) of thawed cells, these events should be reported and shared with the processing facility. Some nurses may be unfamiliar with this area. Where adverse events have been shared across One approach is to view audits as assessing the departments, the inspector will require evidence care you give, reviewing the evidence and making that the events were discussed, and if any changes changes to improve the patient’s or donor’s expe- were made to practice that this was recorded, poli- rience and/or nursing care given. After a predeter- cies were updated and the episode monitored. 1 JACIE and Quality Management in HSCT: Implications for Nursing 15

1.4.6 Tracking of Collected Other clinical standards that highlighted lack Products (Table 1.3) of evidence were related to the administration of the preparative chemotherapy regimen and the To enable the safe collection, storage and distri- administration of the transplanted product. The bution of collected products, it is important that inspectors could not find evidence that two per- each stage of the process is recorded. Therefore, sonnel had checked the identity of the recipient collection, laboratory, transport and clinical staff against the dose of the material to be infused. should be involved in signing a transport log to There were issues with quality management accept the product and in some cases recording standards for clinical, collection and processing. the temperature of the product. Policies should be Third-party agreements/service-level agree- in place to include what to do if there is a devia- ments failed to state the responsibilities of each tion in practice, e.g. temperature of the product facility involved within the process, e.g. who falls outside the range of temperature agreed was responsible for transportation of the col- within the transport policy. It is important that lected cellular product either from the collection policies and standard operating procedures that facility to processing or transportation from pro- include responsibilities of more than one facility cessing to the clinical facility. For those clinical are shared and members of staff have ready facilities that provide shared care for donors access. prior to collection of cellular material, it is The donor and recipient’s medical notes must important that third-party agreements/service- be completed, as part of the tracking system, to level agreements also include the responsibilities record the collection or transfusion of the col- for the administration of mobilisation products. lected product. The cellular product identifica- These responsibilities should be described tion, time and date should also be included in the within the appropriate standard operating proce- medical notes dure/policy (SOP), and it is important that all parties involved with the shared care have access to the SOP. 1.4.7 Common Deficiencies: 5th Labelling of collected products was a com- Edition of the JACIE Standards mon issue, either non-compliance with the International Society of Blood Transfusion During the annual meeting of the EBMT (2015), (ISBT128) standards for labelling or personnel the results of a review of JACIE inspection failed to complete all the data fields on the label. reports against the 5th ed. of the JACIE Often the volume and name of the citrate used Standards were presented (JACIE Quality and start and completion time of the collection Management 2015). The aim of the review was were missing. to identify common deficiencies within the standards. Of reports issued against the 5th ed. of the JACIE Standards, 95% (145/152) had been 1.5 JACIE: Implications reviewed. on Nursing – The Nurse’s Standards relating to clinical personnel were Perspective rated as the group of standards with the highest number of deficiencies. This was due to the lack Research demonstrates that patient outcomes and of evidence: donor care are improved (Anthias et al. 2016; Gratwohl et al. 2011) when treatment is delivered • In training and competencies for physicians within a JACIE-accredited centre. Therefore, it • Relating to donor and recipient informed could be assumed that the JACIE accreditation consent process has had implications on nursing practice. • Of diagnosis and management of graft versus A literature search was performed (using PubMed host disease, both acute and chronic and Google search engine with the following 16 C. Charley et al. parameters: quality management, standard Five quality managers operating procedures, nurse education, JACIE Three nurse coordinators accreditation and audit), but no results were One nurse consultant responsible for SOPs in found reflecting the dearth of nursing research on clinical and processing facility implications of JACIE for nursing. Therefore, a simple survey was sent to the members of the 3% (1/30) of respondents were classified as a European Group for Blood and Marrow staff nurse/junior nurse. Transplantation Nurses Group (EBMT (NG)) via *One CNS role includes data manager and email. The aim of the survey was to establish one CNS is responsible for JACIE what implications the JACIE process had for The majority of nurses, 93.3% (28/30), nurses in their daily practice. worked within the clinical area**, 3.3% (1/30) worked in the apheresis facility and 3.3% (1/30) 1.5.1 Results of the Survey within the processing facility. **Two clinical nurses worked in a second area The survey (in the form of a word document) was (one in apheresis and one in processing) distributed via email to 322 nurse members of the EBMT nurses group (EBMT (NG). 135/322 (41%) nurses opened the email received and the 1.7 Does the JACIE Process Have response rate was 31/322 (9.62%). One reply was Any Implications for Nurses? rejected due to the transplant centre not working towards JACIE accreditation; therefore 30/322 The survey showed an overwhelming response (9.3%) replies from 11 countries were evaluated: (90% (27/30)) that the JACIE process has impli- Nurses who responded to the survey per- cations for nurses with 10% (3/30) stating JACIE formed a variety of roles within the area of had no implications for nurses. HSCT, worked in 11 different countries, and The respondents offered either none or several their replies varied from “no implications on examples of their experiences: daily routine” to “nurses obtaining new skills in areas such as developing standard operating pro- 26/27 (96%) offered one or more citations cedures and risk management”. 15/26 (58%) offered two citations 10/26 (38%) offered three citations 1/26 (3.8%) offered four citations 1.6 Results 4/27 (15%) offered no citations

A total of 322 EBMT (NG) members were con- tacted via email with a response rate of 9.62% 1.7.1 Implications: Staff Nurse’s/ (31 replies) from 12 countries. One reply was Junior Nurse’s Point of View rejected due to the transplant centre not working towards JACIE accreditation therefore 30 replies The only staff nurse/junior nurse to respond to from 11 countries were evaluated: the questionnaire described their role, instead of The role, seniority and the involvement of the describing any implications that had occurred in nurse, in the JACIE process, could have an influ- working towards their first JACIE accreditation: ence on how each respondent responded. “Nurses were involved in checking procedures, 97% (29/30) of respondents were classified as therefore providing documented evidence in edu- senior nurses: cation and patient care”. This is a good demon- stration that all staff within the transplant Seven ward managers programme should be involved in the accredita- Fourteen* clinical nurse specialists (CNS) tion process. 1 JACIE and Quality Management in HSCT: Implications for Nursing 17

1.7.2 Implications: Ward Manager’s 1.7.4 Implications: Quality Point of View Can Manager’s Point of View Can Be Summarised as Follows Be Summarised as Follows

JACIE has provided an improved structure to The transplant team now has a greater awareness produce written procedures, which are reviewed and importance of standard operating procedures regularly. (SOPs) by working within a document controlled This uniform working allows procedures to system and being included in the multidisci- be described precisely, enabling all staff per- plinary team meetings. Within the paediatric set- forming the procedure to perform the task in the ting, there has been an improvement in medical same way and can be used an educational tool SOPs for the care of the HSCT paediatric patients especially for new members of staff. The as well as an improvement in collaboration with experience of JACIE has improved patient care, the adult clinic, apheresis and stem cell labora- improved communication between all members tory teams. Patient outcome reviews have been of the team and has allowed for a closer work- valuable in improving care. ing relationship. Nurses were able to learn The JACIE audit programme has encouraged new skills especially in understanding risk the transplant team to perform internal audits, management. which has led to improvements in quality assurance.

1.7.3 Implications: Clinical Nurse Specialist’s Point of View Can 1.7.5 Implications: Nurse Be Summarised as Follows Coordinator’s Point of View Can Be Summarised Initially the documentation and developing the as Follows JACIE programme took many years and was hard work. Extra work had to be incorporated into a JACIE has highlighted more attention is required busy schedule, and time had to be allocated to for nurse training, evaluation of competencies, attend the many meetings relating to JACIE. Now document control and the registration process. accreditation has been achieved, and the team The standards relating to donors has emphasised works within an established programme. All the to the team the importance of the role of a “donor effort was worthwhile because everyone feels advocate”, to prevent a conflict of interest of the confident with the quality standards and pro- transplant physician, and JACIE is a very useful gramme. Quality is always a priority. working tool, especially for new colleagues. Additional management hours were required to administer/manage the increased numbers of protocols and procedures. New presentation 1.8 Conclusion of the Survey skills were learnt in presenting audit results to the transplant team, and new opportunities arose to Although there was a very low response to the develop a donor care programme to conform to survey (9.62%), the results represent the views of the JACIE Standards. senior nurses (97% of respondents). After review- There was only one negative feedback: ing the 45* comments from the 30 respondents, “Unfortunately no impact on daily practice”. the authors of this survey would like to suggest 18 C. Charley et al. that the JACIE accreditation process has had a “Quality improvement is a science of process man- positive impact on nurses. Only 9% of comments agement. If you cannot measure it you cannot prove it, therefore quality improvement must be data driven”. could be classified as having a negative impact on the nurse due to extra workload. As specialised nurses, working in the field of * See Appendix 1.1 for a full list of citations HSCT, we should be asking ourselves why are written by the respondents to the survey. we not publishing our data or audit findings. A further study is required within the BMT Using the development of the apheresis collec- nursing community to fully understand the impli- tion services across Europe as an example, many cations for nurses during the initial JACIE accred- teams will be nurse led. When the collection of itation phase and post JACIE accreditation whilst HSCs became an established practice, the num- maintaining and improving the quality system ber of nursing teams increased, training became that is now embedded into daily practice. The more formalised and apheresis nurse forums study could be based on the Donabedian model were established to try and reinforce policies and looking at structure, process and outcomes. procedures. A QMS was introduced in the form The JACIE Standards are reviewed every 3 of JACIE accreditation with risk management years, allowing them to be adapted to the rapidly and audit became integral to the apheresis nurse developing field of HSCT. Nurses are required to role. maintain compliance with the QMS and JACIE Deming also states:” If nurses are going to Standards and must familiarise themselves with the manage care, they require the right data delivered changes that occur in each edition of the JACIE in the right format at the right time and in the Standards. Each edition will present fresh chal- right place”. Therefore, nurses with the HSCT lenges to achieve the standards especially given the programme should take ownership, perform present day competing pressures on resource and audits, assess the results, make changes to patient finance. It is noteworthy that none of the surveyed care and reassess. These experiences and findings nurses mentioned this aspect as a concern for nurses should be shared and published. in their practice. As nurses working within JACIE- If the reluctance to publish is a lack of owner- accredited centres, it is important to provide evi- ship of quality management, or nurses perceive dence of our continued monitoring of practice and quality management as the responsibility of the processes through the QMS and not regard the quality manager, then they must be reminded that JACIE accreditation process as a tick box exercise. JACIE has a significant impact upon each and every role and that they must be aware and fully participate in the process. Audit, review of poli- 1.9 Discussion Points cies and procedures, competencies and risk assessment will become a key part of the nursing Since the introduction of JACIE accreditation, routine for the QMS to be maintained and to nurses have submitted oral and poster presenta- evolve. tions at the annual EBMT (NG) conference on the topic “Preparing for JACIE”. The small response to our EBMT (NG) survey and a litera- Key Readings ture search that could not identify published arti- • JACIE 6th Ed. Manual cles on the topic of “JACIE and implications for • JACIE 6th Ed. Standards nurses” could suggest the JACIE accreditation • www.jacie.org process has not impacted greatly on nurses. • JACIE Quality Manual One of the five Deming principles (Health • Smith J, Jones M Jr, Houghton et al Catalyst 2014) that help health-care process (1999) Future of health insurance. N improvements: Engl J Med 965:325-329 1 JACIE and Quality Management in HSCT: Implications for Nursing 19

Acknowledgements The authors would like to thank the Citations classed as positive: JACIE Office for the use of materials and Tuula Rintala • Now we are JACIE accredited and working Apheresis Nurse JACIE Inspector and member of the JACIE Accreditation Committee for her help and advice. within an established programme, it was well worth it and, we feel confident about our quality standards and programme. • Quality is always a priority in every aspect Appendix 1.1. Citations Classified of the transplant process. in the Role of the Nurse • Maintain patient records more accurately. • We have started the donor care programme according the JACIE. 1. 1. Staff nurse/junior nurse: citation classed as Citations classed as neither negative nor positive positive (only one citation) • Preparation of QMS and developing SOPs • As nurses, we have checked procedures to x four citations. enable the team to demonstrate our work • Increased number of protocols and proce- on education and patient care. dures to follow and manage, requiring 2. Ward manager’s citations additional management hours to administrate. Citations classed as positive: • We had to prepare and update all SOP doc- • Improved structure to create procedures. uments from the nursing field. • A more uniformed way of working. • As a centre preparing for our 1st accredita- • (Almost) everything we do is now described tion, we are preparing documents, SOP and in the policies, and everybody performs the the nurses’ education programme. procedure the same way, which is better for • Perhaps not implications, many checklists the patient. and SOPs have been revised or developed • Communication processes have improved which has developed our work. between the different professionals (e.g. • I personally worked on the SOPs and rou- nurses, physicians) improving the way we tines in HSCT. are working together. • I was required to present results at the clini- • We now have the knowledge to implement cal audit meetings and answer questions. the method and the instruments of risk Citations classed as negative: management. • Initially the documentation and developing • There have been improvements on patient the programme took many years and was care, central venous catheter management, hard work. team work and communication and safety • As our quality manager is from a labora- of the patients. tory background, I have had to incorporate • A tool that can be used to helped introduce clinical quality lead into my CNS role, and new staff to the daily routine of transplant this has added to my workload. care. • Finding time for many meetings related to Citations classed as neither negative nor quality and JACIE was difficult due to positive: other demands. • Started to use many procedures. • Unfortunately no impact on daily practice. • We regularly update the quality documentation. 4. Quality manager’s citations • Description of working processes. • It’s an Issue of quality management. Citations classed as positive: • There is a greater awareness of the routines. 3. Clinical nurse specialist’s citations • An improved structure. 20 C. Charley et al.

• Patient safety is highlighted. References • All nurses are working in a more quality assured way, by only using adequate and Anthias C, Ethell ME, Potter MN, Madrigal A, Shaw current documents and working procedures. BE. The impact of improved JACIE standards on the care of related BM and PBSC donors. Bone Marrow • The internal audits, which we have per- Transpl. 2015;50:244–7. https://doi.org/10.1038/ formed for several years, whilst working bmt.2014.260; published online 10 November 2014 with JACIE, have led to improvements in Anthias C, O’Donnell PV, Kiefer DM, et al. European quality assurance. Group for Blood and Marrow Transplantation Centres with FACT-JACIE Accreditation Have Significantly • Before JACIE accreditation, we actually Better Compliance with Related Donor Care Standards. did not have strict medical SOPs for treat- Biol Blood Marrow Transpl. 2016;22(3):514–9. ment of our paediatric transplant patients. Babic A, Wannesson L, Trobia M, Lazzaro M. Transplant • Since first accreditation as a separate pae- unit personnel competency maintanance: online testing by sharepoint application. EBMT. 2015; oral pre- diatric centre, we have broadened our cor- sentation N003. poration with the adult clinic, apheresis Caunday O, Bensoussan D, Decot V, Bordigoni P, Stoltz and stem cell lab. Since then SOPs are JF. Regulatory aspects of cellular therapy product in more in common. “Nurses are now Europe: JACIE accreditation in a processing facility. Biomed Mater Eng. 2009;19:373–9. involved and appreciate being involved in Cornish JM. JACIE accreditation in paediatric haemo- the review meeting for patient outcome”. poietic SCT. Bone Marrow Transpl. 2008;42:S82–6. Citations classed as neither negative nor positive: https://doi.org/10.1038/bmt.2008.290. • More SOPs to write Demiriz IS, Tekgunduz E, Altuntas F. What is the most appropriate source for hematopoietic stem cell trans- • Increased audits plantation? Peripheral Stem Cell/Bone Marrow/Cord • Working with documents and internal Blood Bone Marrow Res. 2012; (2012):Article ID audits 834040 (online). • Updating SOPS, ensuring staff, including Gratwohl A, Brand R, Niederwieser D. Introduction of a quality management system and outcome after the multidisciplinary team, understand the hematopoietic stem-cell transplantation. J Clin Oncol. importance of following the SOP 2011;11. https://doi.org/10.1200/JCO.2010.30.4121. Gratwohl A, Brand R, McGrath E, van Biezen A, 5. Nurse coordinator’s and nurse consultant Sureda A, Ljungman P, Baldomero H, Chabannon C, Apperley J. Joint Accreditation Committee (JACIE) citations of the International Society for Cellular Therapy and the European Group for Blood and Marrow Citations classed as positive: Transplantation, and the European Leukemia Net. • Separate donor and recipient management. Use of the quality management system “JACIE” and outcome after hematopoietic stem cell transplantation. • JACIE is a good working tool, especially Haematologica. 2014;99(5):908–15. for new colleagues. Harolds J. Quality and Safety in Health Care, Part I. Five Citations classed as neither negative nor Pioneers in Quality. Clin Nucl Med. 2015;40(8):660–2. positive: Health Catalyst. www.healthcatalyst.com Proprietary.© 2014. Five deming principles that help healthcare pro- • More attention in the control of the work- cess improvement by John Haughom, MD). ing activities. https://www.ebmt.org/Contents/Resources/Library/ • More attention in the registration of Slidebank/Pages/JACIE2015. 24 Mar 2015 – JACIE processes. Quality Management Day 2015. Common deficiencies, Carole Charley. • More attention in the nurse training and Pamphilon D, Apperley JF, Samson D, Slaper-Cortenbach evaluation of competency. I, McGrath E. JACIE Accreditation in 2008: dem- • My mission is to work for the HSCT pro- onstrating excellence in stem cell transplantation. gramme of quality programme improve- Hematol Oncol Stem Cell. 2008;2(2):311–9 (online). Passweg JR, Baldomero H, Gratwohl H, et al. The EBMT ment process as required by the activity survey: 1990-2010. Bone Marrow Transpl. accreditation body JACIE. 2012;47:906–23; pubilised online 30th April 2012. 1 JACIE and Quality Management in HSCT: Implications for Nursing 21

Piras A, Aresi P, Angelucci E. Analysis of the accredita- of JACIE accreditation in Europe: a special report tion process. JACIE Transplant Program Businco. Prof from the Joint Accreditation Committee of the ISCT Infern. 2015;68(2):167–73. https://doi.org/10.7429/ and the EBMT (JACIE). Bone Marrow Transpl. pi.2015.6822167. 2007;39:133–41. Samson D, Slaper-Cortenbach I, Pamphilon D, McGrath www.Ebmt.org home/quality Management/about JACIE E, McDonald F, Urbano Ispizua A. Current status www.jacie.org. Accessed 15 Dec 2016.

Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. HSCT: How Does It Work? 2 Letizia Galgano and Daphna Hutt

Abstract The HSCT (haematopoietic stem cell transplant) is a particular treatment for many haematological and non-haematological diseases. Broadly, there are three different categories of transplantation, autologous, allogeneic and syngeneic, which can be applied to most disease scenarios. Haematopoietic stem cells can be derived from the bone marrow, peripheral blood and umbilical cord blood. HSCT treatment can be divided into separate phases that start with the harvest of the stem cells and passing through the conditioning, aplasia and engraftment until the recovery of the haematopoietic functions. HSCT is indicated in many diseases, and these indications depend on numerous factors such as the disease type, stage and response to previous treatment. Among non-malignant diseases, aplastic anaemia, sickle cell disease and, more recently, autoimmune diseases can also be effectively treated with HSCT. One third of the transplants in children are performed for rare indications such as severe combined immunodeficiencies. Allogeneic HSCT can also cure a number of non-malignant diseases in children, such as Wiskott-Aldrich syndrome and chronic granulomatous disease (CGD). This chapter will include transplant in primary immunodeficiency in children as well as inherited bone marrow failure and inborn errors of metabolism.

Keywords HSCT • Indications • Autoimmune diseases • Haemoglobinopathies Paediatric • Immunodeficiencies

L. Galgano (*) Department of Transfusion Service and Cell Therapy BMT Unit, AOUCareggi Hospital, Florence, Italy e-mail: [email protected] D. Hutt Department of Pediatric Hematology-Oncology and BMTs, Edmond and Lily Safra Children Hospital, Sheba Medical Center, Tel-Hashomer, Israel e-mail: [email protected]

2.1 What Nurses Need to Know the inefficient patient immune system with the donor one (Michel and Berry 2016; Hatzimichael and Tuthill 2010). 2.1.1 Introduction

Haematopoietic stem cell transplantation (HSCT) 2.1.3 Outcomes is a therapeutic option for several haematological diseases including acute and chronic leukaemia, Outcomes vary according to: lymphoma and multiple myeloma, some of inherited disorders such as severe combined immuno- • The stage of the disease deficiency and thalassemia and other inborn • The age of the patients errors of metabolism (Maziarz 2015). • The lapse of time from diagnosis to transplant HSCT involves the use of autologous haema- • The histocompatibility between donor and topoietic stem cells (HSC) obtained from the recipient patient’s own bone marrow (BM) or peripheral • The donor/recipient sex combination (the blood (PBSC) or allogeneic HSC where the overall survival decreases for male recipi- donor cells come from a family-related or an ents having a female donor) (Sureda et al. unrelated donor, from the bone marrow, periph- 2015a) eral blood or cord blood. • Advances in immunogenetics and The collected HSC are infused into a recipient immunobiology (Gratwohl et al. 2010). Before the infusion, the • Conditioning regimens recipient is treated with a conditioning regimen • Disease characterization and risk stratification (see Chap. 6), involving the use of different types • Immunosuppression and dosages of chemo and/or radiotherapy and/or • Antimicrobials immunosuppressant drugs (such as anti-• Other types of supportive care thymocyte globulin) (Copelan 2006). All these factors contribute to improvements in disease control and overall survival (Maziarz 2015). 2.1.2 Aims of HSCT Patient selection influences outcomes. Patients with better overall functional performance status, • In the autologous setting, patients with che- limited comorbidities and underlying organ damage mosensitive malignant diseases are offered have more favourable outcomes (Maziarz 2015). high-dose chemotherapy in order to destroy or further reduce the malignant disease, ablating the marrow with this aggressive therapy. In 2.1.4 Nursing Considerations this case, the stem cell infusion is intended to treat the prolonged chemotherapy-induced Patients require specific care to overcome the hypoplasia and not the disease itself (Maziarz physical and emotional problems resulting from 2015; Michel and Berry 2016). this treatment. Usually after myeloablative condi- • In the allogeneic setting (see below Sect. 2.2): tioning, HSCT recipients typically experience a • In malignant haematological disease, donor period of profound pancytopenia lasting days to HSCs replace the immune system and help weeks depending on the donor source. The rapid- to eradicate malignancy (Maziarz 2015; ity of neutrophil recovery varies with the type of Michel and Berry 2016). graft: approximate recovery time is 2 weeks with • In non-malignant diseases, where the cause G-CSF-mobilized peripheral blood stem cells, is dysfunction of the haematopoietic stem 3 weeks with marrow stem cells and can be as long cell (HSC), the HSCT procedure replaces as 4 weeks with umbilical cord blood stem cells. 2 HSCT: How Does It Work? 25

However, re-establishment of immune system 2.2.1 Autologous Haematopoietic takes at least several months due to prolonged Stem Cell Transplantation lymphocyte recovery process, and some patients continue to show immune deficits for several years Autologous HSCT is defined as “a high dose che- after HSCT (Mackall et al. 2009). During this motherapy followed by the reinfusion of the period, the patient has a high risk of developing patient’s own HSC” (cit. NCI Dictionary). After complications; thus, HSCT units require multidis- mobilization (see Chap. 5), the patient’s HSCs ciplinary teams of physicians, nurses, pharmacists, are collected and cryopreserved. Auto-HSCT social workers, nurse practitioners, physician facilitates the prompt reconstitution of a signifi- assistants, nutrition experts and occupational and cantly depleted or ablated marrow following very physical therapists, in addition to a specialized aggressive chemotherapy and sometimes radio- facility and technical resources (Maziarz 2015). therapy intended to eradicate haematologic and Nurses who work in HSCT units have a key non-haematologic malignancies (Michel and role in treatment management and require spe- Berry 2016). cific training to: There is no risk of rejection or graft versus host disease (GvHD) and no GvT (graft versus • Understand, prevent and manage the early and tumour) effect (see Chaps. 11 and 12). Graft fail- late effects of HSCT. ure can occur rarely, and some trials demonstrate • Care for multiply treated patients. how relapse remains an issue for the majority of • Inform and educate patients and their patients with multiple myeloma (Michel and caregivers. Berry 2016; Mackall et al. 2009). • Administer drugs and blood products safely. • Manage the central venous catheter (cvc). • Give emotional support. 2.2.2 Allogeneic Stem Cell Transplantation These topics will be covered in later chapters. In allogeneic transplantation, the recipient receives HSCs from a related or unrelated donor 2.2 Different Types of HSCT who can be fully or partially human leukocyte antigen (HLA)-matched (Fig. 2.1); related donors HSCs may be obtained from autologous (BM or are family members; unrelated donors are identi- PBSC) or allogeneic (HLA-matched related fied through a donor registry or from a cord blood (MRD), HLA-matched unrelated (MUD) or bank. In allogeneic HSCT, the major histocom- HLA-mismatched related or unrelated donors patibility complex (MHC) HLA class I and II and UCB) sources (Table 2.1). molecules located on chromosome 6 play an important role (Maziarz 2015). (Please refer to Table 2.1 Summary of HSCT types and HSC sources Chap. 3 for HLA typing and donor selection.) Type of In allogeneic HSCT, the aim of conditioning transplantation Cell source Donor is to: Autologous Bone marrow Recipient Peripheral blood • Kill tumour cells (in malignant diseases). Allogeneic Bone marrow Related • Eradicate existing bone marrow tissue (in Peripheral blood Unrelated order to provide space for engraftment of Umbilical cord blood transplanted donor stem cells). Syngenic Bone marrow Monochorionic • Suppress the patient’s immune response and Peripheral blood twin minimize the risk of graft rejection of the Adapted from Tura (2003) donor HSC (Maziarz 2015). 26 L. Galgano and D. Hutt

Fig. 2.1 Scheme of HLA-matching HLA compatibility Mother Father (Adapted from: Soiffer 2008) A A A A B B 25% chance of B B C C identical sibling C C DR DR DR DR

A A A A A A A A A A B B B B B B B B B B C C C C C C C C C C DR DR DR DR DR DR DR DR DR DR

Haploidentical Patient Incompatible Haploidentical Identical sibling sibling sibling sibling

Allogeneic HSCT has been subject to several matched unrelated donor (MUD); if there is a improvements during recent years. partial incompatibility, the donor is called a mis- Reduced intensity conditioning regimen, alter- matched unrelated donor (MMUD). native donor transplants and new stem cell sources The time between the activation of the unre- have increased the accessibility and availability, lated donor research and the beginning of trans- especially for older patients who have poor toler- plantation procedure is fundamental. The more ance of the high toxicity of the treatment. These time spent in the search phase, the greater is the improvements have resulted in reduced trans- risk that the patient’s disease will worsen or die plant-related mortality, although relapse remains (Hatzimichael and Tuthill 2010). an issue (Michel and Berry 2016).

2.2.2.1 Allogeneic Transplantation 2.2.2.3 Cord Blood Transplantation from HLA-Matched Related Unrelated donor umbilical cord blood unit trans- Donor (MRD) plantation (UCBT) provides an alternative donor The ideal donor is an HLA-identical sibling. option in patients who lack a conventional MRD Patients have a 25% chance of each sibling being and MUD. Advantages of UCBT include the fully HLA-matched, because siblings inherit capacity to tolerate greater degrees of HLA mis- 50% haplotype from each parent (Fig. 2.1). match than is possible using MUD (Bashey and If donor is an identical twin, they are referred Solomon 2014). to as syngeneic (see Sect. 2.3). UCBT have the advantage that the cryopreserved units at the cord blood banks are readily 2.2.2.2 Allogeneic from Unrelated available, with results comparable to those from Donor (MUD, MMUD) an unrelated donor or only partially compatible If recipient has no sibling or the blood tests con- units (also HLA 5/8 loci). UCBT shows a lower firm that there is no HLA compatibility with the incidence of GvHD, without losing the GvL sibling, then a search of “Bone Marrow Donors effect (Copelan 2006) (see Chap. 12). However, Worldwide” registry database (BMDW) is acti- delayed haematopoietic recovery and slow vated (Apperley et al. 2012). immune reconstitution and acquisition cost If the donor histocompatibility is fully remain important challenges (Bashey and matched with the recipient, the donor is called a Solomon 2014). 2 HSCT: How Does It Work? 27

2.2.2.4 Haploidentical Transplantation 2.2.2.5 Syngeneic Transplantation In case of unavailability of a conventional HLA Syngeneic is a type of transplantation where the identical sibling, MUD or CB unit, it is possible donor is the recipient’s monochorial twin and to transplant with an available haploidentical who is genetically identical to the patient. There donor. The donor may be a parent, child, brother, is no immunological conflict such as GvHD sister or other relative that matches for one haplo- (graft versus host disease) (see Chap. 11) but at type (HLA-mismatched related donors with com- the same time no beneficial GVL (graft versus patibility >6/8 loci). Leukaemia) effect (Mackall et al. 2009). The most important criterion for a haploiden- (see Chaps. 9 and 11 for HSCT complications) tical transplant is the urgency of the transplant in order to avoid early relapse or progression of the disease (Aversa 2015). 2.3 The Stem Cell Sources The advantages of the haploidentical transplantation are: HSC can be isolated from the bone marrow (BM), peripheral blood after mobilization (PBSC) and • The donor can be changed in case of a poor umbilical cord blood (UCB) (Maziarz 2015). stem cell mobilizer or if optimal graft compo- “Bone marrow cells are capable of repopulating sition was not achieved. all hematopoietic and lymphocytic populations • Easy family donor availability (if patients are while maintaining capacity for self-regeneration, not fostered or orphans without other assuring long -term immunologic and hematopoi- relatives). etic viability” (Maziarz 2015). • The benefit of natural killer (NK) cell Until the early 1990s, the bone marrow (BM) alloreactivity. represented the only source of stem cells. • Easy access to donor-derived cellular thera- However, this practice has almost been replaced pies after transplantation (Aversa 2015). by peripheral blood stem cells (PBSC). More recently, cord blood (CB) has been shown to be a good alternative source of haematopoietic stem There are two haploidentical procedures: cells. All three types of HSCs regardless of source are capable of regeneration after a high- • Haploidentical transplantation with haemato- dose chemoradiotherapy treatment (Richard poietic stem cells T-replete with cyclophos- 2000). phamide in immediate post-transplant phase that involves the induction of transplantation tolerance; it appears to have overcome many 2.3.1 Peripheral Blood Stem Cells of the obstacles historically associated with haploidentical donor transplantation, such as PBSCs have been increasingly used in both auto- too high rates of graft rejection and post- and allo-HSCT. Mobilization of haematopoietic transplant infections (Bashey and Solomon stem cells to the peripheral blood can be achieved 2014), and promotes a graft versus leukaemia by the administration of growth factors such as (GVL) therapeutic benefit with improved sur- G-CSF (allo-HSCT) and/or myelosuppressive vival (Maziarz 2015). chemotherapy (auto-HSCT) (Apperley et al. • Haploidentical transplantation with depletion 2012). of T-lymphocytes exists in aggressive and An advantage HSCT performed with PBSC is severe immune depleting conditioning regi- a relatively rapid recovery of haematopoiesis men followed by infusion of mega-doses of compared to BM and increases the disease-free highly purified peripheral stem cells (Bashey survival and overall survival in high-risk haema- and Solomon 2014). tological malignancies. The disadvantage is an 28 L. Galgano and D. Hutt increased risk of chronic GvHD in the allogenic 2.3.3 Umbilical Cord Blood HSCT because of an increased number of T cells circulating (Maziarz 2015). Cord blood cells are collected and cryopreserved from the umbilical cord immediately after birth, but generally before the placenta has been deliv- 2.3.2 Bone Marrow ered in order to avoid clots (Demiriz et al. 2012). UCB cells have been used both in related and unre- BM is traditionally harvested from the posterior lated HLA-matched and HLA-mismatched alloge- iliac crests under general or epidural anaesthe- neic transplants in children and in adults (Demiriz sia in a surgical room where trained haematolo- et al. 2012; Apperley et al. 2012). The advantage is gists or surgeons collect stem cells and blood a low criteria for a match (4/6 match is acceptable) directly from the bone marrow cavity in the increasing the chance of identifying a suitable cord bilateral posterior iliac crest region using aspi- unit or cord units in a matter of days. Less GvHD is ration needles. often observed. A key disadvantage is often slower HSCT performed with BM leads to less GvHD engraftment compared to BM and PBSC and compared to PBSC source, but has the disadvan- increased infection complications due to slow rate tage of a slower neutrophil and platelet engraft- of haematopoietic recovery (Maziarz 2015). ment (Maziarz 2015). (see Chaps. 3 and 5).

2.3.4 HSCT Phases

Mobilization PBSC and harvesting collection See Chap. 5

Conditioning regimen Bone marrow See Chap. 6 collection

Reinfusion Cord blood See Chap. 6.6 collection HSCT

phases Neutropenic phase See Chap. 3.4.1

Engrafment and recovery See Chap. 13

Follow up See Chap. 14

2 HSCT: How Does It Work? 29

2.3.4.1 Neutropenic Phase 2.4 Indications for Transplant After the chemotherapy, the blood count in Malignant Disease decreases for about 7–14 days in autologous HSCT and until 20–30 days in allogeneic The patient assessment for a transplant procedure HSCT. The neutropenia occurs when the absolute is complex and includes several factors such as neutrophil count is <500 cells/mm3 (Maziarz the patient’s overall health and performance sta- 2015). tus, comorbidities, disease risk/status (e.g. remis- During this period, several complications may sion state and responsiveness to treatment) and occur: graft and donor source. For example, autologous transplantation is not useful for diseases in which • Increased risk of infections due to a not effec- normal HSCs cannot be collected as in CML or tive immune system. Infection following myelodysplasia (Rowley 2013). HSCT is associated with significant morbidity The indications for transplant are based on and mortality, so prevention is critical to best available evidence from clinical trials or, improve outcomes. The risk of infection is where clinical trials are not available, registry, based on multiple variables including the type multicentre or single centre observational studies of transplantation (autologous or allogeneic), (Majhail et al. 2015). The HSCT specialist deter- source of haematopoietic cells (related or mines if transplant should be considered as an unrelated donor, peripheral blood, bone mar- option for disease consolidation, but the final row, or cord blood), underlying disease, dis- decision will be made in conjunction with the ease status (remission or relapse), intensity of patient (Maziarz 2015). the preparative regimen (ablative or non- There have been major changes in indications, myeloablative), prior infections, endogenous such as the rise and fall of autologous HSCT for microflora and environmental exposure to breast cancer or of allogeneic HSCT for chronic microorganisms. In addition, risk may vary myeloid leukaemia (CML), and in technology, as based on infection control measures used by illustrated by the change from the bone marrow transplantation centres. Practices in infection to peripheral blood, the rapid increase in use of control such as type of isolation, dietary unrelated donors and the introduction of reduced restrictions and antimicrobial prophylaxis intensity conditioning. It is clear how some guid- vary widely among transplantation centres. ance is warranted, for transplant teams, hospital Nurses are pivotal in implementing practices administrators, health-care providers and also to prevent and manage infections and associ- patients (Apperley et al. 2012). ated effects following HSCT (Sureda et al. The HSCT indications are not the same in 2015a). children and in adults (Table 2.1). • Bleedings because of thrombocytopenia The Table 2.2 is a scheme of the main indica- (platelets have a slow recovery after tions for autologous and allogeneic transplanta- transplantation). tion. It includes the standard of care. • Tiredness caused by the decreasing of haemoglobin levels. • Pain because of mucositis. 2.4.1 Indications for Allogeneic • Reduced nutrition. Oral intake is usually HSCT severely reduced because of, on one side, the oral mucositis that many patients develop and, Adult patients with acute myeloid leukaemia on the other side, the prolonged post condi- (AML) should always be considered for allo- or tioning nausea. When oral intake is reduced auto-HSCT, while allo-HSCT cannot be recom- and the body mass index decrease, total mended as first-line treatment for chronic enteral/parenteral nutrition may be provided myeloid leukaemia (CML) because of the effi- especially for children. cacy of the first-line therapy with imatinib for 30 L. Galgano and D. Hutt

Table 2.2 Indication for transplant: Recommendation categories (see text for definition): Standard of care (S); Standard of care, clinical evidence available (C); Standard of care, Rare indication (R) Adult Paediatric Disease Auto Allo Auto Allo Acute myeloid leukaemia CR1, intermediate risk/not in remission C C CR1, high risk/CR2+ S S Acute promyelocytic leukaemia, relapse R R R R Acute lymphoblastic leukaemia CR1, high risk/CR2 S S CR3+/not in remission C C Chronic myeloid leukaemia C C Myelodysplastic syndromes Low risk C C High risk/juvenile myelomonocytic leukaemia/ C S therapy related T-cell non-Hodgkin lymphoma CR1, high risk/CR2 S S CR3+/not in remission C C Lymphoblastic B-cell non-Hodgkin lymphoma (non-Burkitt) CR1, high risk/CR2 S S CR3+/not in remission C C Burkitt’s lymphoma First remission/first or greater relapse, sensitive C C C C First or greater relapse, resistant C C Hodgkin lymphoma Primary refractory, sensitive/first relapse, sensitive/ C C C C second or greater relapse Primary refractory, resistant/first relapse, resistant C C Multiple myeloma S C Anaplastic large cell lymphoma Primary refractory, sensitive/first relapse, sensitive/ C C C C second or greater relapse Primary refractory, resistant/first relapse, resistant C C Solid tumours Germ cell tumour/Wilm’s tumour, relapse/ C C osteosarcoma, high risk/medulloblastoma, high risk/ other malignant brain tumours Ewing’s sarcoma, high risk or relapse S S Non-malignant diseases Severe aplastic anaemia, new diagnosis, relapse/ S S refractory Sickle cell disease C C Thalassemia S S 2 HSCT: How Does It Work? 31

Table 2.2 (continued) Adult Paediatric Disease Auto Allo Auto Allo Fanconi’s anaemia/dyskeratosis congenita/Blackfan- R R diamond anaemia/congenital amegakaryocytic thrombocytopenia/severe combined immunodeficiency/T-cell immunodeficiency, SCID variants/Wiskott-Aldrich syndrome/haemophagocytic disorders/lymphoproliferative disorders/severe congenital neutropenia/chronic granulomatous disease/other phagocytic cell disorders/IPEX syndrome/other autoimmune and immune dysregulation disorders/mucopolysaccharoidoses (MPS-I and MPS-VI)/other metabolic diseases/ osteopetrosis/globoid cell leukodystrophy (Krabbe)/ metachromatic leukodystrophy/cerebral X-linked adrenoleukodystrophy Juvenile rheumatoid arthritis/systemic sclerosis R R Adapted from: Majhail et al. (2015)

chronic patients, even if HSCT remains the only 2.4.2 Indications for Autologous curative treatment. Allo-HSCT at the moment is HSCT the only curative option for patients with myelo- proliferative disorders such as primary myelofi- Auto-HSCT remains the standard of care for brosis and is considered the treatment of choice patients with Hodgkin lymphoma in first chemo- for adult patients with myelodysplastic syn- sensitive relapse or refractory to the first-line dromes (MDS). Allo-HSCT from an HLA- therapy and in chemosensitive relapse of DLBCL identical sibling or MUD is a treatment option for (diffuse large B-cell lymphoma), while in young patients previously treated with relapsed patients, allo-HSCT should be consid- fludarabine-containing regimens and poor-risk ered. Auto-HSCT is clearly indicated for patients disease. Patients with acquired severe aplastic with multiple myeloma (MM) who respond to anaemia (SAA) are considered for a first-line first-line treatment, but age and general health HLA-identical sibling HSCT (if available) or in should be considered; in MM all-HSCT has a case a haploidentical donor or a mismatch 9/10 curative potential, but the risk of mortality needs donor. Allo-HSCT is the only treatment for to be considered; autologous is also a standard of Fanconi anaemia. More than 20% of allo-HSCT care for follicular lymphoma in first or subse- are performed in patients under 20 years, and at quent relapse, while the auto-HSCT consolida- least one third are performed for rare indications. tion is considered a standard part of first-line Clinical trials are limited because of small num- treatment of younger(<60–65 yrs) patients with bers, and chronic GvHD is still major limitation mantle cell lymphoma and for peripheral T-cell for the procedure. Well-matched donors must be lymphomas and represent a reasonable treatment considered as the primary cell source (Sureda option. Patients with amyloidosis and without et al. 2015a; Majhail et al. 2015; Rowley 2013). severe heart failure benefit from high dose- 32 L. Galgano and D. Hutt therapy and auto-HSCT, while allo-HSCT consanguineous parents (Rivers and Gaspar should be considered in relapsed younger 2015). The incidence of SCID varies according to patients after at least one new drug such as ethnicity (Booth et al. 2016). The different forms lenalidomide or bortezomib (Sureda et al. of SCID can have different patterns of lympho- 2015a). cyte development. Nearly all SCIDs have absent HSCT in solid tumours needs further prospec- T cells but are then further divided by the pres- tive trials (Sureda et al. 2015a). ence or absence of B and NK cells (Fig. 2.2; For further information on HSCT in non- Rivers and Gaspar 2015; Booth et al. 2016). malignant paediatric indication, see below. Patients with SCID usually present in early infancy with recurrent, severe or opportunistic infections. Multiple pathogens may coexist, and opportunistic infection, for example, with 2.5 Indications for Transplant Pneumocystis jiroveci, is common (Gennery in Non-malignant Diseases 2015). This can also be accompanied by failure to in Children thrive with persistent diarrhoea and persistent oral thrush. Infants that present with lymphope- More than 20% of allogeneic haematopoietic nia should be further evaluated (Rivers and stem cell transplants (HSCT) are performed in Gaspar 2015). patients below 20 years. However, at least one The severity of the clinical and immunologic third of HSCTs in children are performed for rare situation requires prompt intervention, and for indications (Sureda et al. 2015b). Allogeneic most patients, the only curative treatment is allo- HSCT can cure several non-malignant disorders geneic HSCT (Gaspar et al. 2013; Gennery in children. 2015). Gene therapy and enzyme replacement therapy are available for some specific genetic subtypes (Gennery 2015). The objective of HSCT 2.5.1 Transplant in Primary in patients with SCID is to provide normal hae- Immunodeficiencies matopoiesis, facilitating correction of the immune defect. Therefore, it is critical to minimize poten- Primary immunodeficiencies are genetic disor- tial long-term effects of treatment but to establish ders characterized by defective or impaired effective long-term immune function (Gennery innate or adaptive immunity. Of these, severe 2015). Once the diagnosis of SCID is made, there combined immunodeficiencies (SCIDs) are the is an urgency of finding a suitable donor (Gaspar most severe, leading to death in infancy or early et al. 2013) and proceeding to transplant. Factors childhood unless treated appropriately (Sureda et al 2015b). NK+ IL-7Rα deficiency

B+ 2.5.2 Severe Combined Immunodeficiencies NK- X-SCID/JAK3 deficiency

T- Severe combined immunodeficiencies (SCIDs) are a genetically heterogeneous group of rare RAG 1/2 deficiency NK+ inherited defects characterized by severe abnor- Artemis deficiency malities of immune system development and B- function (Gaspar et al. 2013; Gennery 2015). Most of the genetic defects responsible for SCID NK- ADA deficiency are inherited in an autosomal recessive fashion Fig. 2.2 Some of the more common immunophenotypes and therefor are more common in infants born to in SCID (Reproduced from Rivers and Gaspar 2015) 2 HSCT: How Does It Work? 33 that influence the prognosis include the age, the Over the last 15 years, the use of reduced inten- type of SCID and the clinical state at the time of sity conditioning approaches has been explored diagnosis, in particular the presence of infection in order to reduce acute and late effects (Booth and the degree of HLA matching with the donor et al. 2016). The EBMT and ESID (European (Sureda et al. 2015b). Society for Immunodeficiencies) have published in 2011 guidelines for stem cell transplantation for primary immunodeficiencies (EBMT and 2.5.3 Non-SCID Primary ESID 2011). Immunodeficiencies Outcome In recent years, the outcome of HSCT The three of the more common non-SCID pri- has improved considerably with overall survival mary immunodeficiency (PID) disorders are as rates now approaching 90% in optimal circum- follows: 1. Chronic granulomatous disease stances (Gennery 2015). This is most likely due to (CGD) patients with CGD have a reduced ability earlier diagnosis; improved supportive care, of phagocytes (particularly neutrophils) to kill including the initiation of bacterial and fungal pro- bacterial and fungal pathogens. 2. Wiskott- phylaxis; and early referral for HSCT (Booth et al. Aldrich syndrome (WAS) is an X-linked immu- 2016). For many patients with PID, partial donor nodeficiency caused by mutations in the WAS chimaerism is sufficient to induce cure if the gene, presenting with thrombocytopenia, eczema affected recipient cell lineage is replaced com- and immunodeficiency. 3. Haemophagocytic pletely or partially by donor cells, although com- lymphohistiocytosis (HLH) is a life-threatening plete donor chimaerism is best in some diseases disease of severe hyper inflammation caused by (Gennery 2015). Pai et al. (2014) reported the uncontrolled proliferation of activated lympho- results of 240 infants who received a transplant for cytes and macrophages (Booth et al. 2016). SCID, at 25 centres in the USA between January 2000 and December 2009. The overall survival Conditioning There is a debate about the best rate at 5 years was 74%; most deaths were within approach of treatment. Different centres are using the first year after transplant and were due to infec- a wide variety of conditioning regimes (Booth tions (39%) or pulmonary complications (37%). et al. 2016). In the presence of an HLA-identical Mortality was increased for patients who had family donor, HSCT can be performed in certain active infection at the time of transplantation. types of SCID (particularly those with an absence of NK cells) without any conditioning regimen. These patients can have donor T-cell (and occa- 2.5.4 Newborn Screening sionally B-cell) reconstitution, thereby potentially sparing short- and long-term toxicities Over the past decade, the concept of newborn (Dvorak et al. 2014; Gennery 2015; Sureda et al. screening for SCID has moved into reality in a 2015b). Dvorak et al. (2014) compared the out- number of countries around the world. Early come of transplants in SCID patients’ undergo- diagnosis of these conditions will significantly ing unrelated donors or unrelated cord blood improve the outcome for SCID patients, allowing transplants with matched sibling transplants both a rapid move to curative therapy before symp- with no conditioning. They concluded that toms and infections accrue (Gaspar et al. 2013; patients lacking a matched sibling donor can pro- Booth et al. 2016). Detection of SCID at birth ceed to an unrelated transplant without the use of allows immediate protection with prophylactic conditioning chemotherapy in the same manner Immunoglobulin substitution and antibiotics, as with a matched sibling donor but with careful thus keeping children free from infection until a GvHD prophylaxis. definitive procedure can be undertaken (Gaspar In contrast to SCID disorders, HSCT in non- et al. 2013). Screening is based on a qPCR assay SCID PID always requires conditioning therapy. for T-cell receptor excision circles (TRECs) 34 L. Galgano and D. Hutt which can be performed on the dried blood spot platelet counts, in a child younger than 1 year tests—Guthrie already taken as part of universal (Vlachos and Muir 2010). newborn screening for other inherited conditions. Dyskeratosis congenita (DC) is a multisys- TRECs are essentially a marker of thymic output tem disorder, with a disruption in telomere biol- and their levels are severely reduced in SCID and ogy leading to very short telomeres underpinning in a number of other conditions. If low TREC its pathophysiology. Bone marrow failure is a levels are detected, then assay is repeated before key feature in DC and is the leading cause of the patient is called for further immunological mortality (Barbaro and Vedi 2016). DC is genet- evaluation (Booth et al. 2016). ically heterogeneous with X-linked, autosomal The optimal way to approach transplant in dominant and autosomal recessive subtypes. those infants identified through newborn screen- The clinical features include cutaneous mani- ing programs has yet to be determined (Booth festations of abnormal skin pigmentation, nail et al. 2016). It generated considerable debate dystrophy, mucosal leukoplakia and BMF, pul- among many members of the SCID transplant monary fibrosis and predisposition to malig- community (Gaspar et al. 2013). The use of che- nancy. Allogeneic HSCT remains the only motherapy in pre-symptomatic children with curative approach for the BMF (Mehta et al. SCID is difficult for physicians and families to 2010). accept (Booth et al. 2016). Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare autosomal recessive disorder characterized by isolated thrombocytopenia 2.5.5 Inherited Bone Marrow at birth due to ineffective megakaryocytopoiesis Failure and progression to pancytopenia in later childhood. HSCT remains the only known curative The inherited bone marrow failure (BMF) syn- treatment for CAMT (Mehta et al. 2010). dromes are a rare group of syndromes that are characterized by impaired haematopoiesis and cancer predisposition. Most inherited BMF syn- 2.5.6 Inherited Diseases: Inborn dromes are also associated with a range of con- Errors of Metabolism genital anomalies (Mehta et al. 2010). Fanconi anaemia (FA) is the most common Most of the metabolic diseases considered for inherited BMF syndrome (Mehta et al. 2010). It HSCT are lysosomal storage diseases that rely on is an autosomal recessive disorder that is charac- transfer of enzyme from donor-derived blood terized by a wide variety of congenital abnormal- cells to the reticuloendothelial system and solid ities, defective haematopoiesis and a high risk of organs (Sureda et al. 2015b). This group of rare developing acute myeloid leukaemia and certain diseases includes mucopolysaccharidosis (MPS) solid tumours. The indication for HSCT in FA is as Hurler’s syndrome and leukodystrophy as the development of bone marrow failure X-linked adrenoleukodystrophy (X-ALD) and (Tischkow and Hodgson 2003). Virtually all infantile Krabbe disease. The success of SCT in patients with FA will require treatment with allo- metabolic diseases is determined particularly by geneic HSCT (Mehta et al. 2010). the degree of tissue damage present by the time Diamond-Blackfan anaemia (DBA) is charac- of transplantation and the rate of progression of terized by red cell failure, the presence of con- the disease (Steward and Jarisch 2005). If dam- genital anomalies and cancer predisposition. The age to the central nervous system is present, it is classic presentation of DBA usually includes irreversible and therefore a contraindication for anaemia with essentially normal neutrophil and transplant (Boelens et al. 2008). 2 HSCT: How Does It Work? 35

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Abstract Allogeneic haematopoietic stem cell transplant (HSCT) is the treatment of choice for a variety of malignant and non-malignant disorders. The aim of HSCT is to replace the patient’s haematopoiesis with that taken from a donor, and a prerequisite is the identification of a suitable donor. It is an intense and demanding process and puts considerable strain on both recipients and donors. The choice of donor has an impact on the transplantation process from scheduling to outcome. There are several common donor issues whether the donor is related or unrelated including eligibility, confidentiality, informed consent and right to refuse consent.

Keywords Eligibility • Confidentiality • Informed consent • Donation • HLA match • Donor selection

3.1 Introduction needs to be suitably matched, healthy and willing to donate (Kisch 2015). Allogeneic HSCT is an Allogeneic haematopoietic stem cell transplant intense and demanding process and puts consid- (HSCT) is the treatment of choice for a variety of erable strain on both recipients and donors. malignant and non-malignant conditions. The Donors can be related or unrelated (Fig. 3.1), aim of HSCT is to replace the patient’s haemato- and the primary consideration is the degree of poiesis with that taken from a donor, and a pre- HLA compatibility of the donor to the recipient requisite is the identification of a suitable donor. and this is considered the most important factor There are three conditions which have to be met to determining overall success and the transplant- for a donor to be considered suitable – the donor related mortality (Kulkarm and Treleaven 2009).

M. Níchonghaile St James’s Hospital, Dublin 8, Ireland e-mail: [email protected] © EBMT and the Author(s) 2018 37 M. Kenyon, A. Babic (eds.), The European Blood and Marrow Transplantation Textbook for Nurses, https://doi.org/10.1007/978-3-319-50026-3_3 38 M. Níchonghaile

Table 3.1 The number of HLA alleles currently named Types of donors at each locus (April 2011) HLA Number of Number of ∑ Autologous Patient’s own HSCs locus class I alleles HLA locus class II alleles HLA–A 1601 HLA– 1027 DRB Syngeneic donor HLA matched (M) HLA–B 2125 HLA– 44 (identical twin) DQA1 ∑ Allogeneic HLA M or Related donor HLA Mismatched (MM) HLA–C 1102 HLA– 153 (sibling or other relative) or DQB1 Haploidentical

HLA M or HLA– 32 Unrelated donor HLA MM DPA1 HLA– 149 Fig. 3.1 Types of donors DPB1 EBMT Handbook 6th Edition (2012) page 76

Mother Father Table 3.2 An example of HLA nomenclature and its AB CD relation to HLA typing techniques Typing method Nomenclature Serological A1 AC AD BC BD DNA based: Low resolution A*01 Fig. 3.2 HLA typing DNA based: Low resolution A*01:01/01:4 N DNA based: Low resolution A*01:01 EBMT Handbook 6th Edition (2012) page 77 3.2 Human Leukocyte Antigens that have been identified. HLA typing can be Human leukocyte antigens (HLA) are part of the serological or DNA based though currently the major histocompatibility complex and is highly majority of HLA typing is DNA based. polymorphic, meaning that there are a lot of vari- Table 3.2 shows an example of the nomencla- ations of the HLA type with humans, and they are ture used for HLA typing. HLA typing looks at found on the short arm of chromosome 6. The matching recipients and donors at HLAs A, B primary role of HLA molecules is to preserve and C (class I typing) and HLAs DR, DQ and DP peptide to T cells, enabling them to recognise and (class II typing). The nomenclature used is the eliminate “foreign” particles present in an indi- gene name followed by an asterisk with a four- vidual and also to prevent the recognition of self digit allele name; the first two digits indicated the as foreign. Due to the Mendelian1 inheritance of serological groups and the last two digits the HLA types, the first place to look for a potential number of the allele within the group. donor is within the immediate family (Fig. 3.2). When we speak of matching, we describe the Our HLA type is inherited from our parents – one potential donors as being fully matched (6/6 within haplotype from each parent giving rise to a one in the related setting or 10/10 when referring to unre- four chance that sibling may match another. lated donor), a one- or two-antigen mismatch or a Table 3.1 shows the wide variety and number haplotype match (i.e. 3/6 or 5/10). The example of HLA alleles (the variant forms of the gene) below shows a patent and his potential sibling donors. Below is a list of examples when describing degrees of HLA matching between recipient and 1 Mendelian inheritance is where a person inherits two alleles, one from each parent. These alleles may be the potential donor. same or different. 3 Donor Selection 39

Patient Donor Full/Complete A*1, B*8, DRB1*03, DRB3*01 A*1, B*8, DRB1*03, DRB3*01 A*31, B*35, DRB*04, DRB4*01:02N A*31, B*35, DRB*04, DRB4*01:02N HLA Mismatched A*1, B*8, DRB1*03, DRB3*01 A*3, B*7, DRB1*01 A*31, B*35, DRB*04, DRB4*01:02N A*24, DRB1*15, DRB5*01/02/03N Haplotype Match A*1, B*8, DRB1*03, DRB3*01 A*1, B*8, DRB1*03, DRB3*01 A*31, B*35, DRB*04, DRB4*01:02N A*3, B*7, DRB1*01 Single Antigen A*01, B*8, DRB1*03, DRB3*01 A*01, B*8, DRB1*03, DRB3*01 Mismatch A*31 , B*35, DRB*04, DRB4*01:02N A*28, B*35, DRB*04, DRB4*01:02N Single Allelic A*01:01, B*8, DRB1*03, DRB3*01 A*01:02, B*8, DRB1*03, DRB3*01 Mismatch A*31, B*35, DRB*04, DRB4*01:02N A*31, B*35, DRB*04, DRB4*01:02N The differences leading to the mismatch are highlighted in red

The possibility of having a suitably matched not imply consent to donation – and that the poten- sibling donor varies depending on ethnicity as tial donor is not suffering from any conditions that distinct HLA types that occur differ among eth- may be a threat or a risk to the recipient or that may nic groups and family size. If a suitable matched be aggravated in themselves by the donation pro- sibling donor is not available, a search can be cess. As a result potential donors who have had a undertaken of the volunteer unrelated donor pan- malignancy previously or have an autoimmune els that are part of BM Donors Worldwide. There condition should be excluded or given special con- are now in excess of 18 million volunteer unre- sideration. Relevant guidance can be found at lated donors registered on these panels. http://www.worldmarrow.org/donorsuitability/ Gragert et al. (2014) published the chances of index.php/Main_Page#Related_donors identifying a suitable matched donor for a recipi- Sibling donors actively participate in the ent requiring allogeneic HSCT. While a person of quest for a cure for their sibling, but this exposes Caucasian background has a relatively good them to an invasive medical procedure that can chance of identifying a potential donor, some eth- lead to stress and anxiety and places them in a nic groups have a much lower probability of find- complex situation. While it can have a beneficial ing a match through unrelated donor searching. effect for the donor and the family unit as a This has led to an increase in the use of alternate whole, donors often feel responsible for the donors, e.g. a haploidentical donors or alternative recipient outcome. cell sources, e.g. cord blood stem cells. The use With respect to unrelated donors, each registry of haploidentical transplantation with improved will have their own inclusion/exclusion criteria, conditioning and GVHD prophylaxis means that but they usually follow the advice of the WMDA nearly all patients will gave the potential of a (World Marrow Donor Association) on whose haploidentical donor (Table 3.3). website there is comprehensive guidance with respect to donor eligibility. To be listed as a volunteer donor on a blood stem cell registry, you 3.3 Eligibility for HLA Typing must be: of Potential Related Donors • Between 18 and 60 years old (age limits may Every institution will have their own requirements vary per country) regarding eligibility to be HLA typed, and there • In good health should be a policy available locally. The main eligi- • Ready to donate stem cells to any patient in bility criteria is willingness to be tested – this does need 40 M. Níchonghaile

Table 3.3 Likelihood of identifying HLA-matched adult donors and cord blood units Likelihood of Likelihood of identifying a Likelihood of identifying a identifying an adult cord-blood unit for patients ≥20 Yr cord-blood unit for patients <20 donora of ageb Yr of age? ≥7.8 ≥4/6 ≥5/6 ≥4/6 8/8 HLA HLA 6/6 HLA ≥5/6 HLA HLA 6/6 HLA HLA HLA U.S. Racial and match match match match match match match match Ethnic Group Percent White European 75 97 17 66 96 38 87 99 Middle Eastern or 46 90 6 46 91 18 75 98 North African African American 19 76 2 24 81 6 58 95 African 18 71 1 23 81 5 56 95 Black South or 16 66 2 27 82 7 58 96 Central American Black Caribbean 19 74 1 24 81 6 58 95 Chinese 41 88 6 44 91 19 77 98 Korean 40 87 5 39 89 17 73 98 South Asian 33 84 4 41 90 14 73 98 Japanese 37 87 4 37 88 16 72 97 Filipino 40 83 5 42 89 19 76 98 Southeast Asian 27 76 3 37 89 12 70 98 Vietnarnese 42 84 6 44 89 20 76 98 Hawaiian or 27 72 3 32 84 10 64 96 Pacific Islander Mexican 37 87 6 45 91 19 75 98 Hispanic South or 34 80 5 43 90 17 73 98 Central American Hispanic 40 83 5 40 89 17 71 98 Caribbean Native North 52 91 10 54 93 25 80 99 American Native South or 49 87 11 53 93 26 79 98 Central American Native Caribbean 32 77 4 35 86 14 66 97 Native Alaskan 36 83 7 47 91 18 75 98 Gragert et al. 2014 aData are the probabilities of identifying an adult donor who is available bData are the probabilities of identifying a unit with an adequate cell dose

To donate umbilical cord blood, a future 3.4 Algorithm of Donor Choice mother must generally be: and Selection

• Over 18 years of age Many factors affect the choice of donor, and with the • In good health selection of donor sources now available, the possi- • Pregnant without complications bility of offering HSCT has extended to almost all • Registered well before the onset of labour patients who require it (Apperley et al. 2012). 3 Donor Selection 41

Patient and Family Typing

HLA Identical Sibling: No HLA Identical Sibling: HSCT Allele typing for A,B,C,DRB1, DQB1 Search for an unrelated donor in bone marrow registries and cord blood banks

HLA 9/10 or 10/10 Unrelated cord blood Related Haploidentical: matched unrelated donor: ≥3x107 TNC/kg & 1-2 HLA HSCT HSCT MM: HSCT

EBMT 2012 Handbook page 102

3.4.1 Donor Selection 3. Two or more mismatches are associated with a poorer outcome (Shaw 2009). The main determinants when selecting a donor whether related or unrelated are as follows: The “perfect” donor does not exist – no cur- 3.4.3 Cytomegalovirus (CMV) Status rent algorithm will guarantee a positive outcome will always occur. Cytomegalovirus (CMV) is a common virus that can infect almost anyone. Most people don’t know they have CMV because it rarely causes 3.4.2 HLA Match symptoms. However, if you’re pregnant or have a weakened immune system, CMV is cause for The most significant factor in success and overall concern. Once infected with CMV, your body outcome is the degree of match between the retains the virus for life. donor and recipient. Where possible the donor-recipient pairing should be CMV matched with preference given to 1. Most data suggest a 10/10 match is the best a CMV compatible donor, i.e. negative donor in a choice. CMV-negative recipient. The CMV status of the 2. In many circumstance a 9/10 match can be donor is less important in a CMV-positive recipi- considered as good as a 10/10 but where the ent, but there is some evidence that a CMV-positive mismatch occurs is important. A mismatch at donor is preferable in a CMV-positive recipient as HLA DQB1 has been shown to have the least it may protect the patient from CMV infection likely adverse outcome. Worse outcomes (Rovira et al. 2012). Analysis has shown that prior have been seen where the mismatch is at class donor CMV exposure significantly reduces the I. Choosing a HLA A, B or C mismatch risk of CMV reactivation in CMV-positive recipi- should be based on local studies and experi- ents as immunity against CMV seems to be trans- ence as it can be population or ethnically ferred with the donor cells and protects dependent. CMV-positive recipients from reactivation. 42 M. Níchonghaile

3.4.4 Blood Group survival can be lower with increased donor age (Kollman et al. 2001). Blood group mismatch is not a contraindication to HSCT, and there is conflicting data about the role of blood group mismatch in relation to post 3.4.8 Donor Evaluation HSCT relapse, but the majority of research suggest that is does not influence HSCT outcome All donors should be medically assessed and (Kulkarni and Treleaven 2009). consented independently from the recipient med- Matching donor and recipient blood group ical team. The maxim of “Do No Harm” to the may benefit the recipient as it may reduce the donor is paramount, and no donor should be number of transfusions and the period of transfu- selected where there is a risk of aggravating or sion dependency post HSCT. Blood group match- exacerbating a potential medical issue in the ing is an important consideration in transplants donor. where BM stem cells are the product of choice as Table 3.4 lists the investigations that should be it removes the requirement for the product to be undertaken for all donors. There is a concern that red cell depleted to reduce the risk of intravascu- related donors may not always be as forthcoming lar haemolysis in the recipient. about their health as they do not wish to jeop- ardise their relative’s transplant. The table lists the mandatory virology screening that is required 3.4.5 Sex Match on all donors – specific or additional testing may

Donor-recipient sex match is an important pre- Table 3.4 Pre-transplant investigations of the donor dictor of transplant-related mortality (TRM) with the combination of a male recipient with a female Blood group and antibody screening donor known to have an increased risk of chronic Coagulation studies Complete blood count GVHD and a higher TRM but not necessarily a Full/confirmatory HLA typing reduced relapse risk in all diseases. Liver function tests Urea and creatinine Pregnancy test 3.4.6 Parity Viral serology – Cytomegalovirus Epstein-Barr virus If only female donors are available, it is recom- Hepatitis B surface antigen and core antibody mended where possible to use a nonparous Hepatitis C antigen HIV female donor as -parous females have a higher HTLV chance of having HLA-specific antibodies due to Treponemel screen exposure to foetal antigens in utero. It is accepted Herpes simplex virus that recipients (either male or female) who have a Varicella zoster virus Toxoplasma HSCT from parous donors have a higher risk of Chest X-ray chronic GVHD (Kollman et al. 2001). Electrocardiogram Under certain circumstances Cytogenetic studies (chromosome fragility) if family 3.4.7 Age history Bone marrow examination The younger the donor at the time of HSCT dona- Echocardiogram or MUGA scan tion has a favourable outcome after HSCT. It Haemoglobin electrophoresis appears that the risk of acute GVHD (Grade 3 or Lung function tests above) and chronic GVHD is higher, and overall Haemoglobinopathy screen 3 Donor Selection 43 be required in certain countries, e.g. screening for dren and often feel that the donation process has West Nile virus if donor resides in an at risk area, a positive effect on family life not understanding or if the countries’ regulations require it, e.g. Tri- any negative effect it may have on the donor feel- NAT assay. ing a pressure to donate or having that feeling of responsibility. The needs of paediatric donor are sometimes 3.5 Special Considerations left unmet since parents and healthcare professionals cannot always see the effect of the dona- 3.5.1 Screening of Elderly Donors tion process on them. This can also be said to be the case in adult donors although they at least With more than 25% of HSCT now being per- have life experience and knowledge which formed in recipients >55 years of age, the chance enables them to process and deal with their feel- of a higher age in matched sibling donors is also ings in a way that a child often cannot. greater. This group of donors are more likely to have age-related medical conditions, and additional testing may be required to reduce the risk of donor- 3.5.3 Confidentiality derived disease, e.g. transmission of an immune- mediated condition, e.g. asthma or psoriasis to the Information and care of the HSCT patients and recipient, and reduce the risk to the donor. This their donor should be kept separate. Healthcare includes PSA (prostate-specific antigen) in males, professionals must minimise their influence and occult blood in stools, possible BM aspirate if that of the recipient and other family members results are abnormal, protein electrophoresis and which could complicate the potential donors’ CT chest if there is a history of smoking. decision to donate or not. Families are complex entities, and potential donors and recipients can be estranged or influenced, and donors can feel 3.5.2 Screening of Paediatric pressured to donate. A model of care which is Donors independent to the recipient (i.e. independent medical assessment and counselling of the poten- Paediatric sibling donors are a unique underre- tial donor) increases the potential donors’ sense ported group with special challenges for the of security and allows for informed consent or HSCT team and the family. Parents of the paedi- refusal of donation. It is essential to separate the atric donor are in the difficult position of having care of the donor from that of the recipient so that to consent to both the donation and the transplant. each individual can be focussed upon. The pri- JACIE and other professional bodies suggest the vacy of the donor must be respected and pro- use of independent assessor and donor advocates tected, and all potential donors should be given in the case of paediatric donors to ensure the information at the time of the HLA typing about needs of the paediatric donors are met and that the potential process. they are protected. Hutt et al. (2015) state that the intense experience of HSCT has a long-term impact on the whole family indicating the need 3.5.4 Donor Consent and Clearance for follow-up and psychological support. There can be a striking difference between the donors’ All donors should be reviewed and consented and parents’ view of the situation with the donor prior to the recipient commencing conditioning feeling a closer relationship with the recipient chemotherapy. They should be medically cleared and also feeling responsible for them as well as and understand the implications if they withdraw the fact that the recipient owes them a debt of their consent or participation once the recipient’s gratitude. Parents are concerned with two chil- conditioning has commenced. 44 M. Níchonghaile

3.5.5 Stem Cell Source References

While this is primarily dictated by the transplant Apperley J, Carreras E, Gluckman E, Masszi T. medical assessment and the type of HSCT that Haematopoeitic stem cell transplantation. 6th revised ed. 2012. the recipient is undergoing, the donor will also Gragert L, et al. HLA match likelihoods for hematopoietic influence that decision. The donor has a choice in stem-cell grafts in the U.S. registry. N Engl J Med. which type of donation method that they prefer, 2014;371(4):339–48. and both should be discussed. The donor may Hutt D, Nehari M, Munits-Shenkar D, Akalay Y, Toren A, Bielorai B. Haematopoietic stem cell donation: also have medical issues which influence the cell psychological perspectives of paediatric sibling source, e.g. donors with significant back injuries donors and their parents. Bone Marrow Transplant. or issues may not be suitable for bone marrow 2015;50:1–6. harvest, and unrelated donors who do not have Kisch, AM. Allogeneic stem cell transplant. Patient and sibling donors perspective. Malmo University. 2015. adequate peripheral venous access may not be Kollman C, Howe CW, Ansetti C, et al. Donor charac- considered for apheresis due to the reluctance to teristics as risk factors in recipients after transplanta- insert a central access device in an unrelated tion of bone marrow from unrelated donors. Blood. donor. 2001;98:2043–51. Kulkarm S, Treleaven J. Patient selections: preliminary interview and screening of patient and donor. In: Conclusion Treleaven J, Barrett AJ, editors. Haematopoietic stem Allogenic HSCT is a standard therapy in a cell transplantation in clinical practice. Churchill number of malignant and non-malignant con- Livingstone: Elsevier; 2009. Rovira M, Mensa J, Carreras E, Infections in HSCT In: ditions. The choice of donor is a complex Apperley J, Carreras E, Gluckman E, Masszi T. The issue with far-reaching consequences both for EBMT Handbook: Haematopoeitic stem cell trans- the recipient and the donor. plantation. 6th revised ed. 2012. Shaw B. Human leukocyte antigen matching, compatibility testing and donor selection. In: Treleaven J, Barrett AJ, editors. Haematopoietic stem cell transplantation in clinical practice. Churchill Livingstone: Elsevier; Edinburgh 2009.

Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Transplant Preparation 4 Caroline Bompoint, Alberto Castagna, Daphna Hutt, Angela Leather, Merja Stenvall, Teija Schröder, Eugenia Trigoso Arjona, and Ton Van Boxtel

Abstract HSCT is a complex procedure, which involves a long and complicated pathway for the patient and the intervention of many health professionals. Within this multidisciplinary team, the transplant coordinator, usually a nurse, is the ‘essential marrow’, the heart and the vital backbone of this procedure; they are an essential transplant ingredient facilitating a fluidity of the pathway and a good transmission of information. Written information about the procedure is beneficial for patients either prior to clinic visit or during clinic to allow the patients and relatives to reflect on conversations. Transplantation carries a significant risk of morbidity and mortality, and these should be considered regarding the ‘need’ to transplant, based upon risk of disease, versus risk of the transplant. Pre-transplant assess-

C. Bompoint (*) HSCT Unit, Saint Eloi hospital, Montpellier, France e-mail: [email protected] A. Castagna Pediatric Hemato-Oncology and HSCT Unit, AOUI Verona, Verona, Italy D. Hutt Department of Paediatric Hematology-Oncology and BMT, Edmond and lily Safra Children Hospital, Sheba Medical Center, Tel-Hashomer, Israel A. Leather The Christie NHS Foundation Trust, Manchester, UK M. Stenvall • T. Schröder Pediatric Hematology, Oncology and Stem Cell Transplantation Unit, University Hospital, Helsinki, Finland E.T. Arjona Hospital U y Polytechnic “LA FE”, Valencia, Spain T. Van Boxtel UMC Utrecht, Utrecht, The Netherlands

ments must also be undertaken, and the results of these along with suitable donor medical clearance and cell availability are essential to ascertain that transplant is a valid option and can proceed safely. Dealing with fertility preservation upon diagnosis of cancer is often challenging; this issue is even more complex for paediatric patients. PDWP recommends that counselling about fertility preservation opportunities should be offered to each patient receiving HSCT. This chapter will also focus on vascular access for optimal treatment of haematology patients because stem cell treatment cannot be performed without it. Constant advances in haematology have raised challenging ethical dilemmas concerning end of life, palliative care, patient information, donor concerns and impartiality and issues related to the risk we run to our patients. Nurses provide a key role in patient education, providing pre- and post-transplant advocacy and counselling, plan hospitalisations and consultations. They also act as educators and role models to nursing students and share knowledge in accordance with local policies and JACIE guidelines.

Keywords Transplant coordinator • Nurse • Multidisciplinary team (MDT) • Ethics • Complex procedure • Venous access

4.1 The Role of Transplant The TC supports the patient education and Coordinator coordination of all care and embodies a clinical nursing function where emphasis is placed on The role of the transplant coordinator (TC) is to specialisation in a clearly defined area of care. ensure that timely events occur for each patient The TC also takes cares of the donor, to wel- and their families undergoing haematopoietic come and accompany the donor in his proce- stem cell transplant (HSCT), ensuring that dures: information, assessment, reimbursement patients are physically and psychologically pre- of expenses and psychological follow-up. pared for the treatment. Many transplant coordi- They are involved in the creation of informa- nators are nurse specialists who focus their role tion tools for the patient and the donor which are on the individual needs of the patient and fami- evaluated in order to have an accurate knowl- lies; however, some centres have medical staff edge of patients’ needs. A TC actively partici- that organise transplants. TC provide a high level pates in the JACIE process of accreditation of of care and management, inform and educate the transplant centres by writing and evaluating patient, have holistic knowledge of the patient, SOPs. participate in specific or advanced nursing prac- Within the last decade, transplant centres tices (bone marrow sampling, HLA typing, trans- across Europe have invested in new nursing roles plant recipient care) and coordinate all the allowing quality, continuity and coordination of transplant logistics. care, providing a link between all members of the The transplant coordinator ensures that a suit- transplant team (physicians, nurses, cell therapy, able source of cells is available following the immunologist, radiotherapists to name a few) and high-dose chemotherapy or immunosuppressive actively participating in the accreditation treatment that the patient will receive. process. 4 Transplant Preparation 47

4.2 Information and Consent exclusive to) the risk of graft versus host disease (GVHD), infection, bleeding, multi-organ dam- Written information is considered to be benefi- age/failure, infertility, hair loss, pain and possi- cial for patients either prior to clinic visit or dur- bility of death. ing clinic to allow the patients and relatives to Consent for data collection is also important reflect on conversations (Patient Information and is in line with the data protection act since Forum 2010). It is good practice to have had in- 1998 and allows EBMT to collect anonymous depth discussions with patients on at least two information about the transplant, disease groups occasions prior to transplant consent and admis- and outcomes, enabling future developments, sion. There are many good information leaflets trends and research opportunities. Patients should available for patients and their relatives to gain an provide consent for their centre to send this overview of the procedure, some generic and oth- information. ers disease specific. Information should be offered to the patient early in their transplant journey where appropriate. Consent for trans- 4.3 Information and Consents plant should be taken prior to admission and in the Paediatric Population before the donor in allogeneic transplants starts any mobilisation therapy. Each country will have Informed consent is an essential part of health- different legislation to follow, and guidelines for care practice. Parental permission and childhood this will be available within your centre. Consent assent is an active process that engages both should be obtained by medical personnel who adults and children, in their health care. Paediatric have received the appropriate, documented train- practice is unique in that developmental matura- ing in consenting to medical treatment and exam- tion allows, over time, for increasing inclusion of ination. Usually, for transplant consent due to its the child’s and adolescent’s opinion in medical complexity and significant mortality risk, it decision-making in clinical practice and research would be considered as reasonable that this will (Katz et al. 2016). be taken by the patient’s consultant or designated A paediatric patient or a minor can be defined deputy, to ensure all known factors and concerns as a patient who has not reached the legal age of are addressed appropriately. majority (in most countries, 18 years of age), a Consent and information given to the patient patient younger than 18 years. An adolescent should be balanced against the risk of disease. refers to a person in the transition between child- Indications and suitability of potential transplant hood and adulthood, classically defined as candidates are identified, as indicated by EBMT 13–18 years of age. A child refers to a person guidelines and local policy. Yet decisions are the from the ages of 1 through 12 years, and an infant responsibility of medical teams with input from refers to a person in the first year of life (Katz other members of the multidisciplinary team et al. 2016). (MDT) based around EBMT guidelines; how- Children and parents have the right to informed ever, the patient needs to be in agreement and participation in all decisions involving their fully informed of the process, and the final deci- health care so that they can make informed con- sion should be with the patient, with appropriate sent. Participation in decision-making requires support and guidance. advance information about all measures that need During the consent process, patients should be to be taken. The right of children to participate in informed of the reason for transplantation and the their health care requires that staff members shall risks and potential benefits associated with the create an environment based on trust. Staff mem- procedure; this will vary depending upon condi- bers shall have the capacity to listen, share infor- tioning, individual risk factors and the donor cho- mation and give sound guidance. They have to sen. Information should include (but not be respect the right of children to express their view 48 C. Bompoint et al. in all matters affecting them, give due weight to requirements and discussed in detail with the their opinion in accordance with their competence patient with regard to the decisions. and render a culturally appropriate interpretation Some patients are not solely living with the of the child’s view and accept that children have haematological disease or disorder and may have the right to not express an opinion or to express other factors that need to be taken into account. their views through their parents (European The presence of one or more diseases or disor- Association for Children in Hospital 2016). ders along with a primary diagnosis is called co- EACH Charter points out that the rights of the morbidity. This may be psychological or physical children and parents to informed consent require and may include illnesses such as diabetes and that staff members respect the child’s and the par- cardiac, respiratory or renal disease. Sometimes ents’ ability and competence. The staff need to social and practical considerations may exclude a provide adequate and timely information to the patient from undergoing stem cell transplant, yet child and the parents regarding their child’s as nurses we must aim to support where possible health condition, the purpose and value of treat- to ensure the best treatment options can be ment, the process and the risks. They have to delivered. offer adequate, reliable information on alterna- Co-morbidity index tools have been used to tive forms of treatment. They have to advise and predict outcomes in patients with cancer for sev- support the child and the parents to evaluate the eral years, and some validated index tools such as proposed course of action and acknowledge and Charlson co-morbidity index (CCI) consider take seriously the child’s and parents’ knowledge medical history to estimate a prognosis or one- and experience relating to their child’s general year mortality. Each factor is assigned to a point health condition or present condition (European number of 1, 2, 3 or 6. Patients may have more Association for Children in Hospital 2016). than one disorder in each group, clearly increas- Children have the right to express their views ing risk; however, the CCI was felt not necessar- and may disagree with their parents. Providing ily relevant to patients undergoing HSCT because they are mature enough to make decisions in their the factors within the groups would often already own best interests, staff should respect the child’s be considered an exclusion to transplant and did opinion, depending on the stipulations of national not reflect frequent morbidities experienced by laws. Staffs are required to proceed with the haematology patients (Sorror et al. 2005). utmost care to properly evaluate the situation. Subsequently the HCTI, which is considered Hospital staff should also ensure that the neces- more relevant to HSCT, was designed. This tool sary counselling and support is given to the par- reflects the conditions that some of the patients ents (European Association for Children in face prior to transplant, which may be as a result Hospital 2016). of previous therapies used to treat the disease or indeed the disease itself and can be used to risk assess potential co-morbidity prior to allogeneic 4.4 Role of Risk Assessment transplant. and Co-morbidity Scores Karnofsky Performance Status, also known as KPS, has scores ranging from 0 to 100 (0 being Transplantation carries a significant risk of mor- deceased and 100 being normal with no problems bidity and mortality, and these should be consid- with activities of living or disease present). ered regarding the ‘need’ to transplant, based KPS can be used to infer a patient prognosis upon risk of disease, versus risk of the transplant; and ability to perform activities of normal living. often this can be finely balanced. Suitability must Dependent on the indication for transplant and be individualised to each patient need and patient wellbeing prior to commencing condi- 4 Transplant Preparation 49 tioning, a KPS may limit options and be sugges- 4.5 Fertility Preservation tive of outcome (Karnofsky et al. 1948). With advancing treatments more and more 100 Normal; no complaints; no evidence of disease women and children are cured of a cancer or hae- 90 Able to carry on normal activity; minor signs matological disease but may subsequently be or symptoms of disease deprived of their ovarian function or exposed to 80 Normal activity with effort; some signs or premature menopause due to the ovarian toxicity symptoms of disease of treatments. Any patient undergoing therapy 70 Cares for self; unable to carry on normal likely to impair fertility should be referred activity or to do active work 60 Requires occasional assistance, but is able to according to local referral pathway. care for most of their personal needs Fertility is a well-known and significant con- 50 Requires considerable assistance and cern for patients receiving high-dose chemother- frequent medical care apy +/− radiotherapy. However, the risk to 40 Disabled; requires special care and assistance fertility depends on the treatment received and 30 Severely disabled; hospital admission is the age of the individual at transplant. Evidence indicated although death not imminent suggests that some young patients under the age 20 Very sick; hospital admission necessary; active supportive treatment necessary of 16 at transplant may recover some gonadal 10 Moribund; fatal processes progressing rapidly function in later life (Suhag et al. 2015); however, 0 Dead this is dependent upon conditioning therapy, although the majority of the patients treated will be rendered infertile as a consequence of treat- Post-transplant performance scores can be ment. In male patients, there is some evidence used to determine ongoing treatment. Similar to that following induction therapy spermatogenesis the KPS, the Lansky score is specific to children may recover after 5–10 years of treatment, but and activities that they will encounter (Lansky this is very much variable (Tal et al. 2000, Viviani et al. 1987) and may be the preferred tool in the et al. 1999). Azoospermia rates range from 10% paediatric setting. to 70% in males following stem cell transplant; again, this is often dependent on conditioning 100 Fully active, normal agents employed (Anserini et al. 2002, Jacob 90 Minor restrictions in strenuous physical et al. 1998). activity Fertility options must be discussed prior to 80 Active, but gets tired more quickly initiation of ANY chemotherapy regime, and 70 Greater restriction of play and less time consequently many patients should have already spent in play activity had a discussion regarding fertility preservation 60 Up and around, but active play minimal; keeps busy by being involved in quieter well before transplant discussions are undertaken activities particularly if they have had induction therapy for 50 Lying around much of the day, but gets their diagnosis. However, it is also essential for dressed; no active playing participates in all this to be clarified and discussed in detail prior to quiet play and activities transplant conditioning. 40 Mainly in bed; participates in quiet activities Although ovarian function is more affected by 30 Bedbound; needing assistance even for quiet chemotherapy and certainly high-dose regimes, play 20 Sleeping often; play entirely limited to very female fertility preservation remains challenging. passive activities Egg harvests are not often viable for later fertili- 10 Doesn’t play; does not get out of bed sation. IVF followed by embryo storage can be 0 Unresponsive more effective but takes 2–3 weeks revolving 50 C. Bompoint et al. around the menstrual cycle and is not always fea- The oocyte median lethal dose for radiation sible, especially in newly diagnosed patients with therapy is less than 2 Gy and sperm production is aggressive disease. Post-transplant, donor eggs susceptible to damage at doses of more than may be a possibility for some women who may 1.2 Gy; testicular Leydig cell function seems to have limited options and should be explored in a be present at radiation doses up to 20 Gy (Fallat full discussion with a fertility specialist. et al. 2008). Male patients should be offered sperm storage The alkylating agents, such as cyclophospha- before initiation of any treatment. Radiotherapy mide and busulfan, which have frequently been and Alkylating agents amongst others have a used in the treatment of childhood cancer, are far severe impact on spermatozoa. Assuming that more gonadotoxic than other chemotherapeutic masturbation is possible, this is much simpler to agents (Schmidt et al. 2010). organise than for female patients. It can usually Hypogonadism is common after HCT (Sklar be arranged and performed quickly in an androl- et al. 2001; Smith et al. 2014). In both boys and ogy department. Once collected, the semen is girls, hypergonadotropic hypogonadism (primary analysed for sperm number, motility and quality. gonadal failure) is more common than hypogo- Quality of the sperm may be affected by several nadotropic hypogonadism (due to hypothalamic factors, including disease and current wellbeing pituitary dysfunction) (Baker et al. 2009). of the patient. Children with hypogonadotropic hypogonadism have an absence of sex hormone production, delayed puberty, delayed pubertal growth spurt 4.6 Fertility Preservation and a decrease in final adult height (Bourguignon in the Paediatric Population 1988). The type of presentation depends on the The numbers of long-term survivors following pubertal status at the time of HCT (Dvorak et al. haematopoietic stem cell transplantation (HSCT) 2011; Sanders et al. 2011). Puberty status is have been noticeably increasing in recent years. defined in two categories: ‘Pre-puberty’ for chil- Preparative regimens are associated with a high dren aged up to 12 years and ‘puberty’ for chil- risk of infertility. Infertility is considered a major dren aged 13 years and older at the time of HSCT late effect in patients receiving haematopoietic (Borgmann et al. 2011). stem cell transplantation (HSCT) (Borgmann- The earliest manifestation of impaired sex hor- Staudt et al. 2012). mone production is delayed puberty in prepubertal The infertility induced by cytostatic drugs is patients, but older patients may show asynchro- dependent on type and dosage of the drug used nous or incomplete pubertal development, primary and also on the patients’ age at the time of or secondary amenorrhea and infertility due to treatment. azoospermia or premature menopause. Sex ste- More than two-thirds of former paediatric roids are also required for the growth spurt during patients who had received allogeneic HSCT adolescence. Delayed or incomplete puberty showed signs of impaired fertility. Significant occurs in about 57% of females and 53% of males risk factors were total body irradiation (TBI) for (Dvorak et al. 2011; Sanders et al. 2011). males and busulfan (Bu) for females (Borgmann- In prepubertal males, the only option here is tes- Staudt et al. 2012). ticular tissue freezing. Options for use are autolo- For radiation therapy, variables for infertility gous transplantation, xenografting or in vitro risk also include the: maturation. No children have been born from the use of prepubertal test tissue. In post-pubertal • Age and developmental maturity of the patient males, the most common option here is freezing of • Dose and fractionation of therapy ejaculated sperm, but storage of testicular tissue is • Site of radiation therapy also a possibility (Shenfield et al. 2004). 4 Transplant Preparation 51

4.6.1 Fertility Counselling on Fertility Preservation (RTP) for girls and young women with childhood cancer: Studies emphasise the need for comprehensive ‘All girls should be examined regarding pubertal counselling for patients undergoing HSCT, par- development (Tanner stage and menstrual history) ticularly those receiving TBI- or busulfan-based at diagnosis and should be informed of the risk for preparative regimens and their parents regarding impaired fertility following the planned treatment’. fertility-preserving measures (Borgmann-Staudt et al. 2012). Counselling patients of child-bearing age or their parents regarding future fertility when 4.6.4 Who? faced with a life-threatening cancer diagnosis is difficult but extremely important. Therefore, the Regarding this, in 2013 the original language health-care team has a responsibility to provide used by the American Society of Clinical screening to identify these patients, provide Oncology (ASCO) has been revised: The word education so that an informed decision can be ‘oncologist’ was replaced with ‘health-care made as rapidly as possible and have a team provider’ to include medical oncologists, radia- ready to preserve fertility once a decision has tion oncologists, gynaecologic oncologists, been made. urologists, haematologists, paediatric oncologists and surgeons, as well as nurses, social workers, psychologists and other no physician 4.6.2 When? providers. Regarding the role of health-care providers in Counselling at the primary diagnosis would be advising patients about fertility preservation ideal. options, ASCO recommends: In the current treatment era, optimal care for paediatric patients with cancer would include fer- All oncologic health care providers should be tility preservation options at diagnosis prior to prepared to discuss infertility as a potential therapeutic exposures that can cause azoosper- risk of therapy. This discussion should take mia. Sperm banking can be offered to even early place as soon as possible once a cancer diag- pubertal patients, while development of methods nosis is made and before a treatment plan is to preserve spermatogonia from prepubertal formulated. (Loren et al. 2013 patients represents an area of active research Recommendations for Fertility Preservation (Dilley 2007). for Patients with Cancer). However, what remains unclear is how these discussions are initiated, whether these discus- 4.6.3 Issues sions occur with all patients and which members of the oncology team are responsible Fertility preservation is often possible, but to pre- for communicating with patients about these serve the full range of options, fertility preserva- risks and available options (Nobel Murray tion approaches should be discussed as early as et al. 2015). possible, before treatment starts. The discussion can ultimately reduce distress and improve qual- In 2008, the bioethics committee, 2006–2007, ity of life. The discussions should be documented from the American Academy of Paediatrics in the medical record (Loren 2013). (AAP) published in this technical report reviews In 2015, the Nordic Network for Gonadal the Guidance for Counselling of Parents and Preservation after Cancer Treatment in Children Patients about Preservation of Fertility Options in and Young Adults revised its Recommendations Children and Adolescents with Cancer. 52 C. Bompoint et al.

‘Evaluation of candidacy for fertility preser- gynaecologist or fertility specialist for evalua- vation should involve a team of specialists, tion, counselling and considering the possibility including a paediatric oncologist and/or radiation for ovarian hyper-stimulation and cryopreserva- oncologist, a fertility specialist, anesthetist, and a tion of oocytes. mental health professional. 4.6.5.1 Menstruating Girls 1. Cryopreservation of sperm should be offered If the girl is menstruating, mature enough to give whenever possible to male patients or families informed consent and is facing cancer therapy of male adolescents. with very high risk of infertility, therapy can be 2. Current fertility-preservation options for delayed 1–2 weeks, and ovarian hyper-stimulation female children and adolescents should be and cryopreservation of oocytes may be consid- considered experimental and are offered only ered. The responsible oncologist must be con- in selected institutions in the setting of a sulted to make sure that no contraindications, research protocol such as bleeding disorders or too long delay of 3. In considering actions to preserve a child’s cancer therapy, to such procedures are present. fertility, parents should consider a child’s The girl should get information adjusted to her assent, the details of the procedure involved, age. and whether such procedures are of proven utility or experimental in nature. 4.6.5.2 All Girls Regardless In some cases, after such consideration, of Maturational Stage acting to preserve a child’s fertility may be All efforts should be done to minimise the radia- appropriate. tion exposure to the ovary, such as optimal dose 4. Despite it’s not an options for children, planning and irradiation modality, shielding and instructions concerning disposition of stored oophoropexy. Present knowledge indicates that a gametes, embryos, or gonadal tissue in the radiation dose lower than 10 Gy may preserve event of the patient’s death, unavailability, or some ovarian function. other contingency should be legally outlined Girls, who are facing or receiving oncological and understood by all parties, including the treatments associated with a very high risk of patient if possible. infertility, could be offered the experimental pro- 5. Concerns about the welfare of a resultant off- cedure of ovarian cortical tissue spring with respect to future cancer risk cryopreservation. should not be a cause for denying reproduc- In menstruating girls, cryopreservation of tive assistance to a patient’ (Fallat et al. 2008). ovarian tissue can precede controlled ovarian hyper-stimulation (see above). The responsible However, in 2015, the Nordic Network and oncologist must be consulted to make sure that Nordic Society of Paediatric Haematology and no contraindications to such procedures are Oncology (NOPHO) revised the recommenda- present. tion provided in 2012.

4.6.6 Recommendations on Fertility 4.6.5 Recommendations on Fertility Preservation for Boys Preservation for Girls and Young Men and Young Women with Childhood Cancer with Childhood Cancer 4.6.6.1 Pubertal and Post-pubertal After treatment All girls who have received Males alkylating agents or abdominal irradiation should All males who are physically mature enough to after sexual maturation be offered referral to a produce sperm should be offered cryopreserva- 4 Transplant Preparation 53 tion of sperm before oncological treatment with cryopreservation and to participate in the potentially gonadotoxic effect (i.e. all chemo- research. therapy and radiotherapy with the gonads in the radiation field) is started. All boys should be examined regarding puber- 4.6.7 Techniques tal development (Tanner stage and testicular volume). If the volume of testes is between 6 and The objective of ovarian tissues’ cryopreserva- 8 ml, there is a reasonable probability of sperm in tion is to maintain viability of tissue after long- an ejaculate. term storage. It is the basis for all forms of The boy should be informed by a professional, fertility preservation for cancer sufferers. specially assigned for this purpose, e.g. an Cryopreservation requires cooling tissue from andrologist, paediatric endocrinologist or fertility 37 °C to the temperature of liquid nitrogen specialist, according to local availability and rou- (−196 °C), storing at this temperature and then tines. It is important that the autonomy of the boy rewarming to 37 °C at some later date. is respected and that he is offered the opportunity Freezed ovarian cortex segments can be used of individual consultation. for later thawing and transplanting either back to If the boy is unable to produce an ejaculate, the ovarian site (orthotopically) or to some other alternative methods like vibrator stimulation or location (heterotopically). The ovarian cortex is electro stimulation during anaesthesia could be used because it is this part of the ovary that is offered. particularly rich in primordial follicles. In order If the boy is unable to produce an ejaculate or for cryoprotectants to penetrate the tissue, the has azoospermia, an invasive procedure to cortical strips need to be no more than 2 mm retrieve testicular sperm may be considered, pro- thick. Tissue samples from cancer patients need vided that the boy is motivated himself. The to be evaluated by a pathologist to detect the responsible paediatric oncologist must first be presence of any metastatic cancer cells (Agarwal consulted to make sure that no contraindications and Chang 2007). (such as risk of tumour spread (e.g. in ALL) or Spermarche occurs over a wide age range and bleeding disorder) to such procedures are is associated with a highly variable testicular vol- present. ume, including in individuals with testicular vol- The boy, as well as his parents, should get ver- umes of less than 5 mL, pubic hair stage I or both. bal and written information about the procedures As a result, intraoperative assessment of the and the legal implications. The information should biopsy sample at the time of tissue retrieval has be adjusted to the boy’s age, and he must give his been suggested to be useful for allocation of tis- informed consent to the cryopreservation. sue to a specific freezing protocol (Anderson et al. 2015). 4.6.6.2 Prepubertal Boys For pubertal patients in whom complete sper- Boys, who are facing oncological treatments matogenesis has occurred, semen cryopreservation associated with a very high risk of infertility, is a well-established option. Recommendations are could be offered the experimental procedure of that all men and teenage boys should be offered testicular biopsy cryopreservation. At present, semen cryopreservation for prepubertal patients there are no methods to ensure fertility after and pubertal patients who are not able to produce a such procedures; thus, further research is semen sample; approaches for fertility preservation warranted. Since the patient number is limited, are experimental (Anderson et al. 2015). the cryopreservation and research should be Sperm cryopreservation after masturbation is centralised. the most established and effective method of fer- The parents and, if old enough, the boy should tility preservation in males. Sperm should be col- get verbal and written information about the lected before initiation of cancer therapy because research project and give informed consent to the 54 C. Bompoint et al. of the risk that sperm DNA integrity or sample experimental procedure, its associated risks quality will be compromised. and legal implications and give informed con- Nevertheless, recent progress in andrology sent to the cryopreservation (NOPHO). laboratories and with assisted reproductive tech- • In the interest of the child, the PDWP recom- niques allows successful freezing and future use mends that counselling about fertility preser- of a very limited amount of sperm; collection of vation (FP) opportunities should be offered to semen through masturbation in adolescents may each patient receiving SCT, as part of the pre be compromised by embarrassment and issues of stem cell transplant (SCT) workup. The informed consent. Alternative methods of obtain- PDWP recommends that should be offered by ing sperm besides masturbation include testicular a dedicated and trained task force that may aspiration or extraction, electro ejaculation under include medical staff from the stem cell trans- sedation or anaesthesia or from post masturba- plant unit as well as fertility preservation spe- tion urine sample. Testicular aspirates do not cialists. The presence of dedicated nurse staff freeze well and cannot be used as a method of and psychologists in the counselling task force preserving sperm (Fallat et al. 2008). should be considered to create a broader communication opportunity for the patient, who may be more at ease with non-medical staff 4.6.8 Fertility Preservation Options (PDWP, EBMT 2017). for Children and Young Adults with Distinction Between Established and Experimental 4.6.9 Sexuality in Adolescents Options and Young Adults

• In prepubertal boys, before onset of spermato- Children at risk for impaired growth as a result of genesis, testicular biopsy and cryopreserva- cancer therapy should be examined regularly, tion are options (experimental). In pubertal with their growth plotted on the appropriate and post-pubertal male patients, the ability to growth chart. produce a sperm-containing ejaculate enables Monitoring should be more frequent from the sperm cryopreservation (established); if this is time of expected onset of puberty through the not possible, testicular biopsy with cryo- fusion of growth plates at full sexual maturation preservation of sperm or tissue is needed. (Nobel Murray 2015). • In prepubertal girls, ovarian stimulation is Although we know that, after the transplant, inappropriate, so ovarian tissue cryopreserva- some adults process experience psychological tion can be offered (experimental). After and social issues, there is an absence in the litera- puberty, cryopreservation is an option, but ture about the ‘adolescents and young adult’ ovarian stimulation enables recovery of (AYA) HCT population (Cooke et al. 2011). mature oocytes for cryopreservation or of The AYA cancer population is a vulnerable embryos after fertilisation (established) group due to variety of social, psychological and (Anderson et al. 2015). developmental reasons. AYA patients also can • Safety of tissue with regard to contamination have disturbed endocrine function, body image with tumour/leukaemia cells. Cancer contami- disruptions and sexual problems (Cooke et al. nation in the cryopreserved tissue is a contra- 2011). indication for re-transplantation. Experimental Who should be in charge of talking with chil- studies are ongoing regarding the in vitro mat- dren? It is impossible to consider parent–child uration of oocytes for fertilisation from such interactions on the topic of fertility without fram- tissue. Further research is warranted. The paring the issue within the larger, complicated topic ents and, if old enough, the girl should get ver- of parent–child discussions about sex, given that bal and written information about the the two are inextricably linked. Discomfort in the 4 Transplant Preparation 55 general area of discussing sexuality will impact fertility-sparing procedures prior to treatment, the parental willingness and perception of com- careful monitoring of reproductive function is petence in discussing fertility, especially at a warranted, and current technologies will still moment of high stress (Clayman 2007). The allow many of those patients to parent their own growing literature on parent–child discussions of biological children (Dilley 2007). sex reflects the tendency of mothers to discuss this topic more frequently with their children, particularly daughters; even when both parents 4.7 Transplant Workup are involved, they are more likely to talk about sex with daughters rather than sons (Clayman HSCT is often considered as part of a therapeutic 2007). pathway, dependent on disease response and ini- In 2006, Sloper’s study concludes that there tial presentation. It is often proposed as a consoli- was an emphasis on the need for professionals to dation treatment to avoid a relapse. Prior to raise the subject sooner, more frequently, in a discussions regarding transplantation, it must be low-key way and without ambiguity. Respondents considered that the recipient can withstand the wished professionals would treat them as part- procedure without excessive risk and that there is ners, therefore prioritising their input over their no contraindication and the disease status is suit- parents. able to undergo the procedure. Transplanting patients with relapsed or relapsing disease may not provide sufficient benefit for the patient given 4.6.10 Conclusion the risks of the procedure and is often considered as futile. Pre-transplant assessments (disease sta- Dealing with fertility preservation upon diagno- tus, bloods with virology status, radiology, car- sis of cancer is challenging even for a young diac, pulmonary and renal examinations) must be adult patient. This issue is even more complex for undertaken, and the results of these along with paediatric patients where decision-making gener- suitable donor medical clearance and cell avail- ally falls to the parents but where high cancer sur- ability are essential to ascertain that transplant is vival rates increase the possibility of survivors a valid option. needing to confront infertility later in life. Parents The results of this pre-transplant assessment and adolescent patients report that achieving a will help to inform and adapt the transplant healthy state is most important and that while modality: conditioning regimen, type of graft, they are interested in fertility preservation stem cell source and post-transplant strategy options, they may not be willing to delay treat- (immunomodulation, DLI). It also allows doctors ment for pursuit of those options. Optimal care of to detect any abnormalities that could lead to paediatric cancer patients undergoing gonado- post-transplant complications. This complete toxic therapy should include enrolment in avail- review serves as a reference and facilitates com- able trials that will continue to refine knowledge parison of results of the examinations carried out of the effects of therapy on fertility for both male before and after the transplant. In some cases the and female patients. Patients and families need pre-transplant workup/assessment may mean that information at diagnosis regarding the potential the risk of transplant is considered too great and impact of therapy on fertility as well as referral to therefore is no longer a suitable option due to appropriate specialists for fertility preservation higher-than-acceptable rates of morbidity and when desired. Studies and resources that allow mortality and should be discussed with the potentially fertility-sparing interventions such as patient. The previously mentioned morbidity ovarian cryopreservation will not only need to be indexes are useful in helping to determine this. expanded, but adequate education and support During transplant workup, the patient should for oncology providers who screen for patients at be offered to meet other members of the multidis- risk will be key. For patients that did not undergo ciplinary team such as social worker, dietician, 56 C. Bompoint et al. physiotherapist, psychologist, etc. where Sufficient cell collections are required with a possible. minimum PBSC (HPC-A) of 2 × 106/kg CD34+ Transplant workup may vary from centre to or BM (HPC-M) of 2.0 × 108/Kg MNC cells for centre and will be dependent on clinical indica- infusion unless instructed otherwise by the trans- tion. The list below is not exclusive but gives plant consultant for autologous transplantation indication of workup required prior to transplant and PBSC (HPC-A) of 4 × 106/kg CD34+ or BM admission. The transplant coordinator would (HPC-M) of 4.0 × 108/Kg for donor harvested usually organise and collate this information and cell infusion. Donor cell collection results are not results. normally known prior to admission as the donor cells are not often cryopreserved and are coordinated a day prior to infusion (local policy may differ slightly), but clearance and agreement of • Full blood count. the donor must be confirmed prior to patient • U & E and liver function profile. admission. • Virology transplant assessment including HIV; Hep B, C, and E; CMV; and EBV status. 4.8 Venous Access Devices: • Group and save sample. Principles of Placement • HLA antibody screen. and Care • Coagulation. • Tissue typing and verification typing of Since the introduction of vascular access devices patient and donor for allogeneic (VAD) in the seventeenth century and the first transplants. intravenous (IV) infusion procedures during the • Patients who have been heavily trans- cholera epidemic in 1832 (Rivera et al. 2005), IV fused prior to transplant should have therapy is slowly developing towards a part of the serum ferritin levels taken to identify treatment that all haematology patients will expe- iron overload, >1000 ng/ml. rience. In most countries infusion therapy is • Cardiac function is assessed by echocar- underestimated with a high incidence of compli- diography (ECHO) or MUGA scan cations. Although the positive effect of an infu- (ECHO is favourable). Healthy individ- sion team is well proven (Brunelle 2003; Rutledge uals typically have left ventricle ejection and Orr 2005), IV therapy still is a major burden fractions (LVEF) between 50% and for most patients. Health-care workers still miss 65%. the state-of-the-art knowledge and skills to make • Calculated creatinine clearance or eGFR the right choice for the right patients and to use to estimate renal function. the VAD as it should. For venous access, we now • Pulmonary function tests have several VAD options to choose from. The • Bone marrow aspirate and trephine +/− most recent overview of VAD shows all options cytogenetics, dependent on disease and available now (Chopra et al. 2013) (Fig. 4.1). cytogenetics at diagnosis. In many centres the first option for vascular • Lumbar puncture +/− IT chemotherapy access is inserting a peripheral intravenous can- if acute lymphoblastic leukaemia or nula (PIVC) for the initial IV therapy. If inserted CNS disease/other clinical indication. by experienced health professionals in the right • CT/PET scan for lymphoma patients vein for the right indication, a PIVC is often the and other clinically indicated patient first VAD the patient is offered. Unfortunately group. PIVC’s are still used for irritating infuses for as • Double lumen central venous catheter. long as veins are accessible. Even small veins at • ECG – a 12-lead electrocardiograph. the back of the hands, wrists and the ante cubital veins are used even if this is restricting the patient 4 Transplant Preparation 57

a d

g b e

c f

Fig. 4.1 Types of vascular access devices. (a) Peripheral ter. (e) Tunneled central venous catheter. (f) Implanted IV catheter. (b) US-guided peripheral IV catheter. (c) port. (g) Peripherally inserted central catheter Midline catheter, (d) Nontunneled central venous cathe- in mobility of hands and arms and often causing tion of these VADs and the high risk during chemical phlebitis. Once peripheral veins are no explanting of this type of VAD, these risks make longer accessible with conventional techniques the VAP in haematology not a real option. and several hospital ‘experts’ accessed the last During the EBMT congresses, the attention veins, an alternative is found in a tunnelled sub- for vascular access is mainly limited to care and clavian or jugular central venous access device maintenance of CVADs in the annual nurses’ (CVAD), mainly the so-called Broviac and group congress program. It is suggested that vas- Hickman catheters, named after the inventors of cular access gets more attention in the EBMT these VADs. A venous access port (VAP) is program both for doctors and nurses and a multi- hardly seen in haematology treatment. The more disciplinary approach should be chosen. Vascular invasive procedure for subcutaneous implanta- access should not be limited to care and 58 C. Bompoint et al.

Fig. 4.2 Algorithm Properties Duration of Condition of the Treatment Catheter Choice intravenous access for Infusion Fluid Treatment vein non-acute treatment in adults, University 3 or more Medical Center Utrecht, accesible veins < 2 weeks 2008 Osmolarity < 500 mOsm, 5 ≤ pH ≤ 9 2-4 weeks hardly 1 accesible vein Peripheral IV Therapy > 4 weeks Canula

Osmolarity > 500 mOsm, Midline < 1 week pH < 5 of pH > 9 or 3 or more intrinsically irritating accesible veins

hardly 1 PICC accesible vein

< 3 months

> 3 months tunneled CVC or TIP

maintenance after insertion of the VAD but 4.8.1 Vascular Access Devices should be focused on wellbeing and patient safety. An algorithm for choosing the right VAD Access to the venous system is required for all for the right patient should start with the diagno- haematology patients. Access can be limited to sis and treatment plan. The best VAD should be drawing blood for research and diagnostic pur- chosen based on the pH and osmolarity of the poses and/or for administration of fluids, drugs drugs used during the whole treatment period and and blood components. For drawing blood by the vein condition and should include the option venipuncture, a steel needle is used that will be for (partial) home infusion treatment. In 2008 a removed immediately after the blood samples are model was introduced for non-acute patients collected using a vacuum collecting system. VAD choice in the UMC Utrecht, the Netherlands For IV therapy, there are two options that can (Giesen et al. 2008) (Fig. 4.2). be used. Option one is a PIVC (Fig. 4.1a): a short Extensive expertise, best materials, equipment flexible catheter that ends in a peripheral vein and skills are needed to offer state-of-the-art with limited blood flow. As seen in Fig. 4.1, a insertion of the preferred VAD. The Infusion PIVC should only be used for non-vesicant drugs Therapy Standards of Practice suggests estab- with an osmolarity <600 mOsm/L for a short lishing or maintaining an infusion team for period of time. An alternative PIVC might be a peripheral and central venous access device midline catheter. This VAD is inserted in the (CVAD) insertion, management and removal upper arm and the tip lies in the cephalic, brachial (Gorski et al. 2016). This chapter will mainly or basilic vein. focus on insertion and care for VADs used in hae- Option two is a CVAD with the tip of the cath- matology patients. Based on haematology patient eter ending in a central vein with high blood flow. characteristics, only the tunnelled CVAD such as The definition for all CVADs is that the distal tip centrally inserted central catheters (CICCs) and ends in a large vein close to the heart, the superior peripherally inserted central catheters (PICCs) vena cava (SVC) or inferior vena cava (IVC) for will be addressed. femoral catheters. In adults, both SVC and IVC 4 Transplant Preparation 59 have a blood flow up to 2–2.5 litre per minute and other parts from this publication might also be dilution of drugs happens so fast that the endo- helpful to use in your practice (Chopra et al. thelium is not damaged. 2013) (Fig. 4.3). Within the range of CVAD, a PICC (Fig. 4.1g) Early studies show that a PICC is a safe and is seen more frequently in haematology patients, reliable option for central venous access (Maki often as an alternative for a tunnelled CICC such et al. 2006; van Boxtel et al. 2008) (Table 4.1). as a Hickman catheter. More recent results even come close to zero The insertion of a PICC is safe and non- infections for PICCs if a bundle of preventive invasive and can be performed even with low measures are taken (Harnage 2013). This bundle platelet counts. The PICC is first described in includes: 1975 by Hoshal (1975) and has evolved to a VAD that can be the first option if central venous access • Site selection in haematology patients is needed. A PICC can • Skin disinfection with 2% chlorhexidine in be used as an alternative to subclavian, internal 70% gluconate jugular or femoral venous catheters. CICCs such • Hand hygiene as subclavian or internal jugular catheters may • Maximum barrier precautions cause a pneumothorax, and femoral catheters are • Daily control on indication relatively more prone to infections. PICCs do not • Daily control on complications have these disadvantages. A recent published algorithm in the MAGIC Many clinicians still have the old-fashioned paper is based on latest evidence and supported ideas that a PICC has a high incidence of infec- by VA experts from many countries. This and tions and thrombosis, often based on their own

Proposed Duration of Infusion Device Type ≤5 d 6–14 d 15–30 d ≥31 d

Peripheral IV catheter

US-guided peripheral IV catheter

Nontunneled/acute Central venous catheter preferred in critically ill patients central venous or if hemodynamic monitoring is needed for 6–14 d catheter

Midline catheter

PICC PICCs rated as appropriate at all proposed durations of infusion

Tunneled catheter neutral No preference between tunneled catheter and PICC for Tunneled catheter for use ≥15 d proposed durations ≥15 d

No preference among Port port, tunneled catheter, or PICC for ≥31 d

Appropriate Neutral Inappropriate Disagreement

Fig. 4.3 Venous access device recommendations for infusion of non-peripherally compatible infuses 60 C. Bompoint et al.

Table 4.1 CRBSI in PICCs CRBSI per 100 CRBSI per 1000 No. of catheters Catheter days No. of BSI devices cath. days UMC inpatient 418 13.258 11 2.63 0.82 UMC outpatient 92 4397 1 1.09 0.23 UMC in- and 510 17.655 12 2.35 0.68 outpatient Maki inpatient 625 7137 35 2.4 2.1 Maki outpatient 2813 98.702 15 3.5 1.0 Maki in- and 3566 112 3.1 1.1 outpatient

Table 4.2 Blood flow reduction based on vein diameter versus catheter size Initial Vein flow 2 Fr 4 Fr 6 Fr 8 Fr Cephalic (4 mm) 10 5 48% 3 28% 1.5 14% 0.5 0.5% Brachial (5 mm) 25 13 53% 9 36% 6 22% 9 12% Basilic (6 mm) 52 29 56% 21 41% 15 28% 9 18% Axillary (8 mm) 164 100 61% 79 48% 62 38% 47 28% Subclavian (10 400 256 64% 212 53% 175 44% 143 36% mm) experience with drum catheters and the Intra proximal position were 16 times more likely to Cath. Since the introduction of ultrasound-guided thrombose than those with the tip in a distal posi- PICC insertion around 2004 and the introduction tion. None of the 58 CVADs with the tip located of ECG tip confirmation techniques, only well- in the right atrium thrombosed or caused compli- designed studies, later than 2005, should be cations (Cadman et al. 2004). analysed and used for local policies on VAD Another important criterion to prevent throm- selection and insertion. bosis is the vein-catheter ratio when choosing the The correct position of a CVAD tip is at the catheter size. Based on the Nifong study, the lower third of the SVC (Gorski et al. 2016), cavo- catheter-vein ratio should be at least 1 to 3. For atrial junction (CAJ) or right atrium (RA) (Espen example, for a 4 French catheter, the diameter of 2009), lower third SVC or RA (RCN 2010), the vein should have a minimal diameter of cavo-atrial region or RA (SIR 2010) and SVC 4 mm. For a 5 French catheter, the diameter adjacent to the RA (ASPEN 2010). A CVAD should be at least 5 mm, etc. (Nifong and (PICC and CICC) can be used over a prolonged McDevitt 2011) (Table 4.2). period of time, e.g. for multiple, extensive or Unfortunately many studies used for prepar- long-term chemotherapy regiments, extended ing guidelines and/or local policies for VAD antibiotic therapy or prolonged total parenteral selection are based on poorly designed retrospec- nutrition (TPN). The position of the catheter tip tive studies. At the 2016 World Congress Vascular is very important in preventing thromboses. The Access (WoCoVA), Pittiruti presented a thorough distal tip of the CVAD should be placed at the analysis of all published papers on catheter- junction between the superior vena cava and the related thrombosis (CRT). Relevant criteria, such right atrium to have the lowest incidence of as vein-catheter ratio and tip position, are often thrombosis (Debourdeau et al. 2009). In a study not taken as outcome criteria. In the review by from Cadman, CVADs with the tip in a distal Pilker et al., the authors included at least five position (lower third of the SVC or right atrium) studies dealing with PICCs inserted without US had a 2.6% thrombosis. CVADs with tips in a in their analysis for PICC-related thrombosis. 4 Transplant Preparation 61

One of the studies used the same size of Before starting the actual insertion procedure, PICCs regardless of the vein’s diameter. Only the selected vein should be well examined, and three of the studies had declared diagnostic crite- the diameter of the vein should be documented. ria used for thrombosis. No study was prospec- As for all VAD insertion techniques, materials tive and/or randomised (Pikwer et al. 2012). The and procedures and care and maintenance are very ‘meta-analysis’ from Chopra included any type important. To offer high-quality IV treatment and of clinical papers (retrospective, non-ran- improve patient safety and satisfaction, insertion domised, etc.) and even abstracts and papers and the use of VADs should be limited to well- published on non-peer- reviewed journals. At trained and certified health-care providers. Vascular least 14 of the 64 studies reported are old-fash- access should be a specialty based on clear criteria- ioned with PICCs inserted without micro-intro- certified training programs and state-of-the-art ducer and without ultrasound, at the ante cubital materials and procedures (Moureau et al. 2013). fossa (Chopra et al. 2013). Fallouh and col- Although the insertion protocol might be leagues in their paper have not conducted any slightly different in each country, a state-of-the- systematic assessment of the studies; they just art protocol should be available and executed discuss some studies from the literature (Fallouh only by VA experts. et al. 2015). The review by Zochios is carried out without any systematic methodology. It describes a few studies about PICC-related thrombosis. 4.8.2 Care and Maintenance Moreover, most of the studies quoted in his review are affected by bias related to the inser- If a CVAD is placed in the correct vein and the tip tion technique, to the type of device used (inap- of the catheter is right position, the VAD should propriate calibre) and to the retrospective design function properly with the lowest rate of compli- (Zochios 2015) (Fig. 4.4). cations possible. The care professional using the In those recent studies on haematology catheter should be sure that the catheter is fully patients with a PICC, the CRT rate varies between functional before any drugs are administered. 0 and 5.8%. If studies are well analysed, it is still One has to be sure about functionality in order to evident that the expected rate of CRT with PICCs take responsibility for any infusion. A back flash is not really different from the expected rate of of blood is a good parameter, but not always pos- CRT with CICCs. If an insertion bundle like the sible with a poor tip position or minor thrombus GAVeCeLT (Gruppo Aperto di Studio ‘Gli at the catheter tip, allowing infusion but no aspi- Accessi Venosi Centrali) bundle for CRT preven- ration of blood. If this problem is occurring since tion is implemented, the best options to prevent the CVAD insertion, it is most likely that the CRT are given: catheter is too short. If occurring after some time and normal functioning in the beginning, it might 1. Proper choice of the vein be a ‘little’ thrombus at the catheter tip. An x-ray 2. Minimal trauma during venipuncture of the chest might be part of the assessment. A 3. Appropriate tip location urokinase or alteplase instillation in the catheter 4. Proper securement will help to restore patency if a thrombus at the tip is preventing aspiration of blood. The weekly care of the catheter and insertion site is different Bellesi 2013 (hemato-BMT) 5 % for a well-healed tunnelled CVAD with a subcu- Mitrovic 2014 (hemato) 3.8 % taneous cuff. This Hickman-type CVAD does not Martella 2015 (hemato) 0 % need a dressing covering the insertion site (Gorski Sriskanadarajah 2015 (hemato) 5.8 % et al. 2016). A PICC and other non-tunnelled Morano 2015 (hemato) 2.6 % CVADs need weekly dressing change. If sterile Fig. 4.4 Thrombosis rates in haematology patients with gauze is used in case of skin irritation or allergy, a PICC dressing change is every 2 days. 62 C. Bompoint et al.

4.8.3 Flushing and Locking any drugs are administered. One has to be sure about functionality in order to take responsibility Optimal functioning of a CVAD should be possi- for any infusion. A back flash of blood is a good ble by using a strict flushing and locking protocol. parameter, but not always possible with a poor In most protocols for preventing occlusion in tip position or minor thrombus at the catheter tip, CVADs, a heparin solution is still used. In a recent allowing infusion but no aspiration of blood. If study in Leuven, Belgium, a randomised trial con- this problem is occurring since the CVAD inser- cluded that normal saline is a safe and effective tion, it is most likely that the catheter is too short locking solution in implantable ports if combined and aspiration is blocked when the opening of with a strict protocol for device insertion and the CVAD is sucked against the vein wall. An maintenance (Goossens et al. 2013). This conclu- x-ray should be made to confirm the diagnoses. sion supports the hypothesis that a catheter lumen If partial occlusion (easy infusion, but no blood will not occlude if materials such as a neutral or return) occurs right after taking blood samples positive displacement needle-free connectors are form the catheter lumen, it is most likely that the used and the technique of flushing and locking lumen is blocked by hemolyses of blood in the does not allow blood or any drug to stick to the catheter or it might be a ‘little’ thrombus at the catheter wall. Preventing any adhesion to the cath- catheter tip. An x-ray of the chest might be part eter wall also reduces the biofilm and bacteremia. of the assessment. A urokinase or alteplase instillation in the catheter will help to restore patency if a thrombus at the tip is preventing 4.8.4 Securement aspiration of blood. CVADs should be regularly assessed for patency and proper function as Use of tape or sutures is not effective for secure- defined by the ability to flush the catheter with- ment or VAD stabilisation. Suturing should be out resistance and the ability to yield a blood avoided to prevent needle stick injuries and infec- return. If the VAD is occluded, restoration should tions. There are different types of securement be done after assessment of the origin of dys- devices. Frequently used is an adhesive attaching function. If blood return is not possible from the catheter to the skin covered with a semiper- right after insertion, it might be that the catheter meable folio. These securement devices should is too short. be changed together with the weekly dressing The use of a thrombolytic agent such as uroki- change. If dressing change is not well performed, nase can be used to restore patency. A 10,000ie there is a major risk of pistoning of the catheter vial should be diluted in 2 ml saline solution. The increasing the risk of insertion site infections. A estimated volume of the catheter lumen should be recently introduced subcutaneous securement instilled and left for 30–60 min before aspirating device, an anchoring device, holds the catheter in the solution. Slow infusion of 10,000ie urokinase place and stays in situ during dwell time of the can also be performed. Using this protocol is catheter. This device is easy to remove after only on doctor’s order and dependent on the removal of the catheter by folding the base or coagulation status of the patient. with a firm pull of each part after cutting the base For restoration of a totally blocked catheter in two. The nitinol anchor pieces will stretch and lumen, a vacuum protocol can be used to restore not damage the skin or cause any pain. As for all patency. A three-way stopcock is placed directly insertion and care protocols, training is required at the blocked lumen. An empty 20 ml syringe is for inserting and removal. connected to one side. A 2 ml syringe with 10,000ie urokinase is connected to the other side. With the stopcock opened between the 2 ml 4.8.5 Occlusion syringe and the lumen, a firm vacuum is created. While vacuuming, the stopcock is switched to The care professional using the catheter should the urokinase catheter. Repeat this a second time. be sure that the catheter is fully functional before Leave this situation for 30–60 min and check 4 Transplant Preparation 63 patency. If not successful, this procedure may be catheter, a specialised colleague should be con- repeated once. In most cases the patency will be sulted. If sepsis is suspected, the ‘sterile’ tip of restored when done properly. If not, it might still the CVAD should be collected and sent for have an effect after a few hours. This procedure culturing. should only be performed after training and doc- If a PICC is removed at the end of indication tor’s order. It prevents removal of the CVAD and without problems, the same site might be used is a safe, cost-effective and patient-friendly for future access through the same vein. Thorough method. If the origin of the occlusion is an acidic assessment, including scanning the route of the drug precipitate (low pH, less than 6), use a catheter, should be performed prior to insertion 0.1 N hydrochloric acid solution for declotting. of the CVAD. For alkaline drug precipitate (pH greater than 7), sodium bicarbonate 8.4% or sodium hydroxide 0.1 mmol/L should be used. If the occlusion is 4.8.7 Pre-transplant Disease from a lipid residue, 70% ethanol in a sufficient Assessment volume should been used to fill the catheter lumen; for paediatric patients, a dose of 0.55 mL/ Diagnosis and prognosis are based on the mor- kg has been used with no more than 3 mL maxi- phological examination of the blood and bone mum. Use ethanol with caution with polyure- marrow blasts, the immunophenotype and the thane CVADs as ethanol may damage the cytogenetic and molecular study (Willekens catheter material; refer to vascular access device 2013). (VAD) manufacturers’ directions for use regard- Remission can be defined as the disappear- ing exposure to any form of alcohol (Gorski ance of clinical signs (anaemia, infections, bleed- et al. 2016). ing, gingival hypertrophy, hepatomegaly, cutaneous leukaemia, etc.), but correction of cytopenias and disappearance of medullary blasts 4.8.6 CVAD Removal with a normal/normalising maturation of the bone marrow function should be observed. If the indication for the VAD is no longer there or Moreover, recent and sophisticated methods if the VAD is source of unsolvable complications, (flow cytometry, molecular biology) can make it removal is indicated. Depending on the type of possible to follow the ‘minimal residual disease’ CVAD, removal can be done in the operating (MRD). suite, bedside or at the patients home. Diagnosis and remission can be determined A venous access port (VAP) removal can only by one or more of the following: be performed as a sterile surgical procedure, mainly done in the operating suite. Also being an invasive procedure is the removal of a tunnelled, cuffed CVAD. A PICC however, even if the • Haematological status: review of the PICC is tunnelled, can be removed at the bedside blood and bone marrow would indicate or outside the hospital. After removing the dress- percentage of normal/abnormal cell ing and the adhesive securement device, the population. PICC can easily be removed by gently pulling • Cytogenetics: karyotype becomes nor- the catheter. After removal and checking on mal – cytogenetic abnormalities disap- complete removal, there will not be much blood pear (sensitivity: 1/100). spilling, but compression of the insertion site is • Molecular: molecular biology (minimal needed to prevent air embolism. The insertion residual disease) – undetectable tran- site is covered with a dressing of sterile gauze or script (sensitivity: 1/10000 to 1/100000). folio. If there is too much resistance at removal, • Imaging: CT/PET scan, MRI scan. it might help to apply warmth and try again after • Blood and urine tests (myeloma). 10 min. If still not possible to remove the 64 C. Bompoint et al.

4.9 The Advocacy Role of HSCT knowledge and skills in accordance with local Nurses policies and JACIE guidelines. The presence of dedicated nurse staff and psychologists in the Patient preparation for HSCT involves the use of counselling task force is a mandatory. chemotherapy and/or radiotherapy to eradicate Educating or teaching helps establish a rela- the underlying disease of the patient. This initial tionship in order to encourage the individual to step leads to immunosuppression in order to trig- make free and informed choices. The nature of ger aplasia of the bone marrow and thus prevent the disease and the transplant itself require graft rejection (Ortega 2004). patients to learn about it in order to cope with the Throughout the procedure, the patient needs consequences of treatment and to be involved in special care to overcome the complications asso- decision-making processes. Counselling and pro- ciated with treatment. Nurses must be aware of viding education is mandatory at each stage of the possible complications in order to play a role the pathway. in preventing or early detection of alarming signs, Nurses should be able to work within a team, such as sepsis, fluid overload and organ dysfunc- communicating with both the nursing colleagues tion, taking appropriate measures to minimise and doctors, ensuring excellent medical care of adverse effects and restoring the clinical balance the patient giving useful and clear information to of the patient. This care is very complex and the whole team. They help to identify early symp- requires a high level of skill to be able to provide toms and are aware of the treatments to adminis- those (Ortega et al. 2009). ter and the side effects to monitor and to Specific technical care activities require nurs- accurately inform the medical teams of any ing knowledge and specific skills in the field of changes or concerns. haematopoietic stem cell transplantation such as Whatever the department or place of practice, instrument manipulation, knowledge of technol- the nurse’s missions and activities are diverse and ogies and use of special protocols to effectively varied. Our primary task is the realisation of care intervene in complex situations that deal with intended to maintain or restore the health of the acute complications (Dallaire 1999, 2008). person. Nurses as ‘health care provider’ (Loren et al 2013) should be part of the interdisciplinary team The treatment team should be knowledgeable 4.10 Ethical Dilemmas about fertility preservation so that they can educate patients and families about available fertility Ethics involves the meaning of words such as preservation options. It is important to consider right, wrong, good, bad, ought and duty on a and discuss all available fertility options with basis where people either individually or collec- patients at the time of diagnosis (Fernbach et al. tively decide that actions are right or wrong and 2014). whether one ought to do something or has a right Health-care providers should be prepared to to do something (Rumbold 1993). discuss the negative impact of cancer therapy on In 1994, Tschudin states ethical dilemmas reproductive health with their patients in the have become a major part of nursing with the same way as any other risks of cancer treatment ever more holistic and patient-centred care. are discussed (Rodriguez-Wallberg and Oktay Nurses are often drawn into case discussions, and 2014). their views are considered and valued. Medical Nurses provide a key role in patient education, ethics must allow access to care for all, without providing pre- and post-transplant advocacy and discrimination of any kind. Medical confidential- counselling, planning hospitalisations and con- ity or patient freedom is part of the rules of medi- sultations and responding to patients’ telephone cal ethics. calls. They also act as educators and role models Constant advances in haematology have raised to nursing students where appropriate and share challenging ethical dilemmas concerning end of 4 Transplant Preparation 65 life, palliative care, patient information, donor Cancer invokes strong feelings and passions, concerns and impartiality and issues related to and it is not infrequent to find a conflict of inter- the risk we run to our patients. est between members of the family, members of In 2009, according to Langlois, ethical dilem- the health-care team and even members of the mas often experienced by oncology and HCST public as to whether to proceed with treatment or nurses include: not. Emmanuel Kant’s theory cited in Kemp Smith (1973) states that to act morally always • Therapeutic relentlessness – continuation of treat other human beings as ‘ends in themselves’ treatment, when the outcome is futile and never merely as ‘means’; by this Kant means • End-of-life intervention leading to death and that it is unethical to treat people as if they are euthanasia or cessation and withdrawal of objects. According to Kant it is fundamentally treatment immoral to exploit a person without considering • Transplantation in complex situation: refrac- them an end in their own right. In transplantation tory disease and older people where the side effects initially are extremely difficult and debilitating to the patient, it is some- To cope with the therapeutic pathway of the times difficult to justify such moral behaviour patient, nurses must understand these complex especially when nurses are striving not to inflict situations. Regular staff meetings with a psychol- harm and to promote good. ogist, palliative care unit and ethical committees What is often lacking, especially in nursing, is and internal discussion in transplant ward will the courage and confidence to go through with a allow nurses to better understand this complex moral decision, which is basically an issue of area by giving their nursing perspective to the personal moral development and personal integ- team. rity (Brykczynska 1997). It is the personal integ- Ethical competencies in the transplant team rity of a particular nurse that will effect a change allow us to solve new and unforeseen moral prob- for the better or worse for an individual patient lems by knowing how to innovate in order to find (Corner 1997). the most legitimate and fairest behaviour possible in the face of a specific contextual situation. The haematological pathway is often complex 4.11 Ethical Issues in Minors and uncertain. Treatments such as allogeneic HSCT can be associated with rapid changes in Parents may act to preserve fertility of cancer the care from curative to palliative (Howell patients who are minors if the child assents, and the 2010). intervention is likely to provide potential benefits The resolution of an ethical dilemma for the to the child. Parents may act to preserve reproduc- nurse is related to the level of professional com- tive options of minor children undergoing gonado- petence and understanding of the ethical con- toxic treatment as long as the minor assents, the cern allowing a better understanding of the intervention does not pose undue risk and the inter- context and of the complexity of the clinical vention offers a reasonable chance of net benefit to situation. Ensuring that fully informed consent the child (Ethics Committee, ASRM). is provided by the patient is ethical dilemma When the child is immature, the decision to which often occurs in medicine. Brykczynska cryopreserve (or not) may be taken by the par- (2000) identifies that the problem most often ents, unless it poses grave prejudice to the well- facing the haematology nurse regarding being/welfare of the child. The importance of informed consent is not a lack of understanding preserving the possibility of having genetically as to what constitutes ‘informed consent’, or related offspring in the future is generally recog- even how informed a patient needs to be for nised, and the parents will have to decide whether ‘informed consent’ to exist, but the vexed issue this benefit outweighs the current risk of inter- of conflict of interests. vention for their child. 66 C. Bompoint et al.

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Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Cell Source and Apheresis 5 Aleksandra Babic and Eugenia Trigoso

Abstract Peripheral blood stem cells have largely replaced harvested bone marrow stem cells both in the autologous and allogeneic settings. Advantages of peripherally harvested cells include higher stem cell dose, more rapid engraftment, reduced donor/patient discomfort, and better graft-versus- leukemia effect in the allogeneic setting. Within the apheresis machine, whole blood is separated into its components by centrifugation, and the red cell-depleted, stem cell-rich buffy coat is extracted for use as a stem cell product, simultaneously returning the other blood components back to the donor. Prediction of procedure length is based on the required cell dose target but still remains challenging. Moreover, the number of apheresis procedures needed should be as few as possible in order to reduce costs and patient/donor discomfort and to increase safety. The volume of blood which needs to be processed in order to collect an adequate number of stem cells depends on several factors such as method of stem cell mobilization, vascular access, and collection efficiency. Another issue to take into consideration is cell storage: according to GITMO’s study (Perseghin et al. 2014) in most Italian centers, even up to 83.4% correspond to useless storage and only the remaining 16.6% to useful storage. Therefore, SIdEM and GITMO proposed a policy for autologous HPC disposal that fulfills clinical, ethical, and economic criteria.

A. Babic (*) Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland e-mail: [email protected] E. Trigoso Paediatric Transplant Unit, Hospital Universitario y Politécnico LA FE, Valencia, Spain

JACIE standards on peripheral blood stem cell (PBSC) collection by apheresis require that collection, manipulation, and clinical use of peripheral blood stem cells must be validated and monitored rigorously. The validation procedure consists of systematic review of all apheresis procedures performed at the collection facility of a transplant program.

Keywords Stem cell source • Peripheral stem cell mobilization • SC mobilization and apheresis • Vascular access • Quality and apheresis

5.1 Cell Source: Where Do bility of multiple antigen-mismatched transplan- We Get the Cells From? tations where there is a lack of related or unrelated volunteer donor. UCB had limited use in adult Hematopoiesis refers to the production of all transplantation because of the small cell dose types of blood cells including formation, develop- collected which may result in greater risk of post- ment, and differentiation of blood cells. In adults, transplant opportunistic infection due to a longer hematopoiesis primarily occurs in bone marrow time to hematologic recovery and a higher risk of contained in the pelvis, sternum, vertebral col- primary engraftment failure. However, the use of umn, and skull. All blood cells are derived from “double cords” has to a certain extent amelio- progenitor stem cells – pluripotent stem cells. rated some of the difficulties by improving These cells have the capacity for unlimited self- engraftment times. Nevertheless, late infections renewal and the ability to differentiate into all remain a concern, and lack of available donor types of mature blood cells starting from the com- lymphocytes means that other products are often mon myeloid or the common lymphoid progeni- favored over UCB in some settings. tor (Fig. 5.1). This process occurs continually in Peripheral blood stem cells (PBSC) have order to maintain adequate concentrations of cir- largely replaced the bone marrow in both autolo- culating components necessary for normal gous and allogeneic transplantation setting. The immune system function and hemostasis. rapid engraftment kinetics of PBSC compared to Cells in the myeloid lineage, such as red blood the bone marrow is widely recognized. Median cells, platelets, and white blood cells, are respon- times to achieve an absolute neutrophil count sible for hemopoiesis (tissue nourishment, oxy- greater than 500/ul after autologous PBSC trans- genation, coagulation) and immune function plantation are approximately 11–14 days in such as innate and adaptive immunity. The lym- autologous setting (Klaus 2007). phoid lineage components, namely, T cells and B In allogeneic settings the choice of HSC prod- cells, provide the foundation for the adaptive uct source for transplantation may depend on immune system. donor availability. The appropriate donor selec- Hematopoietic stem cell (HSC) products for tion, quality control, and risk assessment are autologous or allogeneic transplantation are paramount not only for patient and donor safety available from bone marrow, peripheral blood, but also impact on transplant outcome. In the and umbilical cord blood (UCB) sources. Bone absence of a sibling HLA-identical donor, the marrow was the original source of cells for trans- search and identification of an unrelated donor plantation because of the easier process of collec- may take up to 5 months. Depending on recipi- tion. UCB has been found and established to have ents underlying disease and “urgency” for HSCT, an important role in treatment due to relative haploidentical donors or cord blood unit(s) might immunologic naiveté of the donor with the feasi- be selected (Ruggeri et al. 2015). 5 Cell Source and Apheresis 73

Haematopoietic stem cell

Differentiation Differentiation

Committed lymphoid precursor cells Committed myeloid precursor cells

IL-2 Epo SCF GM-CSF Cytokines IL-7 Tipo IL-3 IL-12 GM-CSF M-CSF IL-3 G-CSF additional

Monocyte/ Red blood B cell T cell Granulocyte Platelets Eosinophil macrophage cell

Differentiated cells

Fig. 5.1 Stem cell maturation cascade (Adapted from macrophage colony-stimulating factor, IL interleukin, EBMT NG (2009)) (Epo erythroprotein, G-CSF granulo- M-CSF macrophage colony-stimulating factor, SCF Stem cyte colony-stimulating factor, GM-CSF granulocyte- cell factor, Tpo thrombopoietin)

Nurses who assist patients during the donation 5.1.1 Cell Collection procedure should be particularly aware of factors that influence risk for donation which include: • Bone Marrow Collection The bone marrow is harvested from the poste- • Age rior iliac crest region under general or regional • Gender anesthesia in a hospital operating room. For • Low weight the healthy donor, the risk of serious compli- • Duration of procedure cation from either general or local anesthesia • Type of anesthesia (BM donation) is similar (Hoffman et al. 2008). With ade- • CD34+ cell dose requested quate fluid and sometimes blood replacement, • Vascular access (PBSC) overnight hospitalization is often not required. 74 A. Babic and E. Trigoso

Multiple aspirations are performed with volume of cord blood collected with earlier collection of approximately 5 ml of liquid clamping relating to greater collection vol- marrow blood from each puncture site. The umes. Cell dose is an important predictor of usual volume harvested from healthy donors outcome after UCB transplantation, and many is approximately 10–15 ml of marrow per cord blood units are discarded because of kilogram of recipient body weight in order to small cell doses. Greater cell quantities are achieve the desired CD34+ cell doses. This found for infants with greater birth weight, results in an average blood loss of 800– independent of gender and gestational age. 1000 ml for an adult donor. Some patients and Many cord blood banks reduce the volume of donors receive pre-donated blood transfusions the product by depleting red cells and plasma to alleviate symptoms of volume depletion in order to minimize storage space and reduce usually with preharvested autologous blood, possible infusion-related toxicities from but salt or colloid solutions are acceptable mature blood cells contained in unfractioned replacements too. Anesthesia and blood loss cord blood units. UCB will maintain viability present the greatest risk of serious complica- for period of at least 15 years if appropriately tions associated with bone marrow harvesting, cryopreserved (Hoffman et al. 2008; and therefore patients and marrow donors Schoemans et al. 2006). Allogeneic transplant must undergo a detailed medical examination access can be severely limited for patients of including questionnaire of health history. racial and ethnic minorities without suitable After confirming they wish to proceed to be a sibling donors. Whether umbilical cord blood donor, they are asked to sign the written con- (UCB) transplantation can extend transplant sent to undergo donation. access because of the reduced stringency of • Peripheral Blood Stem Cells (PBSC) required HLA match is not proven. The concentrations of hematopoietic stem Patients had highly diverse ancestries cells (HSC) in the peripheral blood are nor- including 35% non-Europeans. In Barker’s mally very low compared to 10–100 times article from 2010 (Barker n.d.), of 525 patients greater concentration in the bone marrow undergoing combined searches, 10/10 HLA- (EBMT NG 2009). Therefore it is necessary to matched URDs were identified in 53% of increase the circulating concentrations of HSC those with European ancestry but only 21% of for adequate PBSC collections. HSC mobiliza- patients with non-European origins. However, tion into the peripheral blood can be stimulated the majority of both groups had 5–6/6 UCB by different disease-related and relatively pre- units. Availability of UCB significantly dictable mobilization regimens. Rapid and extends allotransplant access, especially in widespread adoption of PBSC as a source of non-European patients, and has the greatest HSC for transplantation is due to rapidly avail- potential to provide a suitable stem cell source able results of CD34+ count by the laboratory. regardless of race or ethnicity. Minority Before commencing a leukapheresis, we count patients in need of allografts, but without suit- the number of CD34+ cells in peripheral blood, able matched sibling donors, should be and if the number is adequate, the collection referred for combined URD and CB searches procedure may be performed. to optimize transplant access. • Cord Blood Collection UCB is collected from the placental vein after infant delivery and transection of the cord. 5.2 Mobilization of Stem Cells UCB can be collected either by the obstetri- and Apheresis cian before delivery of the placenta or by laboratory personnel after delivery of the pla- Administration of hematopoietic cytokines, centa. The timing of cord clamping after such as granulocyte colony-stimulating factor delivery of the infant is associated with the (G-CSF), causes a transient increase (mobiliza- 5 Cell Source and Apheresis 75 tion) of HSC in the peripheral bloodstream and grastim) are the two forms of this cytokine enables the collection of adequate numbers of available for clinical use. PBSC for transplantation. In clinical practice, for autologous PBSC, the Pluripotent stem cells express the cell surface most frequent mobilization procedure is the marker antigen CD34 (CD34+ cells). Cytokine- administration of filgrastim in combination with mobilized PBSC components contain much chemotherapy. Nowadays we are observing greater numbers of cells expressing the CD34 increased use of mobilization regimens without antigen which then acts as a surrogate marker for chemotherapy (chemo-free mobilization regi- the engraftment capacity of the stem cell mens) in patients affected by multiple myeloma component. (Afifi et al. 2016).

5.2.1 Cytokines 5.2.2 The Role of CD34+

Several cytokines have been identified to play an CD34+ is the indicator most frequently used in important role in hematopoiesis. When progeni- clinical practice to determine the extent and effi- tor cells are exposed to these cytokines, the matu- ciency of peripheral blood stem cell collections ration cascade producing committed mature (Brando et al. 2000). Once specific cell dose tar- blood cell components can occur. Examples of gets are achieved, cell collections are completed important cytokines are listed in Fig. 5.1. These and stored for future use. Standard target levels cytokines are externally administered to patients can vary among treating centers, and a patient’s in an effort to enhance the yield of stem cells specific goal is based on the underlying disease, within a short time period. An example of such a the source of stem cells, and the type of trans- cytokine is glycosylated granulocyte colony- plant to be performed. In general, a target level of stimulating factor (G-CSF). 2 × 106 CD34+ cells/kg recipient body weight is Chemokines are a subset of cytokines and considered the minimum for transplant with opti- can induce activation and migration of specific mal levels being > 5 × 106 CD34+ cells/kg for a types of white cell and assist the process of stem single transplant and > 6 × 106 CD34+ cells/kg cells homing to the marrow compartment. Stem for a tandem transplant (Pierelli et al. 2012). cell CXCR4 is responsible for anchoring stem Peripheral blood stem cell is considered the cells to the marrow matrix through interactions preferred cell source due to patient convenience, with adhesion molecules such as stem cell- decreased morbidity, and faster engraftment of derived factor-1 alpha (SDF-1α). Blockade of white blood cells and platelets (Table 5.1). this receptor with a receptor antagonist such as Poor stem cell yields after mobilization might plerixafor has produced elevations of circulat- occur. The most important risk factor for inade- ing hematopoietic progenitor cells, which has quate mobilization is the amount of myelosup- aided stem cell collections in patients with mul- pressive chemotherapy a patient has received tiple myeloma and lymphoma “poor mobiliz- prior to their autologous collection. Agents which ers,” those not able to reach the sufficient are toxic to stem cells such as cyclophosphamide number of CD34+ cells for commencing a (doses > 7.5 g), melphalan, carmustine, procarba- leukapheresis. zine, fludarabine, nitrogen mustard, and chloram- Because of its efficacy compared to other bucil are particularly detrimental to stem cell cytokines and its low toxicity profile, G-CSF is collection yields. Other risk factors associated the cytokine most commonly used to increase with low CD34+ cell collections include advanced the level of myeloid progenitor cells in the age (> 60 years), previous radiation therapy, short blood. time interval between chemotherapy and mobili- Recombinant methionyl human G-CSF (fil- zation, extensive disease burden, and tumor infil- grastim) and recombinant human G-CSF (leno- tration of the bone marrow (Olivieri et al. 2012). 76 A. Babic and E. Trigoso

Table 5.1 A comparison between mobilization methods CD34+ cells to start apheresis. Those groups of Mobilization regimen Characteristics patients are defined “poor mobilizers.” In this Filgrastim Low toxicity case the use of plerixafor, CXCR4 antagonist that Outpatient administration reversibly inhibits the interaction between High efficacy in most patients CXCR4 and SDF-1, is needed. The use of plerix- Bone pain Lower stem cell yield compared afor in combination with G-CSF has been shown to filgrastim + chemotherapy to improve CD34+ cell collections in lymphoma Shorter time from and multiple myeloma patients (Olivieri et al. administration to collection 2012). compared to filgrastim + chemotherapy Because no single chemotherapy mobiliza- Filgrastim + Higher stem cell yield compared tion regimen has demonstrated superiority, chemotherapy to filgrastim alone some clinicians may elect to mobilize patients Fewer stem cell collections during a cycle of a disease-directed chemother- Potential for anticancer activity apy regimen. With this approach, examples of May impair future mobilization for stem cells regimens utilized have included cyclophospha- Highly toxic in many patients mide, doxorubicin, vincristine, and prednisone Inconsistent results (CHOP) and ifosfamide, carboplatin, and etopo- Longer time from side (ICE). administration to collection compared to filgrastim A comparison between mobilization methods Filgrastim + Low toxicity is listed on Tables 5.2, 5.3, and 5.4. plerixafor High efficacy in most patients Predictable mobilization permitting easy apheresis scheduling 5.2.5 PBSC Collection by Apheresis Gastrointestinal side effects Adapted from EBMT NG (2009) The quantity of CD34+ cells in a PBSC component varies greatly, and its achievement by apheresis procedure depends on: 5.2.3 Chemo-mobilization • Mobilization protocol Chemo-mobilization is a combination of myelo- • Patient condition suppressive chemotherapy with filgrastim which • Timing of the PBSC collection appears to work synergistically to mobilize HSC, • Equipment although the exact mechanism for this observa- • Operator-dependent technique tion has not been fully elucidated. Filgrastim is • Volume of blood processed thought to stimulate HSC mobilization by decreasing SDF-1 gene expression and protein The timing of PBSC collection has a critical levels while increasing proteases that can cleave role, and based on the mobilization regimen, interactions between HSC and the bone marrow we are able to appropriately schedule the environment. These growth factors are typically apheresis procedures. For growth factor mobi- given as subcutaneous injections at a total daily lization alone, the first collection procedure is dose of 3–24 mcg/kg/day. calculated on days 4–5 when the peak of CD34+ cell count is expected to be achieved. After mobilization with chemotherapy regi- 5.2.4 Alternative Mobilization mens and growth factor, the expected day can Strategies vary between days 12 and 15 (Pierelli et al. 2012). Despite different mobilization regimen attempts, The first day collection procedure is deter- some patients are not able to achieve enough mined by WBC count and CD34+ cell count. 5 Cell Source and Apheresis 77

Table 5.2 Advantages and disadvantages of hematopoi- Established thresholds for apheresis initiation etic stem cell collection methods may vary across centers but typically range from Collection 10 to 20 CD34+ cells/mL. Once mobilization has method Advantages Disadvantages reached an optimal level according to WBC and Bone marrow Single collection Performed in an CD34+ levels, a patient can attend their sched- No need for special acute care setting catheter placement as it requires uled sessions in the apheresis area. Optimized No need for growth general scheduling will avoid unnecessary collection factors anesthesia procedures and unnecessary PBSC processing Slower and will save freezing space. neutrophil and platelet The apheresis objective is to collect a product engraftment with requested PBSC counts with low cross cel- Associated with lular contamination in the smallest possible col- higher rates of lect volume (ideally 80–90 ml/bag) and in as few morbidity Peripheral Does not require Collection may procedures as possible. This will ensure cost blood general anesthesia take several days optimization and enhance patient comfort and and can be Sometimes safety. performed in an requires Clinical nurses working in the apheresis unit outpatient setting placement of Faster recipient large double are responsible for educating the patient about neutrophil and lumen catheter the stem cell collection process and monitoring platelet engraftment for collection patients for any adverse reactions. The apheresis Associated with Citrate toxicity nurse challenges are: lower rates of donor morbidity Tumor cell • To understand how and when to administer contamination of agents used in the mobilization process product may be less • To schedule mobilization regimen which Adapted from EBMT NG (2009) occurs with or without chemotherapy • To explain what medications the patient Table 5.3 Complications from chemotherapeutic agents should and should not take during commonly used for mobilization mobilization Chemotherapeutic agent • To expect adverse events and to be aware of or regimen Common side effects their management for all agents used in Cyclophosphamide Appetite loss mobilization Note: must be combined Color change in the skin with mesna Diarrhea • To manage venous access catheter used for administration Leukopenia apheresis Mouth sores • To be aware of the importance of laboratory Nausea, vomiting monitoring and how to manage electrolyte Skin rash Stomach discomfort or pain imbalances Texture change in nails • To be aware of stem cell collection target level Thrombocytopenia and options for patients who mobilize poorly Weakness or fail to mobilize Hemorrhagic cystitis Etoposide Myelosuppression Infusion-related side effects Patients are connected to the apheresis (such as hypotension, machine by their centrally or peripherally flushing, chest pain, fever, inserted venous catheters. One lumen is used to diaphoresis, cyanosis, urticaria, angioedema, and withdraw blood out of the patient and into the bronchospasm) machine. Here the blood is centrifuged in a bowl Nausea and vomiting housed within the cell separator machine. The Alopecia desired stem cells are then siphoned off before Adapted from EBMT NG (2009) 78 A. Babic and E. Trigoso

Table 5.4 Common apheresis complications Side effect Cause Signs and symptoms Corrective action Citrate toxicity Anticoagulant (citrate) Hypocalcemia Slowing rate of apheresis, given during apheresis Common: dizziness, tingling in increasing the blood/citrate hands and feet ratio, calcium replacement Uncommon: chills, tremors, therapy muscle cramps, tetany, seizure, cardiac arrhythmia Hypomagnesemia Slowing rate of apheresis, Common: muscle spasm or increasing the blood/citrate weakness ratio, magnesium Uncommon: decrease in replacement therapy vascular tone and cardiac arrhythmia Hypokalemia Slowing rate of apheresis, Common: weakness increasing the blood/citrate Uncommon: hypotonia and ratio, potassium cardiac arrhythmia replacement therapy Metabolic alkalosis Slowing rate of apheresis, Common: worsening of increasing the blood/citrate hypocalcemia ratio Uncommon: decrease in respiration rate Thrombocytopenia Platelets adhere to Low platelet count, bruising, Priming apheresis machine internal surface of the bleeding with blood products in apheresis machine place of normal saline, platelet transfusion Hypovolemia Patient intolerant of Dizziness, light-headedness, Slowing rate of apheresis large shift in tachycardia, hypotension, session or temporarily extracorporeal volumes diaphoresis, cardiac arrhythmia stopping, intravenous fluid boluses Catheter malfunction Blood clot forms or Inability to flush catheter, fluid Repositioning of catheter, catheter is not well collection under the skin around gentle flushing of catheter, positioned to allow for catheter site, pain and erythema treatment of blood clot adequate blood flow at catheter site, arm swelling, decrease in blood flow Adapted from EBMT NG (2009)

the remaining blood components are returned to teristics and mobilization regimen used the patient through the second lumen of their (Figs. 5.2 and 5.3). catheter. This second lumen can be used to administer intravenous fluids, electrolyte supplements, and medications to the patient if nec- 5.3 Vascular Access essary. Each apheresis session lasts approximately 2–4 h during which an average of Appropriate catheter selection and placement is 7–10 l of blood, or twice the average total human scheduled prior to the first stem cell collection blood volume, is exchanged or processed. (Toro et al. 2007). Catheters used for apheresis Collections can occur on a daily basis until tar- procedures must be able to tolerate large fluctua- get CD34+ levels are achieved, which can last tions in circulating blood volume on more than for up to 3–4 days depending on patient charac- one occasion. Peripheral catheters are preferred 5 Cell Source and Apheresis 79

Fig. 5.2 Frequently used apheresis machines (https://www.google.it/search?q=apheresis+machines&biw=1920&bih= 1018&tbm=isch&tbo=u&source=univ&sa=X&sqi=2&ved=0ahUKEwj2lui0gKvPAhUmLMAKHRDNAf8QsAQILQ)

In the absence of adequate peripheral veins, a large-bore, double lumen device can be inserted. These can be used temporarily during cell collections only, or they can be placed permanently and used throughout the transplant process. As with most centrally placed catheters, when placed in the area of the upper extremities, patients should be monitored for signs and symptoms of hypotension, shortness of breath, and decreased breath sounds as these can be indicative of venous wall perforation and require Fig. 5.3 Separation of components by G-force (https:// urgent attention. Hemothorax and pneumotho- www.google.it/search?q=separation+of+components+b y+G-force&client=safari&rls=en&source=lnms&tbm=is rax, which are rare but serious complications, ch&sa=X&ved=0ahUKEwiHmv36gKvPAhVbF8AKHU can occur and also require immediate attention. f8BVEQ_AUICSgC&biw=1920&bih=1018#tbm=isch& In some cases, catheters for apheresis may be q=apheresis+separation+of+components+by+G-force&i placed in a femoral vein. In case of catheter mgrc=dKciXWNMkHikzM%3A) positioning in the jugular vein, radiographic evaluation is used to verify catheter placement prior to clearance for its use. Instructions on where possible and placed in the cubital vein for caring for the catheter to prevent infection and drawing. If available, a port-a-cath or other previ- maintain patency should be extensively reviewed ously inserted central catheters can be used for with the patient and/or caregivers. Internal SOPs blood return. need to be observed. 80 A. Babic and E. Trigoso

5.4 Adverse Reactions or spasm, decreased vascular tone, and abnormal cardiac contractility. Oral and intravenous sup- Apheresis procedures are relatively safe for the plementation with magnesium and potassium is patient. While the procedure-related mortality often effective. rates are low at an estimated 3 deaths per 10,000 procedures, apheresis-associated morbidity is more frequently reported (Halter et al. 2009). 5.4.3 Hypovolemia

Because large fluctuations in blood volume can be 5.4.1 Citrate Toxicity experienced throughout each collection, patients are at risk of hypovolemia. Prior to starting the One of the most common adverse effects seen collection, baseline pulse and blood pressure during the cell collection process is citrate toxic- should be measured and continually rechecked at ity, frequently manifested by hypocalcemia. designated intervals of approximately 1 h. It is Sodium citrate is used during apheresis to prevent also recommended that hemoglobin and hemato- blood from clotting while it is being processed by crit be monitored after the procedure as well. the machine. Citrate is known to bind to ionized serum calcium leading to hypocalcemia. Signs and symptoms of this complication can include: 5.4.4 Risk Factors

• Burning Patients at risk for developing hypovolemia • Numbness and tingling in the extremities and/ include those with anemia, a previous history of or the area around the mouth cardiovascular compromise, and children or • Muscle twitching adults with a small frame. • Abdominal cramps • Shivering 5.4.5 Preventative Measures

5.4.2 Treatment Preventative measures are aimed at minimizing the extracorporeal volume shift by priming the Citrate toxicity complication can be managed by apheresis machine with red blood cells and fresh slowing the apheresis flow rate and providing frozen plasma in place of normal saline. patients with oral calcium supplements. In severe cases, intravenous supplementation of calcium may be given to the patient in order to prevent 5.4.6 Clinical Manifestations severe reactions such as tetany, seizure, and cardiac arrhythmia. Serum monitoring of calcium Clinical manifestations of hypovolemia can levels prior to each apheresis session is often help- include dizziness, light-headedness, tachycardia, ful in decreasing the likelihood of hypocalcemia. hypotension, and diaphoresis. Most concerning is Other effects stemming from citrate toxicity the development of a cardiac dysrhythmia which include hypomagnesemia, hypokalemia, and can be life-threatening. metabolic alkalosis. Magnesium, like calcium, is a bivalent ion that is bound by citrate. Declines in serum magnesium levels often are more pro- 5.4.7 Treatment nounced and take longer to normalize compared to aberrations in calcium levels. Signs and symp- Sessions should be interrupted and symptoms toms of hypomagnesemia are muscle weakness should subside before proceeding with collec- 5 Cell Source and Apheresis 81 tions. Hypovolemia may also be managed with this time point including past medical history, providing intravenous fluid boluses and slowing cancer status, summary of cancer treatments and the rate of flow on the apheresis machine. response, and complications experienced during therapy. Accompanying this information are any available radiographic information and labora- 5.4.8 Thrombocytopenia tory testing results. After review of the patient’s medical information, the transplant team will ini- Thrombocytopenia is another complication tiate their own procedure-specific tests and evalu- encountered during stem cell collections. When ations to assess a patient’s eligibility to proceed the patient’s blood is in the cell separator with stem cell collection and transplant. This machine, platelets can stick to the bowl used dur- involves restaging the patient to verify or estab- ing the centrifuge process. Decreases in platelet lish their current disease status, ascertaining the concentrations can be precipitous, and obtaining function of various organ systems (e.g., renal, platelet counts prior to each collection is hepatic, pulmonary, etc.), documenting the essential. absence of certain comorbid conditions and diseases (e.g., the presence of human immunodeficiency virus), and evaluating the overall 5.4.9 Treatment performance status and psychosocial condition of the patient. If platelet levels are low, patients may receive a platelet transfusion prior to the procedure. Also helpful, but not necessarily therapeutic, in man- 5.5.2 Patient Education aging thrombocytopenia is returning the collected platelet-rich plasma to the patient at the Education of the patient and their respective fam- conclusion of the collection session. ily and/or caregivers is integral to preparatory phase. Often a member of the nursing profession (clinic nurse, nurse educator, or nurse coordinator) will coordinate the education process for the 5.5 Patient Assessment patient and carers. and Preparation

Prior to initiation of the stem cell collection pro- 5.5.3 Donor Assessment cess, patient candidates for autologous transplan- and Preparation tation procedure must be thoroughly evaluated and determined fit to be able to tolerate all Allogeneic related or non-related donors are sub- involved procedures. mitted initially to interview and medical history questionnaire evaluation, including vaccination and travel history, blood transfusion, and risk for 5.5.1 Medical Assessment transmission of communicable disease together with physical and psychological exams that The medical evaluation is the first step that a involves multidisciplinary teamwork and coordi- patient must complete when undergoing treat- nation as well. ment. This involves the patient’s primary medical The risks of donation shall be evaluated, dis- oncologist making a referral to a transplant cen- cussed, and documented as a possible need for ter or service. The physician provides the trans- central venous access, the risk of hemoglobinop- plant team with information which often includes athy prior to administration of the mobilization specifics relating to the care of the patient up to therapy for collection of HPC, apheresis, and 82 A. Babic and E. Trigoso vascular access or anesthesia for collection of may be achieved by evidence of in-service train- HPC by bone marrow harvesting. ing, attendance at conferences, etc. While initial Allogeneic donor eligibility, as defined by supervised training is easily documented, annual applicable laws and regulations, shall be deter- competency maintenance can be difficult to dem- mined by a physician after history, exam, medical onstrate. Ongoing training for clinical personnel record review, and testing. The donor eligibility should reflect their experience, individual com- determination shall be documented clearly in the petencies and proficiencies, orientation for new recipient’s medical record before the recipient’s staff, and necessary training. Training also needs preparative regimen is initiated and before the to be undertaken in a timely manner to demon- allogeneic donor begins the mobilization regimen strate annual updating (Babic et al. 2015). (EBMT NG 2009; Pierelli et al. 2012; JACIE n.d.). The collection procedure shall be explained in terms the donor can understand the risks and ben- 5.7 Cell Source and Apheresis efits of the procedure, tests and procedures per- in the Pediatric Population formed, and the rights according to applicable laws and regulations. Alternative collection Abstract Hematopoietic stem cell transplanta- methods need to be explained, and confidentiality tion has become a well-established treatment for must be guaranteed (EBMT NG 2009; JACIE many malignant and nonmalignant disorders in n.d.). The donor shall have the right to refuse to children. Small body weight, venous access, and donate but shall be informed of the potential con- ethical dilemmas in minors represent a challenge sequences to the recipient of such refusal. in the pediatric population. Informed consent from the allogeneic donor shall be obtained by a licensed health-care profes- Keywords Apheresis • Cell source • Children sional who is not the primary health-care profes- • Pediatric population sional overseeing care of the recipient.

5.7.1 Introduction 5.6 Quality in Apheresis During the past three decades, bone marrow FACT-JACIE International Standards Accreditation transplantation and transplantation of peripheral (sixth edition) (JACIE n.d.) requires that the clini- blood stem cells have become a well-established cal program has access to personnel who are for- treatment for many malignant and nonmalignant mally trained, experienced, and competent in the disorders in children and in adult patients (Bader management of patients receiving cellular therapy. et al. 2005). The Apheresis Collection Facility shall be licensed, Research has shown a continued and constant registered, or accredited as required by the appro- increase in the annual numbers of hematopoietic priate governmental authorities for the activities stem cell transplant (HSCT) and transplant rates performed. The quality management plan should (number of HSCT/10 million inhabitants) for include, or summarize and reference, policies and both allogeneic and autologous HSCT (Passweg standard operating procedures addressing person- et al. 2013). nel requirements for each key position in the Indications for pediatric HSCT have changed Apheresis Collection Facility. considerably during the last 7 years. These changes provide tools for decision-making in health-care planning and counseling (Miano 5.6.1 Training and Competencies et al. 2007). There is accumulating evidence of the role of Core competencies are specified within the hematopoietic SCT in non-hematological disor- JACIE standards, and evidence of training in ders such as autoimmune diseases (Sureda et al. these competencies must be documented. This 2015). 5 Cell Source and Apheresis 83

Some common nonmalignant diseases treated matched related donor grafts (Bensinger et al. N with hematopoietic stem cell transplant are (Nuss Engl J Med. 2001). More pediatric patients et al. 2011): receive BM than PBSC, irrespective of donor type. This is explained by the higher incidence of • Hematologic (severe aplastic anemia, Fanconi nonmalignant conditions and the higher risk for anemia, thalassemia, sickle-cell disease, chronic GvHD with peripheral blood as a stem Diamond-Blackfan anemia, Chédiak-Higashi cell source (Passweg et al. 2013). syndrome, chronic granulomatous disease, The bone marrow remains the most common congenital neutropenia) graft source for unrelated donors accounting for • Solid tumors (Ewing’s sarcoma, soft tissue 49% in 2013. The use of umbilical cord blood is sarcoma, neuroblastoma, and Wilms’ tumor, declining steadily, after peak in 2009, from 46% where there is high risk or 4CR1, osteogenic to 32% of all unrelated donor transplants per- sarcoma, and brain tumors) formed in this age group (Sureda et al. 2015). • Immunodeficiency (severe combined immuno- However, the recently completed NMDP/ deficiency disease, Wiskott-Aldrich syn- CIBMTR randomized study of unrelated marrow drome, functional T-cell deficiency) versus PBSC, which included pediatric patients, • Genetic (adrenoleukodystrophy, metachro- found that there were no significant differences in matic leukodystrophy, Hurler syndrome, mortality between recipients of PBSC compared Hunter disease, Gaucher syndrome) to the bone marrow. –– Cell Source in Pediatric Population The donor’s preferences must also be taken into account as there are differences in the side There are three commonly used sources of effects experienced by the donors from a BM or hematopoietic stem cells: PBSC harvest (Sureda et al. 2015; Pasquini and Zhu 2016). • BM From 2012 onward, there was an increase in • Cytokine-mobilized PB progenitor cells the numbers of transplants from other relatives, (PBSC) which is likely due to rapid adoption of the strat- • UCB cells egy of posttransplant cyclophosphamide in the haploidentical setting. In 2014, the numbers of The proportion of autologous to allogeneic transplants using other relatives surpassed the HSCT is different in pediatric population (29% total numbers of umbilical cord transplant per- autologous) compared with adults (62% autolo- formed in the USA, accounting for 11% of all gous) and is mainly used for treating solid tumors allogeneic transplants performed in the USA (Passweg et al. 2013). (Pasquini and Zhu 2016). Stem cells may be collected from the bone marrow (BM), peripheral blood, or umbilical cord blood (UCB). Each of these sources has several advantages and disadvantages. Box: Bone marrow stem cell source in Despite the increased use of peripheral blood nonmalignant diseases in pediatric and umbilical cord blood, BM is the primary population graft source in pediatric patients. • The BM remained the preferred source For children and adolescents aged 8–20, allo- of stem cells for allogeneic transplants geneic transplantation of HLA antigen-identical for nonmalignant disorders (62%). For sibling peripheral blood stem cells is associated diseases that do not require graft- with higher mortality than the bone marrow versus-tumor effect, such as aplastic (Eapen, et al JCO 2004). In contrast, previous anemia, sickle-cell disease, or meta- work showed that peripheral blood was superior bolic disorders, many consider it advan- to the bone marrow as a stem cell source for adult tageous to use the bone marrow. and adolescent (aged 12–55) recipients of 84 A. Babic and E. Trigoso

• Concerns about tolerable anticoagulant doses Disadvantages include the need for gen- • Limitations in product volumes that can be eral or epidural anesthesia and the risk safely collected of infection, bleeding, and bone damage. Also this population, although a Therefore, in many countries worldwide, chil- minority, is still a significant minority dren under the age of 18 years are not allowed to that includes a number of unique diag- donate hematopoietic stem cells (HSCs) for unre- noses such as the hemoglobinopathies, lated recipients (Sörensen et al. 2013). immune deficiencies, immune dysregu- Adequate peripheral vascular access is diffi- lation, and metabolic diseases, all of cult to find in young children, so we often need to which are not common or present at all consider a central apheresis catheter placement in the adult HSCT population (Passweg with its attendant risks. et al. 2013). Placement of central venous catheter (5–7 Fr with double offset lumens) is widely used for apheresis procedure; therefore, some PBSC donors receive a general anesthesia, and others Annual numbers for allogeneic transplants in have conscious sedation. pediatric population demonstrate increase in the The apheresis team must consider the size and overall utilization of alternative donors. type of catheter that will yield the highest flow From 2003 to 2011, there was a steady rate during apheresis, as well as patient or donor increase in the numbers of transplants using comfort. Often the catheter used for apheresis umbilical cord blood as a result of several pub- may be used for venous access during the high- lished studies demonstrating its benefit in both dose therapy, reinfusion of stem cells, and recov- children and adults. ery phases. We should try to avoid adverse events Umbilical cord blood (UCB) characteristi- such as pain, hemorrhage, and inadequate seda- cally differs from the marrow in a number of tion. A trained team in pediatric apheresis is ways. The median doses of total nucleated cells mandatory as well as central line placement by (TNC), CD34+ cells, and CD3+ cells in UCB ultrasound technique. unit are approximately ten times lower than that of a bone marrow graft (Moscardo et al. 2004; Barker and Wagner 2003). 5.7.3 Key Differences: Pediatric The indications for the use of UCB as a source vs Adult for stem cells in children are identical to the indications for matched unrelated donor transplants Apheresis procedure in children differs from (Sureda et al. 2015). adult in device (machine set) priming. Priming of the apheresis circuit with heterologous packed red blood cells is widely under- 5.7.2 Apheresis in Pediatric taken where donors weigh less than 20 kg. We Population should consider the risk of heterologous blood product administration in healthy donors – such Experience with pediatric stem cell apheresis as transfusion reaction and the risk of system collections is limited. Challenges of apheresis in overload if primed blood for some reason is rein- small children (<20 kg) include: fused. Usually we prime with RBC cross- matched, irradiated and leukocyte-depleted in • Small total blood volume patient and prime with 4% albumin solution in • Vascular access issues donors. 5 Cell Source and Apheresis 85

In the pediatric setting, the most common where donors were with smaller body weight adverse event is pain, observed after central than recipient and at higher risk for requiring a venous catheter (CVC) placement for PBSC col- blood transfusion, additional apheresis proce- lection. Pain at the site of puncture occurs more dures, pain, and cardiovascular complications frequently in donors with a central (58%) than after anesthesia. Most pediatric physicians who peripheral vein access (38%) (Hequet, 2015). perform transplants believe it is acceptable to Often reported side effects after pediatric apher- expose minors to the risks of a stem cell donation esis are: when donation offers a substantial prospect of benefit to a close family member and when • Hematoma formation proper consent is obtained (often from parents of • Hypotension and cyanosis both, donor and recipient). • Allergic reaction to red blood cells The key issue that must be addressed with • Thrombocytopenia childhood HSC donors is their initial inability to understand and to voluntarily consent the proce- Rare side effects reported are: dure. Understanding increases as they age into an ability to assent and then finally to legally con- • Low-grade fever during the mobilization sent. Because HSC donation can benefit their sib- • Hypovolemic signs: tachycardia >120 (most ling more than any other tissue sources and cases), hypotension, systolic blood pressure < because the procedure can be performed with 80 mmHg, pallor, and diaphoresis limited risk, sibling donation under parental con- • Nausea related to citrate effects during the sent has been considered appropriate to date apheresis procedure (Bitan et al. 2016). Summarizing: In the absence of consensus and in order to prevent signs and symptoms of hypocalcemia, some • Advocacy and medical review of donors by centers administrate orally calcium gluconate (adult individual(s) without dual responsibility to the patients), and some centers routinely replace cal- recipient are recommended. cium i.v. during the entire apheresis procedure • Regarding the relationship between a pediat- (mostly in pediatric apheresis). Nurses who perform ric donor and a family recipient, it is pediatric procedures need to achieve competence in recommended to focus on avoiding psycho- machine settings to allow the proper anticoagulation logical harm rather than predicting whether of the patient during the procedure (ACD-A or hepa- donation will result in a psychological benefit rin or combination anticoagulation). The nurse must to the donor. be competent in blood priming and in use of diluted • Pediatric donors may be considered for or undiluted packed red blood cells, in prevention of research that carries minimal risk above the hypocalcaemia and fluid balance, etc. standard procedure or studies aimed at improving the safety and efficacy of the donation process. 5.7.4 Ethical Dilemmas • Donors with medical conditions that may The approach to minor donors is different in increase the risk of complications associated many countries. with donation are not ever to be considered fit for donation. A donor is a person, no matter how small • Centers should always avoid performing (Styczynski et al. 2012; Pulsipher et al. 2005). human leukocyte antigen typing on potential Styczynski and colleagues compared donor donors with medical/psychological reasons and recipient children’s age, both being small not to donate (Bitan et al. 2016). 86 A. Babic and E. Trigoso

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Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Principles of Conditioning Therapy and Cell Infusion 6

Sara Zulu and Michelle Kenyon

Abstract Prior to haematopoietic stem cell transplant (HSCT), conditioning therapy is used for disease eradication, creation of space for engraftment and immunosuppression. Conditioning therapy includes combinations of chemotherapy, radiotherapy and/or immunotherapy. Chemotherapy is delivered in different phases: induction, consolidation and maintenance. Total body irradiation (TBI) is widely used as part of conditioning regimens preceding allogeneic HSCT and is able to target sanctuary sites where some drugs cannot reach. Cancer immunotherapy treatment harnesses the body’s natural defences to fight the cancer, by involving components of the immune system. Conditioning therapy can have acute and chronic side effects due to the toxicity of the treatment. Nursing implications involve patient education and information, toxicity assessments, close monitoring and action plans. Stem cell infusion is usually a safe procedure but can cause adverse reactions ranging from flushing and nausea to life-threatening reactions. There should be written policies for the administration of cellular therapy products, and nurses must have training and competency in order to safely administer haematopoietic stem cells.

Keywords Haematopoietic stem cell transplant • HSCT • Conditioning therapy Chemotherapy • Total body irradiation • TBI • Immunotherapy • Stem cell infusion

S. Zulu (*) 6.1 Conditioning Cancer Services, Royal Free Hospital, London, UK e-mail: [email protected] Conditioning therapy in haematopoietic stem cell M. Kenyon transplant (HSCT) is central to the preparation or Department of Haematological Medicine, King’s College Hospital NHS Foundation Trust, ‘conditioning’ of the patient for the transplant. London, UK The three main goals of conditioning therapy are:

Table 6.1 Examples of myeloablative, non-myeloablative and reduced intensity regimens Myeloablative Non-myeloablative Reduced intensity Bu/Cy/Mel Flu/Cy/ATG Flu/Bu (busulfan, cyclophosphamide, (fludarabine, cyclophosphamide, ATG) (fludarabine, busulfan) melphalan) TBI/TT/Cy Flu/TBI Flu/Mel (TBI, thiotepa, cyclophosphamide) (fludarabine, TBI) (fludarabine, melphalan) Cy/VP/TBI TLI/ATG Flu/Cy (cytarabine, etoposide, TBI) (total lymphoid irradiation, ATG) (fludarabine, cytarabine) Adapted from EBMT-ESH Handbook

1. Eradication of disease 4. G2 phase—Further protein synthesis occurs 2. Creation of ‘space’ in the bone marrow for preparing the cell for mitosis; this phase lasts donor stem cells to engraft from 2 to 10 h. 3. Immunosuppression to decrease the risk of 5. M phase—The cell splits into two new cells. rejection of the donor cells by the host cells This phase lasts about 30–60 min.

Conditioning therapies include combinations There are three different means of classifying of chemotherapy, radiotherapy and/or immuno- chemotherapy drugs: according to their cell cycle therapy, using different regimens. The aim of activity, their chemical groups or their mode of conditioning regimens is to reduce relapse and action. This chapter will focus on the mode of rejection and can be fine-tuned to reduce action classification, which is summarised in the treatment-related mortality. This can be done table below. with ‘reduced intensity’ or non-myeloablative regimens which are less toxic or with myeloablative regimens which are a higher dose to wipe out 6.2.1 Combination Chemotherapy or ‘ablate’ the marrow (see Table 6.1). As previously mentioned all cells go through five phases during the reproduction cycle. Certain 6.2 Chemotherapy cytotoxic chemotherapy drugs work only at a specific phase of the cycle, whilst other drugs are Dividing cells such as bone marrow stem cells not phase specific. In cytotoxic drug combination proliferate and replicate in order to retain their with synergy like pre-BMT conditioning function. Cytotoxic chemotherapy works by (Table 6.2), it is logical to attack multiple phases destroying rapidly dividing cells, including of the cell replication cycle to prevent mutation malignant cells. This is done by preventing the and resistance from occurring. Combination che- cells from dividing or by causing cell death motherapy allows for maximum cell kill, as each (apoptosis) during different phases of the cell drug targets cells independently at different cycle. stages of the cell cycle. If the toxicities of the The cell cycle comprises of five phases: combination chemotherapy drugs do not replicate, the optimal dose could be administered 1. G0 phase—This is the resting phase which without the high-grade toxicities. can last for months. 2. G1 phase—This is the growth phase, where RNA and protein synthesis occurs. 6.2.2 Cycles and Scheduling 3. S phase—DNA is replicated so that when the cell divides, the new cell will have a copy of Chemotherapy is administered in cycles accord- the genetic information. This phase lasts from ing to a schedule, in order to allow for recovery 18 to 20 h. of the bone marrow and immune system after 6 Principles of Conditioning Therapy and Cell Infusion 91

Table 6.2 Chemotherapy classifications according to their mode of action Cytotoxic classification Mode of action Examples Alkylating agents They prevent replication by substituting alkyl Melphalan groups for hydrogen atoms in cells. This causes Iphosphomide the DNA strands to break leading to mutation or Busulfan cell death Antimetabolites These agents disrupt cellular metabolism Methotrexate resulting in disrupted DNA and apoptosis. Act Cytarabine in the S phase of the cell cycle Fludarabine Antitumor antibiotics They inhibit synthesis and replication by Daunorubicin binding to DNA and RNA Doxorubicin Plant alkaloids These are extracts from the pink periwinkle Vincristine plant. They bind to microtubular proteins Vinblastine causing apoptosis acting mainly in the M phase These agents are derived from the root of the Etoposide mandrake plant and act in the G2 and S phase interfering with topoisomerase II enzyme reaction Miscellaneous They cause lysis of lymphoid tumours. Act in Corticosteroids the G0 phase of the cell cycle Enzymes (L-asparaginase) Rituximab causes lysis of T- lymphocytes that Monoclonal antibodies (rituximab) have the CD20 antigen on their cell surface. Adapted from EBMT-ESH Handbook (2012) administration (Brown and Cutler 2012; Grundy 6.2.3 Modes of Administration 2006). Malignant cells are expected to have a lengthier time to recover than normal cells. In Cytotoxic therapy can be delivered via different this way, by scheduling the treatment, ‘normal’ routes. The four most used in HSCT are: cells can recover from toxicity, whilst the malignant cells will be reduced with continued cycles 1. Intravenous (IV): This is the most common of treatment. Administration of chemotherapy in route of administration in HSCT. The drug is cycles allows for the possibility of a larger dose delivered directly into the blood stream via a of drugs to be given over a short period of time. cannula or a central venous access device. In leukaemia and lymphoma treatment, che- Risks to IV administration include extravasa- motherapy is usually divided into different phases: tion and chemical phlebitis (chemical reaction to the vein causing hardening of the view or • Induction: The first aim of the treatment is to cording). achieve remission. Chemotherapy is admin- 2. Subcutaneous: This is administered as an injec- istered in order to eradicate the malignant tion under the skin. Risks include irritation to cells. the surrounding tissue, trauma (which could be • Consolidation (intensification): After remis- due to low platelet count) or infection. sion is achieved, further treatment is given 3. Oral: This route is usually self-administered. in order to prevent a recurrence of malig- It is important that the patient is able to swal- nant cells. Consolidation chemotherapy can low, has sufficient manual dexterity and is include radiotherapy or a stem cell compliant. Risks including vomiting after a transplant. given dose can reduce bioavailability. • Maintenance: Treatment is given in order to 4. Intrathecal (IT): This is administration by ‘maintain’ remission and prevent relapse. lumbar puncture into the cerebrospinal fluid to Maintenance treatment may include che- treat or prevent disease in the central nervous motherapy, hormone therapy or targeted system (CNS). Intrathecal administration can therapy. be fatal if the incorrect type of cytotoxic agent 92 S. Zulu and M. Kenyon

is used, i.e. vinca alkaloids. National guidance either on their side or in a lateral position at a cal- has been publicised for the safe administration culated distance from the machine. TBI is deliv- of IT chemotherapy. ered in various doses and scheduling. The dose can be single (1–8 Gy total dose), fractionated (10–14 Gy total dose over 3 days) or hyperfrac- 6.2.4 Side Effects and Nursing tionated (14–15 Gy total dose over 4 days). As Implications with chemotherapy scheduling, fractionated doses of TBI minimise toxicity (Apperly et al. 2012). • Chemotherapy side effects can be acute or Some centres use lead shielding blocks to pro- chronic. tect parts of the body such as the lungs and eyes; • Chemotherapy not only destroys malignant however, shielding organs could potentially cells but also rapidly dividing ‘normal’ cells. shield leukaemic cells, so many centres opt not to The ‘normal’ cells that are most frequently do this. affected include bone marrow cells, hair follicles, mucosal lining of the GI tract and skin, fertility and germinal cells. 6.3.2 Side Effects and Nursing • Nursing implications involve patient educa- Implications tion and information, toxicity assessments, close monitoring and action plans. Side effects of TBI can be acute or chronic. As • Chapters 9 and 10 discuss acute complications TBI is usually given in combination with chemo- and supportive care in more detail. therapy, it can be difficult to differentiate between the causes of the toxicities. Immediate side effects of TBI include bone marrow suppression, 6.3 Radiotherapy alopecia, nausea, vomiting, parotid swelling and erythema. Radiotherapy in HSCT is used as part of lym- Chronic side effects of TBI include cataracts, phoma treatment, as prophylaxis and treatment of infertility and interstitial pneumonitis. Nursing disease and as palliative treatment for myeloma implications involve patient education and infor- and lymphoma. Radiotherapy uses ionising radi- mation, toxicity assessments, close monitoring ation to control or kill malignant cells. and action plans (Apperly et al. 2012). Chapters 9 and 10 discuss acute complications and supportive care in more detail. 6.3.1 Total Body Irradiation

Total body irradiation (TBI) alongside high-dose 6.4 Immunotherapy chemotherapy helps to kill off leukaemia, lymphoma or myeloma cells in the bone marrow. The immune system has a natural ability to detect This allows the patient to be in a preparation and destroy abnormal cells and in doing so pre- phase to receive the donor stem cells as part of vents the development of many cancers. the recovery stage of the treatment. However, cancer cells are sometimes able to TBI is widely used as part of myeloablative, avoid detection and destruction by the immune reduced intensity and non-myeloablative condi- system by using a variety of strategies. tioning regimens preceding HSCT. As well as Cancer cells may: eradicating disease, immunosuppressive effect and creating space for donor cells to engraft; TBI • Reduce the expression of tumour antigens on is able to target sanctuary sites such as the CNS their surface, making it harder for the immune or gonads where some drugs cannot reach. system to see them Most centres use a linear accelerator machine • Express proteins on their surface that inacti- as a source of radiation. Patients are positioned vate or neutralise immune cells 6 Principles of Conditioning Therapy and Cell Infusion 93

• Encourage cells in the surrounding environ- An emerging form of ACT is chimaeric anti- ment to release substances that suppress gen receptor (CAR) T-cell therapy. A patient’s T immune responses and help to promote cells are collected from the blood and modified to tumour cell growth and survival express CAR protein. These cells are grown in the laboratory to produce large numbers of CAR T cells, which are then infused back into the 6.4.1 Cancer Immunotherapy patient. In the blood, the CAR T cells bind to the can- This is a type of cancer treatment that is designed cer cells, become activated and attack and destroy to harness the body’s natural defences to fight the them. cancer by involving or using components of the immune system. Some cancer immunotherapies consist of anti- 6.4.1.3 Therapeutic Antibodies bodies that bind to, and inhibit the function of, Therapeutic antibodies are ‘drug’-based antibod- proteins expressed by cancer cells. Other cancer ies produced to destroy cancer cells. immunotherapies include vaccines and T-cell One group of therapeutic antibodies is called infusions. antibody–drug conjugate (ADC). An antibody is A number of approaches are described briefly connected to a toxic ingredient such as a drug, below. toxin or radioactive substance. When the antibody–drug conjugate (ADC) binds to the cancer 6.4.1.1 Immune Checkpoint Blockade cell, it is absorbed, and the toxic substance is Immune checkpoints are pathways embedded released killing the cell. into the immune system that keep immune Not all therapeutic antibodies are connected to responses in check. They help to limit the strength toxic substances. Some antibodies cause cancer and duration of immune responses and prevent cells to commit suicide (apoptosis), and others strong responses that might damage normal as can make the cancer cells more recognisable to well as abnormal cells. Tumours appear to hijack certain immune cells (complement) and help to certain immune checkpoint pathways and their facilitate cell death. proteins and use them to suppress normal immune responses. This therapy targets the immune checkpoint 6.4.1.4 Therapeutic Cancer Vaccines pathways so that when the immune checkpoint Another approach to immunotherapy is the use proteins are blocked, the ‘brakes’ on the immune of cancer vaccines. These vaccines are usually system are released and it behaves normally once made from a patient’s own cancer cells or from again and destroys the cancer cells. substances produced by cancer cells. It is Immune checkpoint blockade with antibodies intended that when a vaccine containing cancer- that target cytotoxic T-lymphocyte-associated specific antigens is injected into a patient, these antigen 4 (CTLA-4) and the programmed cell antigens will stimulate the immune system to death protein 1 pathway (PD-1/PD-L1) has attack cancer cells without causing harm to nor- shown promising results in a variety of mal cells. malignancies.

6.4.1.2 Immune Cell Therapy Further Reading Adoptive cell therapy (ACT) is a treatment that uses a cancer patient’s own T cells. These cells http://www.nature.com/ are collected from the blood of the patient and Search on: then grown in the laboratory or expanded in vitro. Cancer Reviews. These cells are activated by treatment with cyto- Immunology Reviews. kines and then infused back to the patient. 94 S. Zulu and M. Kenyon

6.5 Paediatric Considerations fessional, it should be done by a nurse. Preparations should be started well in advance to Conditioning allow the patient and parents ask questions. It is There are differences between adult and paediat- possible to listen to music or fairy tales whilst ric patient’s conditioning. Children can generally having TBI. Immobilisation is a prerequisite for tolerate side effects better than adults, and higher accurate radiotherapy, so anaesthesia is required doses may be used. On the other hand, condition- for younger children. ing regimens affect growth and endocrine development of the child. Studies so far indicate that reduced intensity 6.6 Stem Cell Infusion conditioning (RIC) in haematopoietic cell transplantation may have an important role in treating Haematopoietic stem cells (HSCs) can be pro- children with primary immune deficiencies: such cured from the patient (autologous) or from a regimens can be used without severe toxicity in donor (allogeneic or cord blood). patients with pre-transplant infections or severe HSCs procured from the patient are almost pulmonary or hepatic disease. RIC has extended always sourced from peripheral blood during the role of allogeneic transplantation to many apheresis (see Chap. 5). patients who until recently were considered ineli- HSCs procured from a donor can be sourced gible for this procedure (Chiesa and Veys 2014). from the peripheral blood (apheresis), bone mar- Disease-specific treatment protocols can be row or umbilical cord. found, for example, in the EBMT Handbook 2012, After harvesting, HSCs can be stored using Chap. 20. Chemotherapy and radiation therapy side cryopreservation. Dimethyl sulfoxide (DMSO) is effects will be discussed in more detail in Chap. 8. a common cryopreservative used in the storage of HSCs.

6.5.1 Chemotherapy 6.6.1 Adverse Reactions Children in general tolerate side effect better than adults, so higher total doses may be used (Satwani An adverse reaction is a noxious and unintended et al. 2008). response suspected or demonstrated to be caused When treating paediatric patients’ prescrip- by the collection or infusion of a cellular therapy tions should be made by body surface area (BSA) product or by the product itself. mg/m2 or mg/kg using recent weight and height. The stem cell infusion is a generally safe procedure, but it can cause a variety of adverse reactions ranging from flushing and nausea to 6.5.2 Total Body Irradiation life-threatening reactions. It is imperative that the healthcare team is trained for early identifi- TBI has severe side effects when administered to cation and managing of possible adverse reac- children and adolescents, and it should be tions. Nurses must obtain baseline vital signs avoided, whenever possible. The risk for second- including temperature, breath sounds, pulse ary malignancies is significantly higher com- oximetry, weight and fluid status prior to the cell pared to pharmacological conditioning (ALL). infusion. Most teams use conditioning regimens (AML) Possible adverse reactions are: that do not involve TBI (EBMT Handbook 2012). When TBI is used, it is commonly given in Fresh stem cells fractions (two doses per day) to minimise the side Allergic reaction effects. Haematolytic transfusion reaction Paediatric patients need age-appropriate Fluid overload preparation for radiotherapy. This can be done Micropulmonary emboli by the play therapist, but if there is no such pro- Infection 6 Principles of Conditioning Therapy and Cell Infusion 95

Preserved stem cells order to minimise interruption to the stem cell Bad taste in the mouth, nausea and vomiting infusion and also ensure safety for the patient. (DMSO) Arrhythmia hypertension Psychological support Day zero can be a Haemoglobinuria momentous occasion for someone who requires a Allergic reaction stem cell transplantation. Patients may experi- Haemolytic transfusion reaction ence a range of emotions, from elation through to Fluid overload distress, anxiety, vulnerability and helplessness. Micropulmonary emboli Using simple techniques such as discussing the Infection (Costa et al. 2014; Tomlinson and Kline procedure, and listening and offering reassurance 2010; Truong et al. 2016; Vidula et al. 2015) may help to reduce patients anxiety.

6.6.2.2 During Stem Cell Infusion 6.6.2 Nursing Care: Pre-, During IV line care Ensure aseptic non-touch technique and Post Stem Cell Infusion is used to prevent the risk of infection.

6.6.2.1 Pre-infusion Assessment Physiological monitoring Should be carried out Maintain a safe environment Ensure that your at least every 10–15 min and increased if there are patient is prepared and the room is organised out any concerns with the patients’ condition during the in a way that you have access to the patient and infusion. O2 saturations are monitored constantly you have access to everything you need includ- during infusion. Treat problems as they arise (i.e. ing oxygen and suction. The patient should be drop in saturations, give O2 as prescribed). nursed on a bed during the stem cell infusion, in case of severe allergic reaction. Assess for potential side effects Patients can have mild to severe reactions to a stem cell infu- Baseline observations Record baseline obser- sion. Autologous stem cells tend to be cryopre- vations in order to assess the patient’s physiologi- served. Patients can experience allergic reactions cal status during and post infusion. including nausea, flushing, rash, chest tightness, shortness of breath and chills. For anaphylaxis, Preparing patient for transfusion If patients are follow your centre guidelines for managing an receiving cells previously cryopreserved with anaphylaxis event. For other side effects, the DMSO, they should receive a premedication with infusion can be slowed down according to how antihistamine, corticosteroids, antipyretics and the patient tolerates the infusion. Reassure the anti-emetics. The nurse should discuss the proce- patient and treat the side effects as they occur. dure including length of time, how they may feel and what to tell the nurse if they experience any of 6.6.2.3 Post Stem Cell Infusion the common side effects. Encourage your patient to Physiological monitoring Assess for later tell you how they feel during the entire procedure, effects of the cell infusion. Observations should to ensure adverse incidents are spotted, to offer be performed half hourly for the next 2 h, then reassurance or to ensure side effects are managed. hourly for another 2 h, and four hourly thereafter.

IV line care Check the IV line for patency. On Documentation Document the care event in the whole, patients undertaking a stem cell infu- patients’ medical records, and complete the cell sion will have a permanent, central line in situ. infusion record. Common lines used for this treatment are PICC lines and Hickman lines. Ensure aseptic non-touch technique is used to prevent the risk of infection. 6.6.3 JACIE Standards

Toileting Discuss with the patient and encour- The JACIE process has been explained in detail age toileting prior to starting the procedure in in Chap. 1. JACIE Standards give instruction 96 S. Zulu and M. Kenyon on how to safely administer the product. Nurses Costa Bezerra Freire N, et al. Adverse reactions related must have training and competency for admin- to hematopoietic stem cell infusion. J Nursing UFPE Online. 9:391–8. istration of cellular therapy products. There FACT-JACIE international standards for hematopoietic shall be also written policies for administration cellular therapy, 6th ed. 2015.; www.jacie.org of cellular therapy products (JACIE Standards Grundy M. Nursing in haematological oncology. 2nd ed. B3.7). Edinburgh: Ballière Tindall; 2006. Mulay SB, et al. Infusion technique of hematopoietic pro- There shall be a policy addressing safe admin- genitor cells and related adverse events. Transfusion. istration of cellular therapy products. These poli- 2014;54:1997–2003. cies should determine the appropriate volume Satwani P, Cooper N, Rao K, et al. Reduced intensity and dose of red cells, cryoprotectants and other conditioning and allogeneic stem cell transplantation in childhood malignant and non-malignant diseases. additives and volume of ABO-incompatible red Bone Marrow Transplant. 2008;46:173–82. cells in allogeneic cellular therapy products. Two Tomlinson D, Kline NE, editors. Pediatric oncology nurs- qualified persons shall verify the identity of the ing: advanced clinical handbook. 2nd ed. New York/ recipient, the product and the order for adminis- Dordrecht/Heildelberg: Springer; 2010. Truong TH, Moorjani R, Dewey D, Guilcher GMT, tration (JACIE standards B7.6). Prokopishyn NL, Lewis VA. Adverse reactions during For more detailed information, please visit the stem cell infusion in children treated with autologous www.jacie.org and allogeneic stem cell transplantation. Bone Marrow Transplant. 2016;51:680–6. Vidula N, et al. Adverse events during hematopoietic stem cell infusion: analysis of the infusion product. Clinical Lymphoma, Myeloma And Leukaemia. References 2015;15:e157–62.

Apperly J, Carreras E, Gluckman E, Masszi T, The EBMT handbook. 6th ed. Paris: European School of Haematology; 2012. Further Reading Brown M, Cutler T. Haematology nursing. Hoboken, NJ: Wiley-Blackwell. 2012. Pan London Guidelines for the Safe Prescribing, Chiesa R, Veys P. Reduced-intensity conditioning for Handling and Administration of Systemic Anti Cancer allogeneic stem cell transplant in primary immune Treatment Drugs. www.londoncanceralliance.nhs.uk. deficiencies. Expert Rev Clin Immunol. 8:255–67. Good practice guide for pediatric radiotherapy, Children’s Published online: 10 Jan 2014. Download citation cancer and leukaemia group, Society and college of https://doi.org/10.1586/eci.12.9 radiographers, The Royal College of Radiologists, 2012.

John Murray, Iris Agreiter, Laura Orlando, and Daphna Hutt

Abstract Despite improvements over the past several decades, infection remains a significant risk to all haematological patients receiving therapy. Those requiring allogeneic transplant and especially those that have HLA disparity or T-cell-depleted grafts have an even higher risk of infective complications due to delayed recovery of T- and B-cell function. Early identification with prompt effective treatment is paramount to improve all patients’ survival. Patient safety through robust adherence to hand hygiene and maintenance of the environment with cleaning and disinfection are the backbone of an effective preventative program. Basic nursing care and a sound knowledge base of the risks, presentation, diagnosis and treatment will improve patient care.

Keywords Viral infection • Bacterial infection • Fungal infection • Handwashing Isolation

J. Murray (*) Haematology and Transplant Unit, The Christie NHS 7.1 Introduction Foundation Trust, Manchester, UK e-mail: [email protected] Infection is a major cause of mortality and mor- I. Agreiter bidity in the haematopoietic stem cell transplant Department of Haematology and BMT Unit, Hospital (HSCT) population due to regimen-related toxic- San Maurizio, Bolzano, Italy ity. Improvements over the past couple of decades e-mail: [email protected] especially in supportive care have helped to L. Orlando reduce this risk. The development of neutropenic Division of Haemato-oncology, European Institute of Oncology, Milan, Italy fever is a frequent occurrence, and centres have e-mail: [email protected] algorithms for identifying and treating infection D. Hutt promptly. In this chapter we will discuss the Department of Pediatric Hematology-Oncology and common viral, bacterial and fungal infections BMT, Edmond and lily Safra Children Hospital, that our transplant patients develop. Sheba Medical Center, Tel-Hashomer, Israel e-mail: [email protected]

Phase III: late phase Phase I: pre-engraftment Phase II: post-engraftment

Graft-versus-host-disease: acute Chronic

Impaired cellular and Neutropenia, barrier humoral immunity; NK cells Impaired cellular and breakdown (mucositis, recover first, CD8 T cell humoral immunity; B cell central venous access numbers increasing but & CD4 T cell numbers recover devices) restricted T cell repertoire slowly and repertoire diversifies

Gram negative bacilli

Gram positive organisms Encapsulated bacteria

Bacterial Gastrointestinal streptococci species Less conmmon

Herpes simplex virus Cytomegalovirus Respiratory and enteric viruses (Seasonal/intermittent) Varicella zoster virus Vira l Other viruses eg. HHV EBV PTLD

Aspergillus species Aspergillus species More conmmon Candida species

Funga l Pneumocystis

Day 0 Day 15–45 Day 100Day 365 and beyond

Fig. 7.1 Phases of opportunistic infections among allogeneic HCT recipients. HHV6 human herpesvirus 6, NK natural killer, PTLD post-transplant lymphoproliferative disease (Mackall et al. 2009)

Mackall et al. (2009) displays the variety of 7.2.1 Cytomegalovirus infections in Fig. 7.1 that may occur and the approximate timeframe for their development 7.2.1.1 Introduction which aids the clinical team to refine and direct Cytomegalovirus (CMV) disease is a serious investigations and potential treatments potential complication of allogeneic stem cell appropriately. transplantation leading to life-threatening complications. CMV is usually acquired in childhood. It is a virus that is present worldwide, and whilst in developed countries approximately 7.2 Viral Infections 50% of the population is seropositive, this rises to almost 100% in developing countries. CMV is Viral infection is spread by close contact with shed intermittently from the oropharynx and infectious secretions, either by large particle from the genitourinary tract of both immunocom- aerosols, formites or subsequent self-inoculation. petent and immunosuppressed people. Prior to Coughing and sneezing will produce aerosol par- allograft the serostatus (IgG) of the patient and ticles, and a virus can also be picked up after con- potential donors are assessed to gauge risk (Zaia tact with contaminated surfaces. et al. 2009). 7 BMT Settings, Infection and Infection Control 99

CMV belongs to the human herpesvirus fam- Risk Factors for Primary CMV Infection ily HHV5 and comes from the subfamily Betaherpesvirinae. Betaherpesvirinae infects • Person-to-person transmission the mononuclear cells, establishes latency in the • Low risk in use of blood not screened negative leukocytes and once reactivated replicates for CMV (Meijer et al. 2003) slowly. CMV is able to lie dormant for pro- tracted lengths of time, and immunity to the 7.2.1.2 Presentation CMV complex involves both the humoral and CMV can occur as a primary infection or as a cell-mediated pathways. Patients treated with reactivation of the previously latent virus. When stem cell transplantation in the context of hae- a CMV IgG-negative patient develops CMV, this matological malignancies can reactivate the is termed a primary infection. When a patient, or latent virus, either from native host leucocytes, donor, is known to be CMV antibody positive from those derived from the donor, or from and then develops CMV, this is termed reactiva- both. The risk of reactivation varies dependent tion. The diagnosis of CMV disease requires the upon the patient and/or donor’s previous expo- presence of symptoms and signs compatible with sure to CMV. CMV status can be shown as end-organ damage, together with the detection of follows: CMV. If left untreated, asymptomatic CMV Risk factors for reactivation infection can progress to CMV disease.

Recipient Donor 7.2.1.3 Diagnosis High risk Positive Negative It is important to diagnose reactivation early and Medium risk Negative Positive institute timely treatment; therefore regular mon- Medium risk Positive Positive itoring of CMV levels is of paramount impor- No risk Negative Negative tance. Polymerase chain reaction (PCR) is the most sensitive and quantitative method of moni- The patient’s CMV status is indicated on the toring at-risk patients especially in the early post- left and donor CMV status on the right. transplant period (until at least day 100 Careful measures are taken to minimize the post-transplant) and longer in those on systemic risk of primary infection with CMV when pre- immunosuppression. scribing blood products in allograft patients. All CMV infection most commonly affects the blood products should be obtained from CMV- lung, gastrointestinal tract, eye, liver or central seronegative donors and leukocyte depletion. nervous system, with CMV pneumonia being the Risk Factors for CMV Reactivation most serious complication with >50% mortality (Tomblyn et al. 2009). • CMV serostatus of recipient/donor (+/− or All bone marrow transplant patients and +/− > > −/+) donors will have their CMV status tested in clinic • Previous CMV reactivation pre-transplant along with the CMV status of the • Time post-transplant – increased in early post- donor. transplant period (to day 100) • T-cell-depleted transplant conditioning proto- 7.2.1.4 Monitoring and Surveillance cols (e.g. Campath 1-H) For disease monitoring post-transplant, all • Systemic immunosuppression (particularly patients who are seropositive themselves or corticosteroids, antibodies directed against whose graft is seropositive must receive twice T-cells, e.g. ATG/Campath 1-H) weekly (if an in-patient) monitoring of CMV lev- • Recipient age – increased in older patients els by whole blood (EDTA sample) for PCR (or • Graft versus host disease (GvHD) once weekly in the outpatient setting). This mon- 100 J. Murray et al. itoring must continue whilst the patient is consid- usually confined to those with low-level reactiva- ered high risk of reactivation; the first 100 days tion around log 3. post-transplant or until systemic immunosuppression has been discontinued, and there is no Treatment with Ganciclovir and evidence of graft versus host disease. Valganciclovir, Dosing and Administration for Nursing Staff 7.2.1.5 Treatment For detailed instructions consult the summary of Treatment of CMV reactivation will be under- product information at website address taken following two consecutive positive CMV http://emc.medicines.org.uk/emc/assets/c/ PCR levels at, or greater than, the limit of sensi- html/displaydoc.asp?documentid=3497 tivity, 500 copies/ml or one result of greater than http://emc.medicines.org.uk/emc/assets/c/ 1000 copies/ml (or depending on local policy). html/displaydoc.asp?documentid=9315 Treatment will also be initiated regardless of (accessed 28/7/17) PCR if signs of organ-specific disease are identi- The normal dose for ganciclovir is 5 mg/kg fied. Some centres may adopt a policy of preemp- given every 12 h by intravenous infusion in tive treatment; please refer to your own institution 100 ml normal saline over an hour, rounded guidelines for advice. dose to the nearest 25 mg. The drug is an irri- The treatment regimen is often undertaken as tant; it is alkaline and may cause chemical phle- an in-patient. In which case, first-line therapy is bitis, so care should be taken to observe the with intravenous ganciclovir 5 mg/kg twice daily cannula and ensure that it is functioning well for a minimum of a week. Second-line treatment prior to each use. may be given if there is significant ganciclovir- The normal dose for valganciclovir is 900 mg related bone marrow suppression (neutrophil taken every 12 h orally. Valganciclovir is the oral count less than 1) or treatment failure with rising prodrug of ganciclovir, so the same consider- viral levels or evidence of viral resistance after at ations should be made as when using least 1 week of treatment. ganciclovir. Second- and third-line treatment is with fos- Both ganciclovir and valganciclovir should be carnet 90 mg/kg twice daily and cidofovir 5 mg/ used with caution in patients with impaired renal kg weekly for 2 weeks followed by fortnightly function; there is additive toxicity in patients tak- until negative. Foscarnet may be adopted as a ing other nephrotoxic drugs (e.g. ciclosporin, first-line treatment if the patient reactivates amphotericin B). In such patients, the dose should within the first month of transplant when blood be adjusted and must not be given or used together counts have not fully recovered as it is less with imipenem-cilastatin due to the increased myelotoxic than ganciclovir. It does, however, risk of convulsions. have more renal complications, and regular elec- Ganciclovir and valganciclovir treatment trolyte replacement is often required. commonly results in cytopenias, and extreme Similarly, cidofovir leads to renal impairment, caution should be applied when using it in and a urine sample should be tested prior to infu- patients with impaired bone marrow function sion for the presence of protein. If proteinuria is (neutrophils <1 × 109/l or platelets <50 × 109/l), greater than 2 on dipstick, or renal function has and the drug is contraindicated with severely deteriorated (please refer to hospital/unit guide- impaired bone marrow function (neutrophils lines), then cidofovir should not be given. <0.5 × 109/l or platelets <25 × 109/l). Dose adjust- In asymptomatic patients, or in those with ment must be made if there is any degree of renal viral levels responsive to the above treatments impairment. Creatinine clearance must be calcu- that are fit for discharge, oral therapy with val- lated, using the Cockcroft-Gault equation for ganciclovir may be used. Outpatient use of val- dosing decisions or another formula at your own ganciclovir in asymptomatic reactivation is institution. 7 BMT Settings, Infection and Infection Control 101

Toxicity in renal function. Electrolyte disturbance occurs Teratogenicity has been shown in animal models frequently with low magnesium, calcium, phos- and therefore care should be used in handling the phate and potassium most commonly requiring drug. It should not be administered by pregnant regular monitoring at least once daily whilst on staff. Bone marrow suppression is very common, treatment and following therapy. Hypocalcaemia and blood counts should be monitored daily dur- complicating the use of foscarnet has been impli- ing therapy and visualized prior to infusion. cated in patients developing seizures on therapy. Patients with significant cytopenias should be Local irritation to veins may occur, and it is treated with haemopoietic growth factors and/or advised that central venous access should be used discontinuation of therapy if growth factor sup- if possible together with maintenance of good port is not available or clinically safe. A patient hydration and diuresis during treatment. Local developing a cytopenia must be discussed with ulceration in the genital area may also occur in the treating consultant for a clinical decision to both men and women, and patients should be be made with regard to continuation of therapy. informed of this at the start of treatment and Gastrointestinal toxicity is common with nau- asked to be vigilant and inform staff if and when sea, vomiting and diarrhoea and should be this occurs. Strict hygiene should be advised to recorded. Other drugs, e.g. ciclosporin, ampho- reduce risk of skin ulceration. tericin B or MMF, may also potentiate the toxic- Gastrointestinal toxicity is common with nau- ity of ganciclovir; for further details consult the sea, vomiting and diarrhoea. CNS toxicity is not SmPC email link or discuss with your pharmacist infrequent, and patients may suffer with head- or lead clinician. ache, dizziness, anorexia and altered mental state. Haematological toxicity is also common and Treatment with Foscarnet Dosing and mainly results in anaemia; leucopenia is less Administration common, whilst thrombocytopenia occurs For detailed instructions consult the summary of infrequently. product characteristics http://www.medicines.org.uk/emc/medi- Treatment with Cidofovir Dosing and cine/174 (accessed 28/7/17) Administration The normal dose is 90 mg/kg given every For detailed instructions consult the summary of 12 h by intravenous infusion. The drug is an irri- product characteristics tant; it is alkaline and causes chemical phlebitis; http://www.mhra.gov.uk/spc-pil/? therefore it must be diluted if administered via a prodName=CIDOFOVIRTILLOMED 75 MG/ML peripheral vein; the undiluted solution (24 mg/ CONCENTRATE FOR SOLUTION FOR ml) may be used if administered via a central INFUSION&subsName=CIDOFOVIR DIHYDR venous catheter. ATE&pageID=SecondLevel (accessed 28/7/17) Foscarnet should be used with caution in The normal dose is 5 mg/kg given once weekly patients with impaired renal function; there is by intravenous infusion for two doses, as an additive toxicity in patients taking other nephro- induction, and then given twice weekly as a toxic drugs, e.g. ciclosporin and amphotericin maintenance. Maintenance treatment starts B. To minimize the risk of renal impairment, an 2 weeks after completion of induction therapy additional 500 ml of fluid (saline or dextrose) and will continue until clearance of virus. Often should be co-administered with each dose of the first dose is given as an in-patient, and further foscarnet. doses are given in outpatients if well staffed with appropriate training. Toxicity Cidofovir is markedly nephrotoxic and if Nephrotoxicity is a major side effect, with damage occurs this is often irreversible. As such 12–30% of patients showing a significant decline cidofovir is contraindicated in patients with pre- 102 J. Murray et al. existing renal dysfunction. Renal toxicity occurs adult population by the age of 40 years. It is an frequently during treatment, and renal function enveloped and double-stranded DNA virus and must be monitored closely; deterioration is likely human herpesvirus 4 (HHV4). Primary infection to necessitate discontinuation of therapy. There is with EBV usually results in mild, self-limiting additive toxicity in patients taking other nephro- illness of the oropharynx in childhood and the toxic drugs, e.g. ciclosporin and amphotericin B. clinical syndrome of infectious mononucleosis in To minimize renal toxicity, hydration and pro- adults and is often asymptomatic. benecid must be administered with each dose of During the primary infection, an immunocom- cidofovir. In patients with hypersensitivity to petent individual will mount a vigorous response. probenecid or sulpha-containing drugs, cidofovir Once the initial infection has cleared, the linear is likely to be contraindicated; such cases must be EBV genome becomes circular forming an epi- discussed with the treating consultant before ini- some in infected B cells and becomes established tiating therapy. as a latent infection awaiting reactivation. This Cidofovir also frequently causes non-dose- has relevant implications for clinical approaches dependent neutropenia, although this may resolve as antiviral agents such as ganciclovir inhibit the spontaneously whilst continuing on treatment. replication of the linear EBV-DNA but are inef- Dose interruption is not mandatory in patients fective against episomal DNA. These drugs developing neutropenia although the risk benefit therefore fail to prevent B-cell proliferation and of continued treatment in such patients must be are of no clinical use in treatment plans (Rasch discussed with the treating consultant or trans- et al. 2014). plant physician. Epstein-Barr virus post-transplant lymphoproliferative disease (EBV-PTLD) results from Toxicity outgrowth of EBV-infected B cells that are nor- Renal dysfunction is the major dose-limiting tox- mally controlled by an effective EBV-specific icity and may be irreversible. Eighty percent of cytotoxic T-cell response that occurs in the patients develop proteinuria due to tubular dys- immunocompromised host (Deeg and Socie function whilst on therapy. Gastrointestinal tox- 1998; Heslop 2009). PTLDs are classified as icity is common with nausea and vomiting. either early-onset lesions which develop within Haematological toxicity is common and is mainly 1 year or late onset occurring greater than a year neutropenia. Alopecia, uveitis and fever are also post-transplant (Ibrahim and Naresh 2012). frequently observed during treatment with cidofovir but resolve on discontinuation. 7.2.2.2 Presentation There are currently several new emerging and Manifestations drugs for the treatment of CMV although these The clinical manifestations of PTLD vary widely have so far not shown superiority to the above and may include nonspecific symptoms such as four drugs following phase 1 and 2 clinical trials. fever, malaise, sweats, weight loss and in some These newer therapies include maribavir, brin- cases obvious enlargement of lymphoid tissue cidofovir and letermovir. Another option for (Ibrahim and Naresh 2012). those patients who are difficult to treat could be Post-transplant lymphoproliferative disease the use of CMV-specific CTLs. Unfortunately, (PTLD) is a rare but potentially life-threatening they are expensive and difficult to obtain. disease with an incidence of 1–11% and a mortality of >80% in the pre-rituximab era (Landgren et al. 2009). It is defined as a lymphoid prolifera- 7.2.2 EBV tion or lymphoma that develops as a consequence of immunosuppression in a recipient of a solid 7.2.2.1 Introduction organ or bone marrow transplant. The immuno- Epstein-Barr virus (EBV) is a latent herpesvirus suppression required to preserve graft function that is thought to infect as much as 95% of the post-transplant leads to an impairment of T-cell 7 BMT Settings, Infection and Infection Control 103 immunity. This allows an uncontrolled prolifera- 1. Early lesions tion of EBV-infected B cells. This results in Are those that show features when biopsied of monoclonal or polyclonal plasmacytic hyperpla- infectious mononucleosis and plasmacytic sia, B-cell hyperplasia, B-cell lymphoma or hyperplasia. These are the first signs in the immunoblastic lymphoma. Immune surveillance spectrum of PTLD diagnosis. is impaired; the balance between latently infected 2. Polymorphic PTLD B-cell proliferation and the EBV-specific T-cell Comprises small- and medium-sized lympho- response is disrupted and leads to the infected B cytes and Reed-Sternberg-like cells. cells developing into PTLD (Heslop 2009). Underlying cell structure is destroyed and The early detection of EBV viral load by poly- may show malignant features. merase chain reaction (PCR) in whole blood is 3. Monomorphic PTLD widely accepted as the preferred method of mon- Comprises large lymphocytes and plasma itoring patients and should commence on the day cells that are uniform in appearance with most of cell infusion. Viral levels should be monitored being B cells with a clonal abnormality. weekly for 3–6 months and longer in those with 4. Classic Hodgkin lymphoma GvHD or on immunosuppression. Those at This is a rare form of PTLD usually found in greater risk are recipients of T-cell-depleted renal transplant patients HSCT, HLA mismatches or patients conditioned (Swerdlow et al. 2008). with antithymocyte globulins (Landgren et al. In practice, a clear separation between the dif- 2009). Other risk factors that have been identified ferent subtypes is not always possible; early as predictive for the development of PTLD lesions, polymorphic PTLD and monomorphic include recipient pre-transplant EBV seronega- PTLD probably represent a spectrum of diseases tivity and donor EBV seropositivity (Styczynski (Parker et al. 2010). More recently Styczynski et al. 2009). et al. (2009) published definitions of EBV that It is presumed that EBV is transmitted from are in common use across Europe. donor to recipient via the graft at a time of considerable immunosuppression for the recipient, EBV-DNA- Detection of EBV-DNA in the blood emia: or the patient develops primary EBV infection Primary EBV EBV detected in a previously unrelated to donor EBV status. It is therefore infection: EBV-seronegative patient advisable if possible to choose a seronegative Probable Significant lymphadenopathy (or other donor if one is available. Reactivation is common EBV disease: end-organ disease) with high EBV but does not always lead to end-organ disease blood load, in the absence of other requiring treatment (Styczynski et al. 2009). aetiologic factors or established diseases Cohen (1991) reviewed cases of PTLD in the Proven EBV (PTLD or other end-organ disease): literature involving renal, cardiac, heart-lung, disease: EBV detected from an organ by biopsy liver and bone marrow transplantation. Allogeneic or other invasive procedures with a test bone marrow transplantation-related PTLD had with appropriate sensitivity and specificity together with symptoms an incidence of 1.6%. This was much higher if the and/or signs from the affected organ patient had received mismatched T-cell-depleted bone marrow (24%) or if the patient had received anti-T-cell monoclonal antibodies for graft versus 7.2.2.3 Diagnosis host disease (17%). The mean time interval from Early diagnosis is important so that treatment can transplantation to a diagnosis of PTLD was be initiated promptly. The exact copy or log num- 5 months, with the majority by 3 months. ber to commence therapy has not yet been fully The pathological diagnosis of PTLD is based established. Action from a blood test alone is not on the WHO classification and includes four indicated and should be in parallel with clinical main categories and is the basis for the UK BCSH symptoms such as fever and lymphadenopathy guidelines: and imaging studies (Heslop 2009). 104 J. Murray et al.

Whether PTLD presents as localized or dis- graft rejection. Those who are significantly fur- seminated disease, the tumours are aggressive and ther away from transplant may reduce the EBV rapidly progressive and often are fatal. Clinical load by removal of immunosuppression alone. presentation is very variable and includes fever Rituximab has been shown to improve outcome (57%), lymphadenopathy (38%), gastrointestinal when initiated early as it targets B-cell-specific symptoms (27%), infectious mononucleosis-like surface antigens present on the EBV-transformed syndrome that can be fulminant (19%), pulmo- malignant cells. Rituximab is a chimeric murine/ nary symptoms (15%), CNS symptoms (13%) human monoclonal anti-CD20 antibody. As CD20 and weight loss (9%). Patients may report fever, cells are not only expressed on malignant cells, weight loss, anorexia, lethargy, sore throat, swol- normal B cells are destroyed in a patient who will len glands, diarrhoea and abdominal pain, short- already be immunocompromised and may lead to ness of breath, neurological symptoms or other viral infections. The effect of rituximab on symptoms that initially would not suggest a diag- the B-cell compartment can be up to 6 months fol- nosis of PTLD. CNS involvement is of particular lowing treatment and should therefore be used concern as it offers a dismal prognosis (Deeg and with caution and under strict surveillance in spe- Socie 1998). cialist centres. Failure to respond to single-agent The most common sites for involvement are rituximab leads to the option of chemotherapy in the lymph nodes (59%), liver (31%), lung (29%), the form of CHOP (cyclophosphamide, doxorubi- kidney (25%), bone marrow (25%), small intes- cin, vincristine and prednisolone). tine (22%), spleen (21%), CNS (19%), large Additional options such as adoptive T-cell bowel (14%), tonsils (10%) and salivary glands therapies are still unavailable in many centres, (4%). T-cell lymphoproliferative disorders not but some series of studies suggest that this may associated with EBV infection tend to occur at offer response to those in whom standard ritux- extranodal sites. imab has failed. EBV-specific cytotoxic T cells (CTL) aim to selectively restore the impaired 7.2.2.4 Monitoring immune function by the adoptive transfer of Reactivation usually occurs in the first 6 months EBV-specific cytotoxic T cells. CTLs can be gen- and up to 1 year post-transplant and is predomi- erated by using EBV-infected lymphoblastic cell nantly derived from donor B cells before reconsti- lines to sufficiently stimulate donor-derived T tution of the EBV-specific cytotoxic T-lymphocyte cells, expand them over a 3–4-week period and response but can occur later if patients are still then give to the patient. This is a time-consuming heavily immunosuppressed, e.g. when taking process and one that the patient can often not ciclosporin (Kuriyama et al. 2014). wait for. A quicker process for rapidly generating CTLs by overnight stimulation of donor mono- 7.2.2.5 Treatment nuclear blood cells with EBV-specific peptides, Withdrawal of immunosuppression in the first selection of Ag-specific T cells by IFN-gamma instance and if patients are still positive then surface capture assays and subsequent immuno- treatment with rituximab monoclonal antibody magnetic selection has been developed although (anti-CD20) once a CT scan and if possible not widely available. There is an associated high biopsy has been taken is the standard therapy for risk of developing acute or chronic GvHD post transplant PTLD. infusion, and so risk benefit should be discussed The removal of immunosuppression to restore with the patient (Rasch et al. 2014). immune response is usually not effective for Rituximab is given by IV infusion and is not a treating those who develop PTLD very close to vesicant. It is initially given slowly to reduce the their transplant date due to their profound immu- risk of a reaction with each subsequent cycle nosuppressed state. The regenerating immune given quicker as tolerated. A reaction to ritux- system is not able to recover fast enough to eradi- imab is thought to be mediated by a cytokine cate the malignant cells. It also carries a risk of release from both normal and malignant B cells. 7 BMT Settings, Infection and Infection Control 105

The most common adverse events (AEs) with The evidence for the relationship between rituximab include infusion reactions, the major- HHV6 positivity and encephalitis is not conclu- ity of which are mild to moderate (grades 1 and sive especially as HHV6 is often asymptomatic. 2) in nature. Seventy-seven percent of any grade Clinically patients present 2–6 weeks post infusion reactions occur during the first infusion, allograft with delirium, amnesia, confusion, and the incidence decreases with each subse- ataxia and seizure. During the transplant process, quent infusion. These infusion reactions gener- HHV6 has been cited by Zerr et al. (2005) to ally resolve with the slowing or interruption of cause a delay in engraftment with up to 60% the infusion and with supportive care. The inci- more platelet requirements in those who become dence of grade 3 or 4 infusion-related events in positive. patients is reported to be 9% for the first infusion of rituximab. The majority of severe reactions 7.2.3.4 Diagnosis occur approximately 30–120 min after starting Memory loss is cited as the most common fea- the first infusion. ture; this can develop to confusion and then finally to unconsciousness. HHV6 may accompany the syndrome of inappropriate antidiuretic 7.2.3 HHV6 hormone (SIADH). On magnetic resonance imaging (MRI) of the head, there are hyperin- 7.2.3.1 Introduction tense lesions noted, and these are referred to as Human herpesvirus 6 (HHV6) is a ubiquitous post-transplant acute limbic encephalitis (PALE). virus, and more than 90% of the population over Upon examination of the cerebrospinal fluid the age of 2 years are seropositive as it is easily (CSF), HHV6 DNA is observed. For a confirmed passed person to person via saliva. It is usually diagnosis to be made, the gold standard would be latent and is commonly reactivated in approx. tissue biopsy. This is impossible in the acutely 30–70% of post-allogeneic stem cell transplant unwell post-transplant patient, and therefore the patients. accepted approach is PCR testing of CSF and the exclusion of other causes for the patient’s 7.2.3.2 Risk symptoms. Those at increased risk are HLA mismatches, and those on corticosteroid therapy for GvHD and 7.2.3.5 Treatment highest of all are umbilical cord (UCBT) Foscarnet and ganciclovir are the recommended allografts with an incidence of 9% compared to treatments and should be started as soon as pos- 1% in BM or PBSC recipients. It is postulated sible following symptoms suggestive of HHV6 that the higher incidence is due to the lack of (Ogata et al. 2015). memory T cells in the UCBT against HHV6 that are present in adult donors. 7.2.4 Pneumocystis jirovecii 7.2.3.3 Presentation HHV6 may be associated with the development 7.2.4.1 Introduction of encephalitis in 1–11% of patients and also in Pneumocystis jirovecii (PCP) is an atypical fun- some reports of pneumonia (Zerr et al. 2005). gus that causes severe pneumonia in immuno- HHV6 can be divided into two groups HHV6 compromised patients. Recognized as a protozoan variants A and B. Primary infection with HHV6B initially and reclassified in 1988 as a fungus, causes exanthema subitum (roseola infantum) in pneumocystis cannot be propagated in culture, infants, whilst the role of HHV6A in disease is and few treatment options exist for those with not yet fully explored (Ljungman et al. 2000). PCP pneumonia. It is ubiquitous with almost uni- HHV6 typically reactivates earlier than cytomeg- versal seropositivity by 2 years of age (Thomas alovirus post allograft. and Limper 2004). The accepted belief for 106 J. Murray et al.

contracting PCP was as a reactivation of a latent homogenous and diffuse as the disease pro- virus. However, evidence suggests that PCP may gresses. Computed tomography (CT) scans show occur following recent infection and may also be extensive ground-glass attenuation or cystic transmitted person to person. Many hospital poli- lesions (Thomas and Limper 2004). cies do not mandate isolation, but a pragmatic approach is often taken, and HSCT recipients 7.2.4.4 Diagnosis should avoid exposure to those with proven PCP Patients have a 50% mortality associated with the (Gea-Banacloch et al. 2009). development of PCP; prompt diagnosis and treatment are warranted with adherence to prophylac- 7.2.4.2 Risk Factors tic cover. Due to the difficulties of culturing It is recommended that all allograft patients are samples, the diagnosis of PCP is made through adequately covered with prophylaxis for PCP for at microscopic examination of sputum or bron- least 6 months and up to 1 year or more if on immu- choalveolar fluid or by polymerase chain reaction nosuppression with combination trimethoprim- (PCR). sulfamethoxazole (TMP-SMX) as this has reduced incidence of infection to approximately 5% (Castro 7.2.4.5 Treatment et al. 2005). Prophylaxis usually starts at the point If PCP pneumonia is suspected, treatment is of engraftment or upon discharge as TMP-SMX with trimethoprim-sulfamethoxazole and the can cause engraftment delay. addition of systemic steroids to reduce the The most effective first-line prophylaxis is a inflammatory lung processes. For those that are combination of trimethoprim-sulfamethoxazole intolerant to trimethoprim-sulfamethoxazole, given in a variety of doses dependent upon your then atovaquone or a combination of clindamy- local policy. If the patient develops any sensitiv- cin with primaquine is licenced for use (Chen ity to these drugs, then alternatives are pentami- et al. 2003). dine nebulizer, atovaquone and oral dapsone. If dapsone is to be used, then glucose 6-phosphate dehydrogenase (G6PD) deficiency should be 7.2.5 Varicella Zoster Virus ruled out. G6PD is highly prevalent in African, Asian, Oceanian and Southern European popula- 7.2.5.1 Introduction tions, and those with G6PD deficiency may Varicella zoster virus (VZV) infection or chick- develop acute haemolytic anaemia. Nebulized enpox is usually a childhood disease, and trans- pentamidine can cause bronchospasm, and mission is either by inhalation of respiratory patients need to be informed of this prior to inha- secretions or direct physical contact. Following lation. Atovaquone is generally well tolerated but exposure the virus remains latent in the dorsal poorly absorbed unless taken with a high fat diet. root ganglion, and when it reactivates, it is Patients in the immediate post-transplant setting referred to as “shingles” or herpes zoster. Herpes may struggle with this especially those with GI zoster is grouped painful vesicular lesions that GvHD issues (Gea-Banacloch et al. 2009). can affect several dermatomes in immunocompetent people. In the setting of allogeneic stem cell 7.2.4.3 Presentation transplantation, VZV carried a major risk of mor- Those with PCP present with symptoms of subtle bidity and mortality with 18–52% patients hav- onset dyspnoea, a low-grade temperature and a ing clinically apparent infection related to non-productive cough, and when examined, the reactivation of latent virus; however, with the use chest is clear on auscultation. However, this may of aciclovir, this number has decreased (Thomson rapidly change with the onset of hypoxia requir- et al. 2005). Complications such as post-herpetic ing admission to a critical care unit. Imaging of neuralgia, skin scarring and bacterial superadded the chest with X-ray reveals bilateral perihilar infection are factors in morbidity (Steer et al. interstitial infiltrates that become increasingly 2000; Boeckh et al. 2006). 7 BMT Settings, Infection and Infection Control 107

7.2.5.2 Risk Factors who have active chronic GvHD or are taking All stem cell transplant patients should receive immunosuppressive medications should have prophylaxis for (VZV) with oral aciclovir or intravenous varicella zoster immunoglobulins valaciclovir for 6 months to 1 year (according to (VZIG). If this passive immunization medication local policy) or until immunosuppression is dis- is unavailable, then high-dose aciclovir, valaci- continued (Kanda et al. 2001). Transmission of clovir or famciclovir (nucleoside analogues that VZV is difficult to prevent as the period prior to interfere with viral thymidine kinase activity) can symptoms where an individual is contagious can be employed. be up to 48 h before the appearance of a rash. The Post treatment for VZV, it is advisable to incubation period varies from 10 to 21 days, and restart prophylactic aciclovir if this was previ- an individual remains contagious until all of the ously discontinued. The length of time prophy- vesicles have crusted over. If the immunocom- laxis should be continued will be guided by local promised patient is in contact with an individual policy and may range from 1 year to lifelong. with VZV infection (varicella or HZ), they are at significant risk of developing varicella themselves and will require prompt action from the 7.2.6 Adenovirus transplant team (Styczynski et al. 2009). HSCT will probably destroy any previous 7.2.6.1 Introduction immunity to VZV. Immunization of family con- Adenovirus (ADV) is a ubiquitous non-enveloped tacts especially children is advised to reduce risk. double-stranded DNA virus. It currently has more than 50 serotypes and is divided into six 7.2.5.3 Presentation subgroups A–F (La Rosa et al. 2001). Adenovirus VZV infection occurs in 40–50% if prophylaxis is more prevalent in children but is becoming stopped at 6–12 months, with a peak incidence more prevalent in adults in the transplant around 5 months and a spread of 2–10 months, population. usually occurring within 5 weeks of cessation of oral prophylaxis (Steer et al. 2000). Risk factors 7.2.6.2 Risk Factors include unrelated donors, myeloablative condi- Adenovirus is spread by aerosolization or the fae- tioning, graft versus host disease (GvHD) and the cal-oral route with approx. 80% of children aged use of systemic corticosteroids. Pain in the back 1–5 years old seropositive. Risk factors include or abdomen with distension and a rise in ALT are mismatched or unrelated donor, acute graft versus seen in approx. Ten % of patients prior to the host disease (aGvHD) and isolation of ADV from development of a rash. The rash may spread to multiple sites (Ljungman et al. 2003). more than 1–3 dermatomes in patients with visceral dissemination and is more difficult to treat. 7.2.6.3 Presentation In healthy individuals, infection is self-limiting 7.2.5.4 Diagnosis causing conjunctivitis and upper respiratory tract, The best method for diagnosing VZV is by poly- urinary tract or gastrointestinal infections and merase chain reaction (PCR) testing of blood or a remains latent in lymphocytes post exposure. glass slide touched to a vesicle as the DNA is Chakrabarti et al. (2002) report a 5–29% inci- highly specific and sensitive. dence of ADV after allogeneic stem cell transplantation. 7.2.5.5 Treatment Treatment for those who have been exposed to a 7.2.6.4 Diagnosis healthy individual with VZV infection is advised Those with viral-like symptoms usually have a depending upon the serostatus of the recipient full screen of virology requested that will and availability of drug. Patients who are sero- include ADV. Samples taken from nasopharyn- negative and are less than 2 years post allograft or geal, rectal and corneal secretions, urine and 108 J. Murray et al. unfixed biopsy tissue can be examined with 7.2.7.2 Clinical Features PCR to assess viral load. Similar to those with Post-transplant HBV infection can arise in differ- viral reactivation of CMV and EBV, low level ent ways. Patients may have active HBV (HBsAg of ADV infection does not carry a high mortal- positive) prior to transplant or reactive latent ity. However, those patients that develop inva- HBV infection (HBsAg negative). Infection may sive disease, such as ADV colitis, have a also occur during the transplantation process, significant mortality of 20–80% (Robin et al. from an infected HSC donor or rarely from 2007). infected blood products. HBV DNA titer may rise to very high levels, particularly in patients 7.2.6.5 Treatment receiving corticosteroids. At the time of immune Cidofovir is first-line treatment and is a mono- reconstitution or during reduction of immuno- phosphate nucleotide analogue of cytosine. suppressive drugs, a flare is given by a rise in Cidofovir inhibits viral DNA polymerase and has serum aspartate aminotransferase (AST) and ala- a low bioavailability with 90% of the drug nine aminotransferase (ALT) levels. Another excreted in the urine. Patients require hyper- clinical symptom is jaundice and fulminant liver hydration and oral probenecid pre, during and failure as a result of HBV (liver-related mortal- post cidofovir to protect nephrons. ity) (Lau et al. 2003). 7.2.7.3 Treatment Lamivudine (100 mg/day) is the first choice for 7.2.7 Hepatitis B antiviral therapy for treatment, which should be continued for at least 6 months following 7.2.7.1 Background discontinuation of immunosuppressive drugs in The hepatitis B virus (HBV) is a DNA virus clas- allogeneic haematopoietic cell transplantation sified in the hepadna virus family. Patients patients (Tomblyn et al. 2009). infected by HBV prior to transplantation have a higher risk (70–86%) of HBV reactivation 7.2.7.4 Prevention 5 years after HSCT transplantation. An active Several studies in the literature describe preven- immunization of donors and early post-transplant tion of HBV reactivation in the setting of immu- vaccination of recipients have been suggested to nosuppression. HBV reactivation has been avoid HBV reactivation. Donors should opti- variably reported as ALT elevation above upper mally receive more than one immunization, a limit of normal or by increases from baseline. rather high Ag dose and a highly immunogenic Patients who undergo HSCT for haematological vaccine (Lindemann et al. 2016). malignancy are an “at-risk” population because The use of chemotherapy and immunosup- of the prolonged immunosuppression following pression can reactivate latent hepatitis B. Further, the conditioning chemotherapy. HBV infection or reactivation contributes to The nucleoside analogue antiviral drugs lami- liver-related morbidity and mortality; it occurs in vudine, adefovir, telbivudine, entecavir and 21–53% of patients, especially after conditioning tenofovir may all be of potential use in the pre- regimens containing alemtuzumab. vention of HBV reactivation in such patients. Transplantation of HBV-negative patients with The majority of reports describe the use of lami- stem cells from an infected donor (HBsAg posi- vudine or entecavir, and both drugs appear to tive) is associated with a high risk of transmis- reduce the incidence of HBV reactivation. sion; some patients develop chronic hepatitis However, entecavir (and potentially tenofovir) B. Donors with active HBV (DNA detection) may be superior to lamivudine because of more should receive, if possible, antiviral treatment potent viral suppression and lower risk of antivi- (Ullmann et al. 2016). ral resistance. 7 BMT Settings, Infection and Infection Control 109

Prophylaxis for HBV reactivation with antivi- tion and viral reactivation. The last two are com- ral nucleoside analogues should be commenced mon, but not associated with increased in susceptible individuals before the initiation of liver-related mortality rates or changes in HSCT chemotherapy, in order to lessen the risk of HBV care (Kyvernitakis et al. 2016). reactivation and the associated adverse clinical A reported case of severe HCV reactivation outcomes (Pattullo 2016). occurred early (<30 days after HCT) with elevated ALT and bilirubin levels. Liver biopsy revealed chronic portal inflammation, bile duct injury and 7.2.8 Hepatitis C moderate cholestasis (Oliver et al. 2017). HCV adversely impacts on platelet recovery, 7.2.8.1 Background non-relapse mortality and overall survival. The hepatitis C virus (HCV) is a double-stranded Sinusoidal obstruction syndrome (SOS), liver RNA virus classified within the Flaviviridae. Six graft versus host disease (GvHD) and hepatic major genotypes have been identified, from problems are more likely to be severe and fatal in HCV1 to HCV6. It can be responsible for several recipients with HCV. Pre-transplant HCV infec- systemic complications. The extrahepatic mani- tion is associated with a lower rate of platelet festations include vasculitis, fatigue, cryoglobuli- recovery. An excess of bacterial infections in nemia and autoimmune disorders. HCV HCT recipients with HCV infection has been replication is significantly increased by immuno- reported, and these findings suggest that the suppression and may cause a direct cytopathic defence mechanisms against bacterial infections effect in infected cells. The identification of pre- are impaired in recipients with HCV (Nakasone transplant HCV infection appears clinically rele- et al. 2013). vant. Being infected with HCV has been indicated as an independent risk factor for post-transplant 7.2.8.3 Treatment veno-occlusive disease (VOD) of the liver. All HSCT recipients with HCV infection should Reactivation of chronic HCV infection after be evaluated for HCV therapy before the start of tapering immunosuppressive therapy can some- conditioning therapy. Whenever possible, HCV- times lead to fulminant hepatic failure (Locasciulli infected HSCT candidates should commence and et al. 2009). complete HCV therapy before transplant. If there is an oncologic imperative for moving quickly to 7.2.8.2 Clinical Features transplant, a therapy with direct-acting antiviral HCV infection is responsible for hepatic and agents (DAAs) should be able to clear extrahe- extrahepatic manifestations. After 1 year post patic HCV from donors more quickly than inter- HSCT, HCV infection course has an increased feron and ribavirin. risk of fatal sinusoidal obstruction syndrome and Treatment of post-transplant HCV infection later hepatic inflammation occurring 3–6 months must be an urgent consideration for patients with after HCT, coincident with immune reconstitu- fibrosing cholestatic HCV, patients with cirrhosis tion and interruption of immunosuppressive whose condition is deteriorating and patients medications. The symptom of liver decompensa- who underwent HSCT for HCV-related lympho- tion among patients who had cirrhosis at the time proliferative disorders. Once HCV therapy is ini- of transplant has been described in the literature, tiated, treatment interruption is not recommended and rarely, fatal fibrosing cholestatic HCV can because it is associated with increased risk of occur before day 100 in recipients receiving treatment failure. The alternative to pre-HSCT mycophenolate mofetil (Torres et al. 2015). therapy for HCV is to treat after HCT using HCV infection is associated with high risk for DAAs following immune reconstitution. several complications, which include accelerated All long-term HCV-infected HSCT survivors liver disease progression, acute HCV exacerba- should be offered DAAs therapy. 110 J. Murray et al.

HCV therapy should be undertaken by provid- usually via contaminated water. In developed ers experienced in management of HCV in countries, HEV 3 and HEV 4 are transmitted HSCT. There are many combinations of DAAs, from animal reservoirs. HEV antibodies were depending on HCV genotype. Commonly used found in pig farmers, slaughterhouse workers, DAAs include daclatasvir, sofosbuvir, ledipasvir, veterinarians, and farm labourers. In Western ombitasvir, paritaprevir, ritonavir, dasabuvir, Europe the food chain is the main source of infec- simeprivir and ribavirin. The choice of regimen tion, where HEV is transmitted through the con- should be individualized on the basis of patient- sumption of contaminated animal meat specific data, and take into consideration poten- (undercooked pig liver). Person-to-person trans- tial drug interactions with tacrolimus, sirolimus mission is uncommon, although nosocomial and and ciclosporin (Torres et al. 2015). parenteral transmission in haemophiliac and in haemodialysis patients has been reported 7.2.8.4 Prevention (Marano et al. 2015). A vaccination against HCV does not exist. However, to prevent the complication of co- 7.2.9.2 Clinical Features infection, people with hepatitis C should be vac- The most common symptom of HEV is jaundice, cinated against hepatitis A and B. Standard followed by: precautions are recommended for the care and treatment of all patients, regardless of their per- • Malaise/lethargy ceived or confirmed infectious status and in han- • Nausea and vomiting dling of blood, all other body fluids, secretions • Abdominal pain and excretions, non-intact skin and mucous • Loss of appetite membranes (ASHM 2012). • Myalgia HCV-infected donors should be evaluated for • Fever HCV therapy and treated before cell harvest, in • Loss of weight order to prevent transmission of HCV to unin- • Neurological features fected recipients (Torres et al. 2015). Extrahepatic manifestations of acute and chronic hepatitis E involve the following systems 7.2.9 Emerging Infections and organs (Dalton et al. 2015) (Table 7.1). (Hepatitis E) 7.2.9.3 HEV in Developing Countries 7.2.9.1 Background After an incubation period of 2–6 weeks, geno- Hepatitis E virus (HEV) is a single-stranded, types 1 and 2 develop to HEV infection. The non-enveloped RNA virus. It was discovered in source of infection is human, mostly by faecal- 1983 by investigators of an outbreak of unex- oral route via infected water. Outbreaks can occur plained hepatitis in Russian soldiers in at times of flooding/monsoon and can involve Afghanistan. In areas with poor sanitation, HEV thousands of cases. Symptoms of HEV progress 1 and 2 are spread orofaecally between humans, with fever, nausea, abdominal pain, vomiting,

Table 7.1 Extrahepatic manifestations of acute and chronic hepatitis E Neurological system Haematological system Other organs Guillain-Barré syndrome Thrombocytopenia Acute pancreatitis Brachial neuritis Lymphopenia Arthritis Transverse myelitis Monoclonal immunoglobulin Autoimmune thyroiditis Bell’s palsy Vestibular neuritis 7 BMT Settings, Infection and Infection Control 111 anorexia, malaise and hepatomegaly. Jaundice is 7.2.9.6 Prevention present in about 40% of patients. Pregnant Immunocompromised patients should be females and individuals with underlying chronic screened for HEV antibodies and RNA not only liver disease present a high mortality. prior transplantation but also post-transplantation and during episodes of liver enzyme 7.2.9.4 HEV in Developed Countries abnormalities. Numerous studies report that autochthonous In immunocompetent patients adequate cook- HEV is a problem across Europe and that infec- ing procedures for porcine and boar/deer meat tion has a predilection for middle-aged elderly are useful to prevent HEV disease (De Keukeleire males (mean age ≈ 60 years). Large outbreaks do and Reynders 2015). not occur, most cases are sporadic and the source This is a list of the more common virus that of infection remains uncertain in most cases. In patients develop during transplantation. the developed countries, we can distinguish between acute and chronic hepatitis E. Rhinovirus Role of treatment is limited Acute by lack of agents and RCT Acute HEV is mostly caused by genotypes 3 and Influenza Oseltamivir +/− zanamivir 4. Jaundice occurs in about 75% of patients, and (research and some limited European areas use IV the clinical manifestations are the same as those peramivir, favipiravir) of hepatitis E in developing countries. HEV Respiratory syncytial Ribavirin (research and infection may be misdiagnosed as drug-induced virus Europe again use liver injury (DILI) and is responsible for extrahe- palivizumab) patic disorders: neurological disorders, kidney Parainfluenza Ribavirin +/− IVIg in some centres injury, acute pancreatitis associated with HEV 1 Metapneumovirus Ribavirin +/− IVIg in some and haematological disorders as thrombocytope- centres nia and aplastic anaemia. Coronavirus Role of treatment is limited by lack of agents and RCT Chronic Bocavirus Role of treatment is limited No studies have assessed the prevalence or inci- by lack of agents and RCT dence of HEV infection among haematological patients receiving chemotherapy. A small number have been found to have a chronic HEV infection and include a patient with untreated hairy cell leu- 7.2.10 Multiply-Resistant Bacteria: kaemia, a patient with idiopathic CD4 T lympho- Reducing the Spread penia and patients treated for lymphoma, chronic myelomonocytic leukaemia and B-cell chronic 7.2.10.1 Background lymphocytic leukaemia. HEV RNA was found in Multidrug-resistant organisms (MDRO) have 8 of 328 stem cell transplant patients and 5 devel- emerged as significant pathogens in haematology oped chronic hepatitis (Kamar et al. 2014). and haematopoietic stem cell transplant recipi- One case of chronic HEV infection following ents. Neutropenia and malignancy are indepen- allogeneic haematopoietic stem cell transplanta- dent risk factors for MDRO-invasive infections. tion was reported in 2015 as differential diagnosis Resistant Escherichia coli and Klebsiella pneu- for graft versus host disease (Bettinger et al. 2015). moniae bacteraemia and carbapenemase- producing K. pneumoniae (KPC) are emerging in 7.2.9.5 Treatment haematology populations with associated mortal- In haematological patients, pegylated interferon ity, as well as increasing rates of vancomycin- alone and ribavirin alone for 3 months have been resistant Enterococci that are responsible for up used (Kamar et al. 2014). to 41% of all gram-positive bacteraemias. 112 J. Murray et al.

Infection prevention, antimicrobial stewardship 7.2.11 Gram-Positive Bacteria and antimicrobial prophylaxis are essential for control and management of MDRO. Hand Gram-positive (gram+) pathogens cause signifi- hygiene, environmental cleaning/disinfection, cant morbidity and mortality in bone marrow isolation and surveillance are indeed the back- transplant recipients. bone of effective prevention programs (Trubiano et al. 2013). • Enterococci In 2014 the World Health Organization • Vancomycin-resistant Enterococci (VRE) declared antimicrobial resistance a worldwide • Coagulase-negative Staphylococcus (CNS) threat that requires urgent action. • Staphylococcus aureus • Methicillin-resistant Staphylococcus aureus 7.2.10.2 Contact Precautions (MRSA) The application of contact precautions (CP) • Streptococcus viridans requires that gowns and gloves should be worn • Streptococcus pneumoniae when entering the patient’s room and removed before leaving it. Dedicated equipment such as 7.2.11.1 Enterococci stethoscopes or blood pressure cuffs should Enterococci are gram-positive aerobes and facul- remain in the patient’s room and not be used for tative anaerobes which are seen microscopically other patients. CP may include single-room iso- as single, pairs and short chains and are part or lation, an entire isolation ward or cohorting of a the normal flora of the gastrointestinal tract. In group of patients (with or without designated transplant recipients, enterococcal infections are staff). The aim of CP is preventing transmission usually nosocomial and occur generally as inva- of epidemiologically important pathogens from a sive infections in the immediate post-transplant colonized or infected patient through direct period, mostly as a consequence of endogenous (patient or healthcare personnel) or indirect (sur- gram-positive translocation. faces or roommates in the patient’s environment) contact. In addition to hand hygiene, appropriate 7.2.11.2 Vancomycin-Resistant CP measures should decrease the risk of MDRO Enterococci (VRE) transmission. VRE, also known as glycopeptide-resistant Current controversies remain whether patients Enterococci, are increasingly causing outbreaks only colonized, rather than infected, with MDROs in haematology units. should be subjected to isolation. Another issue is At many transplant centres, VRE are the pre- the impact of CP on patient’s well-being. dominant organism causing pre-engraftment bac- Healthcare workers who care for patients in con- teraemia among HSCT recipients. tact isolation enter their rooms less frequently The evidence for an association between act- and have significantly less direct contact with ing contact precautions and surveillance testing them. Patients express greater dissatisfaction or not and the incidence of VRE bacteraemia with their treatment and have less documented starts to stagger. care (Landelle et al. 2013). VRE are strongly associated with colonization A review by Cohen et al. (2015) reports that pressure, and strategies to reduce VRE burden in CP do not represent a statistically significant colonized patients may reduce VRE transmis- improvement in MDRO infection control. Five of sion. Infection control efforts should include con- the six reviewed studies did not find significant tact precautions, and the need for active association between CP and reduction in MDRO surveillance testing should be guided by local transmission (Cohen et al. 2015). epidemiology (Kamboj and Sepkowitz 2014). 7 BMT Settings, Infection and Infection Control 113

However, Almyroudis et al. (2016) reported 7.2.11.5 MRSA on the discontinuation of systemic surveillance According to the Center for Disease Control and and contact precautions for VRE and its impact Prevention guidelines (ref website? access date?), on the incidence of VRE faecium bacteraemia in HSCT centres should follow stringent infection patients with haematological malignancies. In control practices handwashing, contact precau- this study, the incidence of VRE bacteraemia tions, including wearing gloves whenever enter- remained stable after discontinuation of surveil- ing the MRSA-infected or colonized patient’s lance and contact precautions. Furthermore, con- room. MRSA is indeed transmitted via an tact isolation can be associated with medication infected or colonized patient or by a colonized errors, reduced visits of physicians and nurses, healthcare worker. safety concerns such as increased falls and bed- Patients with MRSA should be placed under sores, anxiety and depression among patients and CP until all antibiotics are discontinued and until a significant increase in the cost of care three consecutive cultures, taken >1 week apart, (Almyroudis et al. 2016). are negative. Screening cultures for MRSA include the anterior nares, any body site previ- 7.2.11.3 Coagulase-Negative ously positive for MRSA and any wounds or sur- Staphylococcus (CNS) gical site (Dykewicz and Kaplan 2000). CNS are members of the Micrococcaceae family, produce catalase and divide in irregular clusters 7.2.11.6 Streptococcus viridans to produce packets of cells. Transplant recipients Streptococcus viridans are facultative anaero- with a central venous catheter (CVC) are particu- bic, gram-positive cocci and are part of the nor- larly vulnerable to CNS infections. CNS cause mal microflora, found mainly in the oral cavity surgical wound infections and infections associ- but also in the upper respiratory, gastrointesti- ated with lines, including CVC bacteraemia, nal and female genital tract. Septicaemia is the CVC local infections and drain-associated most common manifestation in bone marrow peritonitis. transplant (BMT) recipients (Ihendyane et al. 2004). 7.2.11.4 Staphylococcus aureus To lessen the risk of oral sources of infection Staphylococcus aureus occurs microscopically as following HSCT, dental treatment and oral single, pairs and short chains and has a strong hygiene instructions given 3–4 weeks before the tendency to form clusters. Staphylococcus aureus HSCT are required (Tomblyn et al. 2009). is mainly found in the nasopharynx and on the skin. 7.2.11.7 Streptococcus pneumoniae Methicillin-susceptible Staphylococcus aureus Streptococcus pneumoniae is a gram-positive (MSSA) and methicillin-resistant S. aureus diplococcus causing significant morbidity and (MRSA) are major causes of infections after mortality in all age groups, wherein children, the transplantations. The prevalence of vancomycin- elderly and immunocompromised patients are intermediate S. aureus (VISA) and heterogeneous especially vulnerable. Pneumococcal infection or heteroresistant VISA (hVISA) is reported to be may occur during hospitalization for the trans- increasing worldwide. S. aureus truly resistant to plant procedure but more commonly occurs as a vancomycin (VRSA) is very rare, and no data are community-acquired infection, months or years available for the transplant population (Garzoni following the transplantation as meningitis or 2009). fulminant sepsis. 114 J. Murray et al.

7.2.12 Gram-Negative Bacteria trointestinal tract, skin and nasopharynx. In the past it has been seen as an important causative Over the last decade, multidrug-resistant (MDR) agent of community-acquired infections, includ- gram-negative (gram-) pathogens have been ing a severe form of pneumonia. In the early implicated in severe healthcare-associated infec- 1970s, infections caused by K. pneumoniae tions, and their occurrence has increased steadily. became a leading cause of nosocomial infections. The emerging problem of carbapenemase- High carriage rates have been recorded in producing Enterobacteriaceae has become a patient’s nasopharynx and hands, as well as the major healthcare threat with associated mortality gastrointestinal tract. K. pneumoniae has a con- also in haematology populations. siderable efficiency of colonization, enhanced by The recommended strategies to prevent acquired resistance to antibiotics, which enables healthcare-associated transmission of gram- it to persist and spread rapidly in healthcare negative bacteria are prompt laboratory-based settings. identification, adherence to contact precautions K. pneumoniae is a notorious “collector” of and strict hand hygiene. Further, more expensive multidrug resistance mechanisms, such as the approaches include dedicated equipment and “carbapenemases” encoded by transmissible staff, especially for patients with MDR in the plasmids. The clinically most important car- respiratory tract. Cohorting patients in a specific bapenemases in Enterobacteriaceae are the class hospital area can be effective but also very dis- A enzymes of the KPC type, then the zinc- ruptive. Finally, integration of antimicrobial dependent class B metallo-ß-lactamases (MßLs), stewardship efforts based on dominant MDR represented mainly by the VIM, IMP and NDM organisms may help prevent future problems types and the plasmid-expressed class D car- (Kamboj and Sepkowitz 2014). bapenemase of the OXA-48 type. Carbapenemase- The ESCMID guidelines for the management producing Enterobacteriaceae (CPE) cause of the infection control measures to reduce trans- serious infections in immunocompromised mission of multidrug-resistant gram-negative patients, in association with prolonged hospital bacteria in hospitalized patients by Tacconelli stay and increased mortality rates, because of et al. (2014) summarize the importance of adher- panresistance to antimicrobials (Tzouvelekis ence to hand hygiene, wearing contact precau- et al. 2012). tions and using disposable single-use or patient-dedicated care equipment and performing 7.2.12.3 Carbapenemase-Producing active screening cultures, as well as the role of Klebsiella pneumoniae environmental cleaning and antimicrobial stew- Carbapenemase-producing Klebsiella pneu- ardship and the role of infrastructure and educa- moniae (CP-Kp) are emerging in immunosup- tion to reduce the spread. pressed patients, and their expansion represents a challenging problem in terms of outcome and 7.2.12.1 Enterobacteriaceae management. A retrospective study by Girmenia Enterobacteriaceae are facultative anaerobes and et al. reports that CP-Kp were documented in 87 are intestinal colonizers. Enterobacteriaceae encom- allogeneic HSCT in 52 Italian centres, and a col- pass a large heterogeneous family of gram-negative onization documented before or after transplant bacteria, which are divided into lactose fermenters was followed by an infection in 39% of alloge- as Escherichia coli, Citrobacter, Klebsiella spp. and neic HSCT (Girmenia et al. 2015). An analysis of Enterobacter spp. and non-lactose fermenters 50 cases of KPC bloodstream infections (BSI) in Salmonella, Shigella, Proteus and Yersinia. neutropenic patients with haematological malignancies or aplastic anaemia, conducted by Tofas 7.2.12.2 Klebsiella pneumoniae et al. reports that all episodes of KPC BSI were K. pneumoniae is encountered as a saprophyte in hospital-acquired, the median duration of hospi- humans and other mammals, colonizing the gas- talization before the onset of bacteraemia was 7 BMT Settings, Infection and Infection Control 115

22 days and 48 of 50 CP-Kp produced KPC ingly identified as the cause of nosocomial enzyme and 2 produced VIM enzyme (Tofas diarrhoea in growing numbers of patients. et al. 2016). Patients who are admitted for treatment of haematological malignancies or undergoing HSCT 7.2.12.4 Pseudomonas aeruginosa are at high risk for Clostridium difficile infection Pseudomonas aeruginosa is a glucose non- (CDI). Risk factors for CDI include exposure to fermenting gram-negative rod. It is a strict aerobe broad-spectrum antibiotics, which can cause pathogen, cosmopolitan in distribution, with a par- changes to the microbiota of the gut, total body ticular predilection for moist environments. irradiation, long hospitalization, immunocom- Pseudomonas aeruginosa has shown the ability to promised state, older age and irritation of the acquire resistance to all traditionally effective intestinal mucosa by chemotherapy drugs (Gu agents, such as anti-pseudomonal penicillins, et al. 2015). third- and fourth-generation cephalosporins, ami- noglycosides, fluoroquinolones and carbapenems. 7.2.13.2 Infection Control Patient gastrointestinal colonization serves as Management an important reservoir for endogenous infection, (Adapted from Debby Weston, Fundamentals of as well as the source of horizontal transmission to Infection Prevention and Control, 2013). other patients. In patients with haematological malignancies, Isolation enteric colonization by Pseudomonas aeruginosa • In the event of confirmation of a Clostridium occurs typically after chemotherapy. difficile (CD) toxin-positive result in a patient with diarrhoea, who is not already isolated, 7.2.12.5 Acinetobacter baumannii the patient must be moved to a single room Acinetobacter baumannii is a nonfermentative with en suite bathroom or dedicated night gram-negative pathogen. Its ability to survive on commode. dry, inanimate surfaces for long periods of time • An isolation notice must be displayed on the suggests that the hospital environment serves as a door. reservoir for MDR strains. Acinetobacter bauman- • The nurse looking after the patient should nii can be resistant to many or all available antibi- inform the infection prevention control otics. Multidrug resistance is common in the US team. hospital-acquired infections, estimated up to 60%. • Isolation can be discontinued once the patient Colonized patients’ skin may serve as effective has been asymptomatic for 48 h and is passing reservoirs, and healthcare workers’ hands can serve “normal” stools. as vehicles for transmission. Commonly employed strategies to avoid the spread of Acinetobacter bau- Equipment and Cleaning mannii include identifying and eliminating com- • Dedicated patient equipment must be used, mon sources of contamination, optimizing contact including disposable blood pressure cuffs and isolation and hand hygiene to minimize cross- tourniquet. transmission, enhancing environmental cleaning to • Floors, night commodes, toilets and bed- reduce contamination and reducing broad-spec- frames are subject to the heaviest faecal con- trum antibiotic use (Lin et al. 2014). tamination; it is important that the ward environment should not be cluttered in order to facilitate thorough and effective ward 7.2.13 Clostridium difficile cleaning. • On discharge or transfer of the patient, it is 7.2.13.1 Background important that an accurate clean of the room is Clostridium difficile is an anaerobic, gram- undertaken using 1000 ppm available chlorine positive spore-forming bacterium and increas- and/or a sporicidal agent. 116 J. Murray et al.

Hand Hygiene The combination of strict hand hygiene and • The patient should be assisted with hand contact precautions (gloves and apron) signifi- hygiene after using the toilet or night com- cantly reduces the incidence of CD (Dubberke mode and before eating if unable to wash his and Riddle 2009). or her hands independently. • Healthcare workers must wash their hands 7.2.13.3 Treatment with soap and water after contact with the First-line treatment is given by oral metronida- patient or his/her environment. Alcohol hand zole (500 mg three times daily for 10–14 days) rubs or gels are not effective against and/or vancomycin (125 mg every 6 h for Clostridium difficile spores. 10–14 days) (Kamboj et al. 2014). Gu et al. (2015) report a treatment with ber- Personal Protective Equipment (PPE) berine when CDI first symptoms appeared and • Wear gloves and apron before entering the they did not have severe cases of CDI in the patient’s room. study. Berberine is a traditional Chinese medi- • Remove apron and gloves before leaving the cine that has been used to treat bacterial or secre- patient’s room. tory diarrhoea for 12,000 years in China. • Hands must be decontaminated before putting Additional studies are needed to demonstrate on and after removing gloves. whether berberine could be a new useful thera- • Ensure that all healthcare workers and visitors peutic agent to alleviate clinical symptoms of wear and dispose of PPE appropriately. CDI (Gu et al. 2015). Further treatments of recurrent CDI are fidax- Waste and Linen omicin, probiotics, intravenous immunoglobulin • Any clinical waste and linen, including bed- and faecal transplants. ding and, if present, curtains, should be considered contaminated and managed properly. 7.2.13.4 Faecal Microbiota Transplant The treatment with faecal microbiota therapy Movement of Patients consists in a technique that involves transfer of • Patients with CD should not be transferred to fresh stool from a healthy donor to the gastroin- other wards in the hospital, except for isola- testinal tract of the patient suffering from severe tion purposes or if they require specialist care or recalcitrant Clostridium difficile infection on another ward. (CDI). In the case report by Neemann et al. • When patients need to attend departments for (2012), the donated stool sample was screened essential investigations, the nurse looking for transmissible pathogens, ova and parasites, after the patient is responsible for informing Clostridium difficile, Salmonella, Shigella, the receiving area in advance of the patient’s Campylobacter and Escherichia coli. After a CD-positive status; if possible, symptomatic brief liquefaction procedure, 30 ml of fresh patients should be seen at the end of the work- stool suspended in non-bacteriostatic saline ing session and should be sent for only when was slowly injected via nasojejunal tube into the department is ready to see them; it should upper jejunum, followed by non-bacteriostatic be avoided to leave them in a waiting area saline flush. Within 2 days of faecal transplant, with other patients. the patient had no further diarrhoea or haemato- chezia. For fulminant CDI unresponsive to CD spores are known to contaminate the envi- metronidazole and/or vancomycin, the defini- ronment, are resistant to standard disinfectants tive treatment has been colectomy, but faecal and are capable of surviving for long periods on microbiota therapy should be considered a dry surfaces. 10% bleach solutions are sporicidal potentially bowel- and life-saving intervention, and should be used for environmental decontami- if other medical modalities fail (Neemann et al. nation during outbreaks. 2012). 7 BMT Settings, Infection and Infection Control 117

Another case reported by Castro et al. (2015) Principal risk factors for infections after describes a persisting CDI infection and diar- HSCT are: rhoea 10 months after bone marrow transplanta- • Status of the haematological disease at tion. The patient had an allergic response to oral HSCT vancomycin and was subsequently treated with • Comorbidities of the patient oral metronidazole and i.v. meropenem. After • Degree and duration of neutropenia performing faecal microbiota transplantation • Disruption of anatomical barriers (mucositis with material from two different donors, the and indwelling catheters) patient’s bowel showed significant improve- • Depressed T- and B-cell function and immu- ments, and any antibiotic were not needed any- nosuppressive therapy more (Castro et al. 2015). Reconstitution of immune status after HSCT depends on: • Type of transplantation (autologous or 7.3 BMT Setting, Infection allogeneic) and Infection Control • Source of progenitor cells (bone marrow, peripheral blood or cord blood) 7.3.1 Introduction • Conditioning regimen (myeloablative, RIC or non-myeloablative) Haematopoietic stem cell transplantation (HSCT) • Degree of histocompatibility between the can be defined as the transfer of haematopoietic donor and the recipient (sibling, unrelated or stem cells (HSCs) from one individual to another mismatch) (allogeneic HSCT) or the return of previously • Type of GvHD prophylaxis (calcineurin or harvested cells to the same individual (autolo- mTOR inhibitors, mono or polyclonal anti- gous HSCT) after manipulation of the cells and/ bodies or T-cell depletion) or the recipient (Tomblyn et al. 2010). • Presence and grade of GvHD and its Haematopoietic stem cell transplantation treatment (HSCT) is a major procedure, which needs the use of chemotherapy. Some patients who are Depending on these factors, the patient can be undergoing allogeneic transplantation for rendered immunodeficient for months or even haemato-oncological malignancies will require years after HSCT (Rovira et al. 2012). radiotherapy. The use of these treatments, cou- There is a clear relationship between the type pled with the patient’s disease, compromises the of immunodeficiency after HSCT and the inci- immune system. The administration of immuno- dence of certain infections. According to this, suppressant to prevent graft rejection contributes three different periods can be distinguished, with also to the high risk of infections in this patient a predominance of specific pathogens in each group (Brown 2010). phase (Fig. 7.2) (Tomblyn et al. 2010; Rovira In recent years, improvement in HSCT sup- et al. 2012). portive care measures, better understanding of The chronology of the previously mentioned the mechanism of immunosuppression, the intro- infections was described in patients receiving a duction of reduced intensity conditioning (RIC) myeloablative HSCT, and some differences can regimens and new anti-infectious agents and pro- be observed in recipients of autologous HSCT or phylactic strategies have decreased infectious RIC-HSCT. Thus, in the autologous setting, bac- morbidity and mortality. However, there is still terial infections are less frequent and severe, and scope for improvement since infection remains a the other infections are exceptional (Rovira et al. leading cause of morbidity and mortality in 2012). patients undergoing HSCT (Gratwohl et al. However, autologous candidates who receive 2005). immunosuppressive agents (steroids, purine ana- 118 J. Murray et al.

I: Pre-engraftment II: Post-engraftment III: late phase Phase (days 0 to +30) (days 30 to +100) (days 100 to >365)

neutropenia ¯ T-cells/ ¯ B-cells ¯ T-cells/ ¯ B-cells Risk barrier breakdown functional asplenia functional asplenia factors ¯ T-cells/ ¯ B-cells acute GvHD and chronic GvHD and functional asplenia its treatment its treatment

Bact. Gram negative bacilli Encapsulated bacteria

Gram positive organisms

Fungi Aspergillus spp Aspergillus spp Aspergillus spp

Candida spp

Pneumocystis jirovecii

Viruses Herpes simplex virus

Cytomegalovirus

Varicella zoster virus

Epstein Barr PTLD

Other viruses: HHV-6, respiratory and enteric

Fig. 7.2 Chronology of predominant infections after HSCT (Adapted from [1] and granted permission from (EBMT Handbook 2012)) logues or monoclonal antibodies such as ritux- in poorer general condition with or without the imab or alemtuzumab) or with severe presence of comorbidities; for all these reasons, hypogammaglobulinaemia prior to the auto- the infection-related mortality has not decreased HSCT run the same risk of developing infections in this setting (Rovira et al. 2012; Masszi and as those patients undergoing allogeneic SCT. Mank 2012). In the past two decades, RIC-HSCT has been used increasingly worldwide (Rovira et al. 2012). Infections related to neutropenia and mucositis 7.3.2 Reverse Barrier Nursing are less common with this modality of HSCT than and Protective Isolation after conventional HSCT. However, viral and fungal infections occurring in the intermediate and Infections are a major cause of morbidity and late period are comparable because the incidence mortality in allogeneic transplantation (Parody and severity of GvHD are similar to that observed et al. 2006). Therefore, it is crucial to have a in myeloablative HSCT. Additionally, RIC-HSCT skilled nursing team to assess, prevent, detect and is usually used in older patients, who are usually treat infections. 7 BMT Settings, Infection and Infection Control 119

Delays in diagnosing an infection that results The Centres for Disease Control and Prevention from a depressed inflammatory response may (CDC) has published in 2007 very specific recom- lead to increased susceptibility to a broad range mendations regarding precautions to be taken in of potentially life-threatening organisms. For this haematopoietic stem cell transplant. reason, in addition to antimicrobial prophylaxis, (HSCT) reported and updated in 2009. there are other important strategies to prevent The CDC recommends a protective isolation infections, for example, building a multi- for patients who are undergoing allogeneic professional network team specialized in infec- HSCT. The indications are the use of single room tion control measures (Masszi and Mank 2012). and the use of filtered air entering through a central or portable high-efficiency filter (HEPA), 7.3.2.1 Protective Isolation capable of removing 99.97% of ≥0,3 uM in and Cleaning diameter particles. The large number of patients considered at risk For autologous HSCT, there is no specific requires an evaluation of all proposals of protec- indication other than the reference to “standard” tive systems, in relation to the effectiveness, precautions (as shown in Table 7.2) for each applicability and cost benefit (Pizzo 1981). interaction with the patient. Protection with lab

Table 7.2 Standard precautions of infection control (https://www.dhs.wisconsin.gov/ic/precautions.htm) Standard Standard precautions are a set of infection control practices used to prevent transmission of precautions diseases that can be acquired by contact with blood, body fluids, non-intact skin (including rashes) and mucous membranes. These measures are to be used when providing care to all individuals, whether or not they appear infectious or symptomatic Hand hygiene Hand hygiene refers to both washing with plain or antibacterial soap and water and to the use of alcohol gel to decontaminate hands. When hands are not visibly soiled, alcohol gel is the preferred method of hand hygiene when providing healthcare to clients Personal protective PPE includes items such as gloves, gowns, masks, respirators and eyewear protectors used to equipment (PPE) create barriers that protect the skin, clothing, mucous membranes and the respiratory tract from infectious agents PPE is used as a last resort when work practices and engineering controls alone cannot eliminate worker exposure The items selected for use depend on the type of interaction a public health worker will have with a client and the likely modes of disease transmission Wear gloves when touching blood, body fluids, non-intact skin, mucous membranes and contaminated items. Gloves must always be worn during activities involving vascular access, such as performing phlebotomies Wear a surgical mask and goggles or face shield if there is a reasonable chance that a splash or spray of blood or body fluids may occur to the eyes, mouth or nose Wear a gown if skin or clothing is likely to be exposed to blood or body fluids remove PPE immediately after use and wash hands. It is important to remove PPE in the proper order to prevent contamination of skin or clothing Needle stick and Safe handling of needles and other sharp devices is a component of standard precautions that sharp injury are implemented to prevent healthcare worker exposure to blood-borne pathogens. The prevention Needlestick Safety and Prevention Act (link is external) mandates the use of sharps with engineered safety devices when suitable devices exit Cleaning and Client care areas, common waiting areas and other areas where clients may have potentially disinfection contaminated surfaces or objects that are frequently touched by staff and clients (doorknobs, sinks, toilets other surfaces and items in close proximity to clients) should be cleaned routinely with EPA-registered disinfectants, following the manufacturer’s instructions for amount, dilution and contact time (continued) 120 J. Murray et al.

Table 7.2 (continued) Respiratory Clients in waiting rooms or other common areas can spread infections to others in the same hygiene (cough area or to local public health agency staff. Measures to avoid spread of respiratory secretions etiquette) should be promoted to help prevent respiratory disease transmission. Elements of respiratory hygiene and cough etiquette include: Covering the nose/mouth with a tissue when coughing or sneezing or using the crook of the elbow to contain respiratory droplets Using tissues to contain respiratory secretions and discarding in the nearest waste receptacle after use Performing hand hygiene (handwashing with non-antimicrobial soap and water, alcohol- based hand rub or antiseptic handwash) immediately after contact with respiratory secretions and contaminated objects/materials Asking clients with signs and symptoms of respiratory illness to wear a surgical mask whilst waiting in common areas or placing them immediately in examination rooms or areas away from others. Provide tissues and no-touch receptacles for used tissue disposal Spacing seating in waiting areas at least three feet apart to minimize close contact among persons in those areas Supplies such as tissues, wastebaskets, alcohol gel and surgical masks should be provided in waiting and other common areas in local public health agencies. Place cough etiquette signs (link is external) where the general public can see them Waste disposal Safe injection Outbreaks of hepatitis B and hepatitis C infections in US ambulatory care facilities have practices prompted the need to re-emphasize safe injection practices. All healthcare personnel who give injections should strictly adhere to the CDC recommendations coat, gloves and mask is not indicated in the is unlikely that exposure to plants causes invasive absence of suspected or confirmed infection of fungal infections in patients undergoing HSCT, it patients (Tomblyn et al. 2010). The effectiveness is recommended that plants and dried or fresh of specific precautions in preventing infections in flowers do not enter the room during hospitaliza- patients undergoing autologous HSCT has not tion (conditioning phase included) because of the been evaluated but must follow the standard pre- Aspergillus sp., isolated from soil of ornamental cautions for every patient contact. plants and flowers. In addition it was found a Some centres use additional protection in an high proportion of gram-negative bacteria in the effort to reduce the risk of infection, but there are water of the cut flower vase (Pseudomonas) insufficient data to recommend such behaviours (Tomblyn et al. 2010). (Tomblyn et al. 2010). Consistent with the orga- For the patient hospitalized in a protective nization of the department, it would be advisable environment, exits from the room should be to hospitalize the patient in a single room with restricted just for the execution of diagnostic tests attached bathroom, in order to give them greater and for a short period. If a construction site is comfort. The ventilation system should ensure at present nearby the hospital, it is indicated to use least 12 air changes per hour; a direct flow area of a filter mask (N95) to prevent inhalation of the room must have the way out on the opposite spores. There are no recommendations regarding side with respect to that of entry. The optimum use of the mask with filter in the absence of the ambient air quality can be obtained without using construction work (Tomblyn et al. 2010). the expensive laminar flow. The rooms, housing highly immunocompromised patients, need to be 7.3.2.2 Handwashing placed under positive pressure to prevent the The most important point in the prevention of entry into the room of airborne pathogens in the infections in hospitalized patients, being in protec- hallway or in adjacent spaces. In the rooms it is tive isolation, remains handwashing. Hand hygiene forbidden to keep fresh flowers and/or dried and is a key element of the standard precautions for all potted plants (Tomblyn et al. 2010). Although it types of patients (Tomblyn et al. 2010). 7 BMT Settings, Infection and Infection Control 121

All staff and visitors must wash their hands The light fixtures and outdoor grills of ventila- before entering the patient’s room in order to tion vents and all horizontal surfaces should be reduce the risk of cross infection. cleaned with pre-moistened disposable cloths Hand hygiene should be performed before with a disinfectant FDA and Environmental touching the patient, before a clean/aseptic pro- Protection Agency approved. The design and cedure, after body fluid exposure risk (blood, selection of the furniture of a transplant program body fluids or excretions, mucous membranes, should be focused in creating and maintaining an non-intact skin or dressing), after touching a environment: free of dust and the floors and fin- patient and after touching patient’s surrounding ishes should be brushable, waterproof, easy to (WHO “My five moments for hand hygiene” disinfect and antistatic (Tomblyn et al. 2010). 2009). It is also advisable not to wear false nails To verify that hospital rooms are at effective or extensions during direct contact with the reduced environmental load, periodic monitoring patient and maintain the natural nails short. Even of the environments must be guaranteed. if there is still an unsolved problem, many studies have shown that the skin below the rings is more 7.3.2.4 Management of Linen colonized than that without; rings and dirty jew- All linen should be changed daily and pillows elry can host microorganisms. and mattresses should have protective coatings. Furthermore hand hygiene cannot be done in a During the hospital stay for the patient undergo- perfect way if you wear bulky rings. The experts’ ing HSCT, it is enough to wash clothes and linens recommendation is strongly discouraging the use at high temperatures in a washing machine of rings during assistance (WHO guidelines (Tomblyn et al. 2010). 2009). Nurses have an important role in educating the 7.3.2.5 Access to Low Environmental family, patient and visitors to an effective hand- Loading Department washing (as shown in Fig. 7.2) and to provide all Each centre has its own policy on the number of relevant information to reduce the risk of con- visitors allowed and the frequency of visits. tracting infections. However, all centres are in agreement in pointing Some transplant centres display cartoons near out that they cannot come into contact with the the sinks at the entrance of the hospital room, patient when cooled or suffering from other where they describe the handwashing procedure infections, rashes, eyes’ infections, nausea and/or step by step and how it needs to be performed vomiting or recent exposure to exanthematous (WHO guidelines 2009). diseases such as chickenpox or measles (Tomblyn et al. 2010). 7.3.2.3 Environmental Cleaning The environmental cleaning plays an important 7.3.2.6 Personal Hygiene role in the prevention of nosocomial infections, Personal hygiene is a key aspect for the patient particularly in patients with haematological can- undergoing HSCT. It represents the most effec- cers and diseases undergoing transplantation of tive way to reduce infections caused by endoge- haematopoietic stem cells. The cleaning staff nous organisms. The interview with the patient must be well prepared and needs to be informed and his family is a very important moment and and trained, with particular attention to the prob- must be programmed before HSCT. The nurse lems of immunosuppressed patients. It is prefer- must be able to define when, how and which are able to assign stable staff to the division, in order the major needs for the patient. It is important to to ensure a continuity of service. The hospital explain the importance of personal hygiene and room must be cleaned more than once a day, with its role in preventing infections. Several centres special dust control, which must be removed are supported by audio-visual media and infor- by damp. mation booklets to reinforce the provided infor- 122 J. Murray et al.

Table 7.3 Recommendations for personal hygiene, Carreras 2006, CDC 2007 When How What Take a shower every day using Patients are advised to gently rub the Do not use sponges or knobs (only if mild liquid soap in dispensers skin and dry it accurately especially at disposable) Thorough intimate hygiene must the level of the armpits and groin, For teeth cleaning, it is recommended be performed after each where the body microorganisms can to use synthetic brushes with soft evacuation, especially in case of proliferate if they find a moist bristles diarrhoea environment Towels need to be replaced every The material for the toilet must be new During the hospitalization period, the day and in closed packs following products should not be used: For dry and peeling skin, it may be Soaps, perfumes, deodorants and useful to apply moisturizer on the body aftershave containing alcohol, cotton sticks for ear cleaning (patient should clean the external pinna with soap and water only), lipsticks Patients should be advised to cut Thorough personal hygiene will allow For men an electric razor is the nails of the hands and feet the patient to evaluate daily the state of recommended; razor blades and before admission, as, during his/her skin and promptly notify the scissors are forbidden due to their aplasia, they are more susceptible physician and nursing staff of any increased bleeding risk to infections and bleeding. Also changes such as erythema, keeping short nails facilitates desquamation, haematomas good hand hygiene. Enamel or false nails should be removed mation. The nurse, giving precise indications, build a multi-professional team including medi- must be able to explain with thoughtfulness and cal, dental and nursing, nutrition, physical ther- sensitivity how incident personal hygiene is on apy and counselling providers. Training and the individual’s intimate and personal sphere. continuing education programs will ensure that Table 7.3 shows recommendations of panel the knowledge will spread to an extensive com- expert and of CDC (Carreras 2006; CDC 2007). munity of healthcare providers, which can make a positive impact on patients’ healthcare (Sharon 7.3.2.7 Oral and Gastrointestinal Elad et al. 2014). All treatment strategies aimed Mucositis to improve mouth care are dependent on four key Oral and gastrointestinal mucositis caused by principles: accurate assessment of the oral cavity, high-dose chemotherapy and/or radiation contin- individualized plan of care, timely preventive ues to be an important clinical problem. measures and correct treatment initiation (Quinn Incidence of WHO grade 3 or 4 oral mucositis et al. 2008). can be as high as 75% in patients undergoing HSCT, depending on the intensity of the condi- 7.3.2.8 Central Venous Devices tioning regimen used and the prophylactic use of The use of central venous catheters (CVC) is methotrexate to prevent graft versus host disease. linked to the need to infuse complex therapies for Management of oral and gastrointestinal mucosi- a long time, having available a valid and secure tis is one of the main challenges during the period access. Generally the choice of the most appro- of aplasia, with risk of sepsis related to degree of priate catheter is shared by a multidisciplinary mucosal barrier breakdown and depth of marrow team taking into account the patient’s compliance suppression (Peterson et al. 2015). and the therapeutic process which he/she will Oral care is an important aspect in the control face. The goals of care, for the CVC manage- of infections in transplant patients (Quinn et al. ment, must aim to ensure prevention of infections 2008). In order to improve oral care in patients and maintenance of the patency. This is feasible undergoing chemotherapy/HSCT, it is useful to if the device is managed by competent healthcare 7 BMT Settings, Infection and Infection Control 123 workers and if the process is based on continuous The rationale was to limit the introduction of improvement of performance (RCN 2010; INS potentially harmful bacteria into the gastrointes- 2011; CDC 2011). tinal tract by the restriction of certain foods that The most important recommendations con- might harbour those organisms (Fox and Freifeld cerning the prevention of CVC-related blood- 2012). stream infections are: However, there is no clear evidence that the use of a low bacterial diet (LBD) actually decreases • Hand hygiene and maximum barrier precaution. the number of infections. It is clear from numerous • Appropriate choice of insertion site and cath- surveys of current practice that the majority of eter material. hospitals place neutropenic patients on a restricted • Plan an echo-guided insertion when possible, diet (Mank et al. 2008). for both centrally and peripherally inserted Many studies have limitations and conclude central lines. that there are no differences in terms of infectious • Use of 2% chlorhexidine for skin antisepsis episodes and survival when comparing a normal for continuous and discontinuous antisepsis of to a neutropenic diet (Van Tiel et al. 2007; the exit site. Gardner et al. 2008; Trifilio et al. 2012). • Use of sutureless devices (StatLock) for fixing In a randomized study of 153 patients with acute the catheter, wherever possible. myeloid leukaemia undergoing induction therapy, • Use of appropriate dressing. no difference in terms of infectious episodes and • Removing the venous catheter when no longer survival was reported between patients prescribed necessary. with a LBD and those put on a normal diet. The • Assessment → inspection (visual and palpa- conclusion was that the LBD has not prevented tion) of the exit site should be performed daily. major infections or death (Gardner et al. 2008). • Proper handling of parenteral solutions. Notably, a study on the use of a non- • Proper management of infusive lines. neutropenic diet showed an increase in satisfac- • Education of the patients on the need to inform tion for the meal from a 42.9% to a maximum of the nurse if changes at the level of the CVC 75%. The feedback of the team was positive (Tarr are noticed. and Allen 2013). Patients who are prescribed a neutropenic diet 7.3.2.9 Low Bacterial Diet may have a poor nutritional status and often need The low bacterial diet (LBD), also known as neu- counselling and nutritional support (Murray and tropenic diet or low microbial diet, is a diet aimed Pindoria 2009). at reducing the ingestion of bacterial and fungal A study conducted in Brazil shows how contaminants excluding it from foods such as dietary restrictions can lead to a deficiency of fresh fruits and vegetables, raw eggs, raw meat vitamin C (Galati et al. 2013). and fish, unpasteurized dairy products, ice and A retrospective study in 2012 of 726 patients yogurt that will be excluded from any type of diet undergoing HCT showed that the rate of acute or raw food containing probiotics. The consump- grade II–IV GI GvHD was higher in the neutro- tion of fruits with thick skin, if peeled and penic diet (ND) group, although the difference washed, in accordance with good hygienic prac- between the groups did not reach statistical sig- tices has low probability to be contaminated nificance. An association between GvHD and (Todd et al. 1999). ND has not been reported previously. Almost For decades, the concept of a neutropenic diet one-half of the patients in the ND group who sub- or diet containing food with low levels of bacteria sequently developed GvHD had a previous C. (LBD) has implied a strict limitation of foods difficile infection, and non-relapse mortality was allowed for consumption, as a presumptive means very high in this group. Nutritional support of reducing the risk of infection in cancer patients. guidelines for patients with GI GvHD, which are 124 J. Murray et al. also on common sense, include a low microbial of an early discharge after transplantation to pro- diet (Trifilio et al. 2012). vide a more comfortable environment for patients The study results are in line with preclinical and their family. experiments conducted on mice where the pres- Increasing implementation of ambulatory ence of a mixed intestinal flora (e.g. Lactobacillus treatment has the potential to decrease patient rhamnosus GG) would be able to decrease the exposure to multidrug-resistant organisms in the proliferation of the most virulent bacterial spe- hospital and to provide patients with the possibil- cies and of the system that immunomodulate ity to spend the neutropenic phase at home and to what is in their intestine (Docampo et al. 2015). facilitate more admissions to the haematology A more liberal diet could bring benefits in ward (Mank et al. 2015). terms of palatability, cholesterol reducing, use of parenteral nutrition and an improvement in qual- 7.3.2.11 Health Education ity of life. at Discharge The LBD, usually poorer from a nutritional Discharging is much desired by the patient, but it point of view and less attractive compared to a is the “most difficult time” in the course of treat- normal diet, may be an unnecessary burden on ment. Patient and family will have to face every- patients who already have difficulties with eat- day life far from a safe hospital environment. In ing. The studies reviewed do not support signifi- fact, in the hospital, the continued support of the cant results on the effectiveness or ineffectiveness multidisciplinary team makes them feel pro- of the LDB, and many useful results still do not tected; in hospital, doctors, nurses and other pro- encourage the use of LBD. fessionals are always present to clarify doubts, give advice and also try to reduce anxiety and 7.3.2.10 Psychological Support fears. Being aware of the risks of infection means Protective isolation can have significant psycho- that going home can be stressful (Brown 2010). logical effects on the patient. Patients are encour- Nurses should spend time with the patient, aged to personalize their rooms with family identify and explore any concerns before dis- pictures. Some may have computer access and charge. In some cases, the patient may become are able to maintain communication with family overdependent on nursing staff, and this may members and friends in this way. However, the need to be addressed. Allogeneic transplant length of time spent in isolation does lead to patients have a high risk of readmission as a many patients having feelings of anxiety, fear for result of infection, and it is critical that discharge the future, concerns about the family and worry planning provides patients with the understand- about whether engraftment will occur (Brown ing and information on how best to minimize the 2010). The need for regular monitoring of blood risk of infection (Grant et al. 2005). is a constant reminder of the patient’s situation. A checklist of information, which patients Loss of body image as a result of weight loss or should receive on discharge, is provided in scars, sexuality issues and concerns about Table 7.4. employment may preoccupy a patient (Gruber Patients should be advised to continue their et al. 2003). Nurses should be aware of the poten- oral care routine. It is very important. tial effect that both, the transplant and the isola- reiterating to patients when handwashing tion, can have on patients. Spending time with should be carried out, particularly: the patient and offering him or her an opportunity to talk about concerns can be helpful. Providing • Before eating information, education and advice may reduce • Before and after meal preparation the negative psychological effects of isolation • Before and after handling pets (Brown 2010). However it should be considered • After sneezing or coughing for selected categories of patients the possibility • Before taking oral tablets 7 BMT Settings, Infection and Infection Control 125

Table 7.4 Discharge checklist for patients following improve patient outcomes in autologous and allo- allogeneic stem cell transplantation (Brown 2010 geneic recipients include raising clinical aware- modified) ness, improving diagnostics, shortening time to Discharge checklist for patients following allogeneic medical intervention and continuing multidisci- stem cell transplantation plinary research (Stephens et al. 2013). The spec- Patients should avoid contact with people who have respiratory illnesses trum of pulmonary complications for transplant Care should be taken when around schoolchildren, as recipients will continue to change, due in part to there is a risk of exposure to sick children rapid advances in supportive care, the increasing Patients should be advised to stop smoking and avoid age of transplant recipients, new antiviral and smoky areas for the first few months following antifungal agents and an increasing use of pro- transplantation phylactic broad-spectrum antibiotics post- Patients should avoid communal swimming pools in the early weeks of discharge transplant (Sharma et al. 2005). The real key, It is advisable to avoid house cleaning, which will however, to decreasing morbidity and mortality disturb dust in adult and paediatric HSCT patient populations When considering travel, patients should seek advice remains in effective diagnostic techniques regarding travel vaccinations, particularly if they would (Stephens et al. 2013). need live vaccines Pulmonary infections are the largest cause It is essential that patients continue to take their medication and attend all follow-up outpatient of post-HSCT infective morbidity and have appointments been reported in most recipients, carrying a mortality rate of 20% (Cooke et al. 2008; Zuccotti et al. 2005). The principal cause of • After touching soiled linen infection is the severe immunocompromised • After going outdoors status of the patients from the disease process (malignant or non-malignant), conditioning (Brown 2010). regimens (non-myeloablative and myeloabla- The patient will require a great deal of infor- tive) and immunosuppressive prophylaxis to mation before and at discharge, and this would prevent and treat GvHD. A CT study by include information on follow-up treatment. Escuissato et al. (2005) found that viral infections (51%) were the most common in post- transplant recipients, followed by bacterial 7.4 Respiratory Infections infections (23%), fungal infection (19%) and protozoal infections (less than 1%). In 5% of As recent research suggests, pulmonary compli- the cases examined, patients had two or more cations are a leading cause of post-transplant infectious agents concurrently. complications and death in HSCT recipients (Alsharif 2009; Roychowdhury et al. 2005). Post- transplant pulmonary complications are classi- 7.4.1 Typical Onset of Pulmonary fied as either infectious or noninfectious. The rate Complications Following Stem of complications is significantly lower for autolo- Cell Transplantation gous transplant recipients than for allogeneic transplant recipients. This is because of the Table 7.5. absent risk of GvHD in autologous transplants, the infrequent use of immunosuppressive medications such as ciclosporin or tacrolimus and the 7.4.2 Diagnostics absence of radiation therapy in the precondition- ing regimen (Ho et al. 2001; Kotloff et al. 2004). Diagnostic techniques for pulmonary disease in Methods that healthcare professionals can use to HSCT patients are similar to that for non- 126 J. Murray et al.

Table 7.5 Typical onset of pulmonary complications following stem cell transplantation divided into three stages based on information from Antin and Raley (2009) Camus and Costabel (2005), Coomes et al. (2010), Polovich et al. (2009), and Soubani and Pandya (2010) Day 0 to day 30 Infections related to conditioning regimen Pulmonary oedema and neutropenia Pleural effusion Transfusion-related acute lung injury Idiopathic pneumonia syndrome Engraftment syndrome Diffuse alveolar haemorrhage Aspergillosis Candidaemia (Candida sepsis) and candidiasis (general Candida infections) Respiratory viruses – Respiratory syncytial virus, parainfluenza, influenza Bacteraemias of gastrointestinal origin Infections of central venous catheter origin Acute respiratory distress syndrome (ARDS) Chemotherapy-associated pulmonary toxicity Day 31 to day 100 Classic opportunistic infections Pulmonary veno-occlusive disease (due to hepatic sinusoidal obstructive Syndrome) Diffuse alveolar haemorrhage Cytomegalovirus Aspergillosis Pneumocystis carinii pneumonia Respiratory viruses – Respiratory syncytial virus, parainfluenza, influenza Toxoplasmosis ARDS Idiopathic pneumonia syndrome Chemotherapy-associated pulmonary toxicity Greater than day 100 Infections from encapsulated organisms Aspergillosis Respiratory viruses – Respiratory syncytial virus, parainfluenza, influenza Varicella zoster virus Cytomegalovirus Pneumocystis carinii pneumonia Post-transplant lymphoproliferative disorder Pneumonia ARDS Bronchiolitis obliterans Bronchiolitis obliterans organizing pneumonia Chemotherapy-associated pulmonary toxicity

transplant patients. Chest radiograph (X-ray) and special-frequency reconstruction during inhala- thoracic computed tomography (CT) scan remain tion and exhalation (Stephens et al. 2013). the most popular and less invasive options. CT Changes such as nodules, “white out” and a scans are particularly useful when compared with “glassy” appearance signal the physician and two-dimensional X-rays because they can expose radiology staff to consider additional diagnostics acute and chronic changes in the lung paren- (Truong et al. 2010). This could include collect- chyma. Respiratory CT scans involve taking pic- ing sputum samples, bronchoscopy with or with- tures of cross-sections of lung tissue using high out bronchoalveolar lavage (BAL), open lung 7 BMT Settings, Infection and Infection Control 127 biopsy and needle biopsy (Kaplan et al. 2011; Staphylococcus aureus, coagulase-negative Truong et al. 2010). Staphylococcus, Streptococcus pneumoniae, Sputum samples can be collected by nurses, Streptococcus viridans and Enterococcus. One also physicians or respiratory therapists according to needs to recognize the risk of Mycoplasma and transplant program protocols. Respiratory virus Chlamydia infections, although the common use of detection is highly dependent on the type of sam- fluoroquinolones will empirically treat these organ- ple collected, the time of collection after the onset isms. Other causes of late pneumonia that should of clinical symptoms, the age of the patient and not be missed include Nocardia, Listeria and the transport and storage of the sample prior to Actinomyces. testing. Several different upper respiratory tract specimens are applicable for testing, including nasopharyngeal (NP) washes, NP aspirates and 7.4.4 Viral Causes of Pneumonia NP swabs placed in virus transport media (Specter 2009; Storch 2000). Expectorations in the early These include CMV, herpes simplex virus (HSV), morning or after a respiratory procedure can be varicella zoster virus (VZV), adenovirus, respira- the easiest for the patient to produce because of tory syncytial virus (RSV), influenza, parainflu- the natural accumulation of secretions at these enza type III, herpesvirus-6 (HHV6), times. About 15 ml of sputum is usually required metapneumovirus and a variety of other respira- for adequate laboratory analysis, and a recent tory pathogens. Non-CMV viral infections may study suggested that the sputum must reach the occur earlier than 30 days or later in the trans- laboratory within a few hours from expectoration plant course. CMV typically occurs after 30 days. (Murray et al. 2010). Sputum can also be col- Early detection of CMV and advances in treat- lected during a bronchoscopy. In some cases, ment have reduced disease and mortality associ- broncholveolar lavage (BAL) will be performed ated with CMV disease. VZV can lead to during the bronchoscopy. BAL involves the flush- pneumonia with or without classic vesicular rash. ing of fluid (usually a sterile normal saline solu- HSV/VZV prophylaxis should be initiated with tion) into a localized area of the lower respiratory the conditioning regimen and continue for 1 year tract and then immediately suctioning the fluid up or until the patient is off all immunosuppressant the bronchoscope and into a sterile specimen con- agents and CD4 numbers have been restored. tainer. BAL allows for the detection and charac- Community-acquired viral infections can be terization of several respiratory pathogens, lethal, especially parainfluenza type III. Since, including viral, fungal and bacterial agents, and is with the exception of influenza, there is no effec- considered a major diagnostic mechanism for tive therapy, the best approach is prevention Pneumocystis carinii (now called Pneumocystis through isolation. jirovecii) pneumonia (PCP) (Forslöw et al. 2010). In patients with focal pulmonary lesions, aspergil- Diagnosis of Viral Pathogens losis or pulmonary GvHD, fine-needle aspiration Diagnosis is based on fever, cough, signs and biopsy is considered the first-line diagnostic symptoms of URI, nasal washing, viral swabs method (Gupta et al. 2010). or PCR.

7.4.3 Bacterial Infections 7.4.5 Fungal Pulmonary Infections

These most commonly occur in the first month but Invasive fungal diseases are a major obstacle to can occur at any time. Both gram-negative and patients after transplant and are a major cause of gram-positive organisms can cause pneumonia, the pulmonary-related mortality (Ji et al. 2011). most common being Escherichia coli, Klebsiella, Aspergillus is the most common and most virulent Pseudomonas, Enterobacter, Acinetobacter, fungal cause of pneumonia following HSCT 128 J. Murray et al.

(Blaes et al. 2009; Wilson et al. 2009). Other fungal 7.4.7 Nursing Implications respiratory infections in post-HSCT patients, particularly those receiving myeloablative condition- All patients undergoing HSCT are at risk for pul- ing, include Malassezia, Zygomycetes and Candida monary complications. Bedside nurses are the species (Wilson et al. 2009). Over the past decade, most likely to observe subtle changes in the several new antifungal medications have demon- patient’s condition, and for this reason it is criti- strated increased success, showing improved cal that nursing staff working with the HSCT remission rates and thereby decreasing morbidity. population be highly trained in oncology and critical care interventions. Prompt reporting of Diagnosis symptoms can ensure proper and timely medical • Fever, pleuritic chest discomfort, dyspnoea. intervention and facilitate improved patient out- • Imaging shows nodules or cavitating comes. This has been found particularly true in infiltrates. identifying GvHD, with clinical nurses at the • The classic “halo sign” may be seen on chest forefront of identifying and reporting suspicious CT, but imaging may not be helpful. symptoms to the healthcare team (Mattson 2007). • A BAL may be useful. Nurses take a central role in patient and family • Galactomannan and beta-glucan testing may education regarding the course of treatment, be helpful but are not always informative. complications and other key pieces of the HSCT process, including caring for a central line Pneumocystis jirovecii Pneumonia (Stephens et al. 2013). By educating patients on Risk of Pneumocystis jirovecii pneumonia what to expect after transplant with regard to (PCP) starts at around day +30. troubling symptoms, nurses ensure patient par- Effectively administered prophylaxis elimi- ticipation in identifying developing complica- nates PCP. tions early and improving HSCT outcomes. A thorough assessment can assist the nursing staff Diagnosis in detecting changes indicative of developing • Fever, cough, ± hypoxemia. complications. Vital signs, including the rate and • Positive BAL. CXR – bilateral ground-glass quality of respirations, and oximetry should be infiltrates. performed per program protocols, usually every • Beta-glucan is typically detectable. 4 h and more frequently for patients at risk for • A history of noncompliance with prophylaxis pulmonary insufficiency. Taking the patient’s medication should be elicited. temperature every 4 h or as necessary is another critical respiratory intervention, as most post- Typically involves the brain, heart and lung. HSCT complications are infectious in nature Biopsy sample has Giemsa stain to confirm (Stephens et al. 2013). Nurses are crucial in diagnosis. assessing patients for symptoms of bacterial infection and should perform routine laboratory tests as necessary. Regarding pulmonary infec- 7.4.6 Mycobacteria tions, nurses should closely monitor patients for symptoms of progressing respiratory disease, Testing with purified protein derivative (PPD) is such as decreased auscultation of air sounds in often not helpful after allogeneic stem cell trans- the lungs, increasing fevers and appearance of a plantation because of depressed delayed-type productive cough with coloured sputum. hypersensitivity reactions. Therefore a skin reac- Antibiotics should start as soon as possible in tion with PPD will likely not occur. these patients. A nursing study of neutropenic patients in the early HSCT phase showed that Diagnosis commencement of antibiotics within 1 h of the Cultured sputum sample/BAL various indirect onset of infectious symptoms can significantly assays such as Quantiferon gold are helpful. reduce infectious complications, including sepsis 7 BMT Settings, Infection and Infection Control 129

(Hyman 2005). The recent addition of monoclonal antibodies (MoAbs) to GvHD prophylaxis BCGitis protocols has been met with mixed results. For If BCG vaccine is given to infants with example, a study using infliximab did not lead to severe primary immune deficiencies, they lower rates of GvHD but did suggest higher rates will develop BCGitis. It is characterized by of bacterial or fungal pulmonary infection in local erythema and purulent regional lymph patients who participated in the study (Hamadani node enlargement. et al. 2008). It is important that patients in the BCG-osis. post-transplant period are encouraged to pace The more severe form is disseminated their activity with their level of ability. Coughing infection that could be fatal. It involves dis- and deep breathing exercises accompanying the tant lymph nodes, bone, liver and spleen. regular use of an incentive spirometer constitute Shrot et al. (2016). critical ways to open deep alveolar tissue and encourage pulmonary toileting on patients prone to fatigue and malaise and whose blood counts are very low (Stephens et al. 2013). References

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Alberto Castagna, Lisa Mcmonagle, Corien Eeltink, and Sarah Liptrott

8.1 Transplanting the Child The ability to cure children with cancer has radi- cally improved over the recent decades. Today, more than 80% of children with cancer are cured Abstract Biologically, a child is a human being of their disease (Franklin 2014). This incredible between the stages of birth and puberty. The legal achievement is one of the greatest triumphs in the definition of child generally refers to a minor, oth- history of medicine and is the result of numerous erwise known as a person younger than the age of factors, including developments in paediatric majority (Oxford University Press (Accessed 5th haematopoietic stem cell transplantation (HSCT). January 2013)). Treatment advances for the sick child have been accomplished in various cancer treatments including chemotherapy, surgery, radiotherapy and HSCT. Whilst these therapies have vastly improved outcomes in childhood cancers, there remains scope for further improvement. A. Castagna Paediatric Hemato-Oncology and HSC Transplant Keywords HSCT • Paediatric Nurse at Paediatric Hematology-Oncology and HSCT Unit, Ospedale Donna e Bambino – Azienda Ospedaliera Universitaria Integrata (AOUI) Verona, Verona, Italy 8.1.1 The Role of EBMT e-mail: [email protected] in Paediatric HSCT L. Mcmonagle, BSc (Hons), MSc, RN Teenage Cancer Trust Advanced Nurse Practitioner Changes in HSCT approaches are responsible for for Teenagers and Young Adults, University College, progress in this particular area. The role and status London, United Kingdom of transplantation have evolved. It is no longer con- e-mail: [email protected] sidered a salvage therapy for patients in desperate C. Eeltink (*) circumstances but is now the treatment of choice Department of Hematology, Cancer Center Amsterdam/ VU University Medical Center, for many diseases. The history of paediatric HSCT Amsterdam, The Netherlands in Europe began in Poland in 1949 (Raszek- e-mail: [email protected] Rosenbusch), with therapeutic transfusion of bone S. Liptrott marrow in children with leukaemia and other blood Division of Haemato-oncology, European Institute diseases. Subsequent developments in paediatric of Oncology, Milan, Italy HSCT were driven on by the creation in 1974, of e-mail: [email protected]

© EBMT and the Author(s) 2018 135 M. Kenyon, A. Babic (eds.), The European Blood and Marrow Transplantation Textbook for Nurses, https://doi.org/10.1007/978-3-319-50026-3_8 136 A. Castagna et al. the European Society for Blood and Marrow which almost 75% are allogeneic. A family mem- Transplantation (EBMT). The goal of the society ber donated cells in 53% of these (70% HLA- remains to promote all aspects associated with identical, 29% non-HLA-identical, 1% syngeneic) HSCT. Since the launch of the EBMT Society in and 47% of unrelated donor (Table 8.1). 1974, several working parties were established, The high proportion of allogeneic transplants and in 1995, the Board of the EBMT founded the in paediatrics is largely due to the characteristics Paediatric Diseases Working Party (PDWP). of paediatric diseases that are amenable to trans- Shortly after, the registry of the EBMT began to plantation such as haemoglobinopathies, immune analyse transplant outcomes in children and ado- deficiencies, immune dysregulation and meta- lescents increasing our understanding which in bolic diseases. turn informed changes and developments in the Furthermore, in paediatric allogeneic trans- field. The continuous progressions and evolution of plantation, the leading indication is ALL (26%), paediatric HSCT in Europe have been resulted in followed by primary immune deficiencies (16%) the establishment of HSCT as a standard therapeu- and then AML (14%). Conversely, in the paediat- tic procedure in paediatric haemato-oncology. ric autologous transplant, the major indications The number of children and adolescents are neuroblastoma (35%), other solid tumours undergoing HCST has been steadily increasing (31%) and lymphoma (15%). since the 1980s. It is clear that close national and The 2012 EBMT report notes that more paedi- international collaboration between HSCT units atric patients receive BM stem cells than PBSC, helps to resolve common difficulties with this irrespective of donor type (Passweg et al. 2014). complex treatment. The scale of collaboration within the EBMT members is underpinned by the EBMT survey of Passweg et al. (2016) reporting 8.1.2 Child Growth more than 40,000 HSCT per year in 680 centres and Development from 49 countries in Europe and affiliated countries. The report described: It is important to know and understand the developmental stages of infants and children because appre- • Transplant rates ciation of the ages, stages, common milestones and • Indications abilities allows nurses to relate to the children and • Donor type their relatives appropriately. The knowledge of the • Stem cell source normal growth and development equips the nurses • Conditioning MAC and RIC to identify any developmental delay. Growth and • Donor lymphocyte infusions development are a single process which begins during pregnancy and continues throughout childhood This report enables us to observe trends and and into adolescence. Growth is a change in the changes in HSCT practice over time. The paper body size and structure, whilst development is a reported 4400 paediatric transplants in 2014 of change in the body function.

Table 8.1 Number of paediatric haematopoietic SCTs in Europe in 2014 by donor type ‘Paediatric centres’ 227 Combined adult- 118 paediatric centre Paediatric only centre 109 Number of 4400 Allogeneic 3279 transplants Autologous 1121 Donor type 3279 Family member 1729 HLA-identical 1224 Non-HLA-id 501 Syngeneic 4 Unrelated donor 1550 8 Transplantation Through the Generations 137

8.1.2.1 Child Growth absorbed into their normal development. Child growth refers to progressive structural and However, if this disconnect exceeds their toler- physiological changes in the size of a child body. ance, it results in a traumatic experience and Physical growth includes gaining full height and becomes in itself a source of anxiety and distress appropriate weight and increasing in size of all (Badon and Cesaro 2015). organs. The measurements of weight, length, head circumference, body composition and tooth 8.1.3.2 Disease Awareness eruption aid assessment of normal and standard A child’s disease awareness is determined by the physical growth (Mona 2015). child’s own level of cognitive function and experience. These factors impact upon a child’s abil- 8.1.2.2 Child Development ity to understand the meaning and significance of Child development concerns a child’s ability to what is happening. The reactions that a child may undertake more complex processes as they exhibit will be governed by: mature. Child development is subdivided into specific areas: • Age and stage of intellectual development • Previous experiences • Motor • Quality of relationships established with ref- • Language erence figures • Cognitive • Psycho-emotional structure • Behavioural and emotional 8.1.3.3 Emotional Reactions to Hospitalisation 8.1.3 The Child and the Experience The child often does not have the ability to under- of Disease stand the causes and the logic of the events that lead suddenly to being excluded from their fam- The child is aware of the condition and often the ily environment, separated from significant fig- severity of their disease whatever his age (Badon ures and entrusted to the care of strangers. The and Cesaro 2015). This consciousness derives child will tend to experience hospitalisation with primarily from their perception of the body and a sense of danger that derives primarily from the wellness state changes but also communicative inability to understand and control the absent and relational aspects. parent (Badon and Cesaro 2015).

8.1.3.1 Hospitalisation The child is sensitive to the experience of discon- 8.1.4 Patient, Caregiver and Sibling nection that disease imposes. The disease acts as Donor Experience HSCT a breaking event in the life of the child and alters the way the body is considered and treated. HSCT is usually an elective, planned treatment. Hospitalisation changes the physical and rela- Children who suffer from malignant disease and tional environment and modifies the emotional undergo- transplantation often have experienced climate and the usual style of education. previous treatments and hospitalisations for treat- During the hospitalisation, the child’s world is ment of complications such as fever, pain, muco- changed; for instance, they are relieved of respon- sitis, nausea and vomiting as well as periods of sibilities, and many rules disappear or are isolation. HSCT is an intensive treatment process replaced. They become the target of therapeutic and offers the chance of a cure, but at the same measures, sometimes with little consideration for time it can generate a range of feelings including privacy or confidentiality, and the child becomes fear, isolation and depression. The skills of the separated from their world. If this disconnect child to address the emotional and psychosocial remains within the child’s limits of tolerance, it is aspects of transplantation depend on their age, 138 A. Castagna et al. development phase, cognitive level, individual post-HSCT time and during isolation and reinte- personality and type of psychological support. gration to life outside the hospital. Pre-transplant The hospitalised child receives important support predictors of QoL include family functioning and from their family. Parents are invited to actively individual resources. It is reported that during participate in the care of their child, and during hospitalisation, children undergoing HSCT pres- the period of transplant, a parent or a close family ent low baseline levels of QoL. However, QoL member usually stays with the child for the dura- improves as early at some months post-HSCT tion of hospitalisation. The experience of HSCT and returns to baseline within some years from should not hinder the psychosocial growth of the HSCT (Tremodala et al. 2009). child and may even aid the promotion of development and self-esteem. Nurses have a principal Cognitive Impact role in providing emotional support to the child The effect of HSCT on cognitive abilities may dif- and the family caregiver and can assist the child fer depending on age at HSCT and conditioning in understanding their condition and overcoming regimens, TBI containing regimes versus non- negative emotions. TBI. The younger the child is at HSCT, the higher the risk for deficits in intelligence quotient, aca- 8.1.4.1 The Paediatric Patient demic achievement, fine motor skills and mem- Experience of HSCT ory. The child with good cognitive developmental Paediatric patients undergoing HSCT can experi- level at the time of HSCT can be at lower risk for ence numerous psychological reactions during cognitive deterioration (Barrera et al. 2007). hospitalisation and recovery: Mental Health and Emotional Concerns • Anxiety Many paediatric HSCT patients demonstrate sta- • Depression ble psychosocial adjustment or return to baseline • Behavioural issues functioning 1 to 2 years after HSCT. However, • Psychosocial issues (adherence, self-esteem, psychiatric morbidity in HSCT survivors is social competence) reported in some studies as higher than in the • Post-traumatic stress reactions (Packman general population and appears to correlate with et al. 2010) lower educational level and shorter post-HSCT period. Furthermore, shorter time post-HSCT, Many of these concerns arise from lengthy higher numbers of major infections, high symp- hospitalisations away from home, school and tomatology score and low educational level are friends, isolation and an uncertain future. These predictive factors of higher psychosocial distress factors contribute to high levels of emotion at (Tremolada et al. 2009). admission and are reported to escalate until 1 Such psychosocial distress is not unique to the week post HSCT (Phipps et al. 2002). The paedi- immediate post-transplant period. There are con- atric HSCT patient can experience multiple hos- cerns later post-HSCT as well. At 1-year post- pitalisations, which can occasionally last up to 1 HSCT when many survivors return to school, year or longer depending on the severity of the they function at a lower academic level than what complications. HSCT and its immediate and late is expected for their age. They can be described consequences have substantial impact on the by peers as absent from school more, less likely child’s physical, emotional, cognitive, and social to be chosen as a best friend, less athletic and less well-being and consequently severely compro- attractive, and those who experience extensive mise the child’s quality of life (QoL). periods of isolation may demonstrate development decline in socialisation and communication QoL (Packman et al. 2010). There is a further possibil- QoL is potentially affected during all stages of ity of long-term emotional and social-behavioural HSCT, including pre-transplant, during the acute problems. 8 Transplantation Through the Generations 139

Depression and Anxiety It is important for the child to benefit from sib- Depression and anxiety in an ill child can result ling support. This can increase tolerance of diffi- in disability and morbidity and are associated cult conditions encountered during the HSCT with psychiatric illness (Chang 2012). Children and aid progress and recovery. During this time, undergoing HSCT are a high-risk group for they can develop deep sibling friendships, fed by developing these problems (Manookian et al. a desire to be more helpful especially when the ill 2014). Contributing factors include: sibling feels lonely. When stem cells are donated by one a sibling, the ill child experiences more • Intense medical treatments positive feelings about him/her (Manookian et al. • Single room isolation 2014). • Parental concern • Uncertainty and loss of control • Parental Concern

Almost all children report some difficulties There is a close relationship between the during the transplant process such as loneliness, child's adaptation to HSCT and the parent's psy- sense of fear and worsening depressive and isola- chological health and comfort (Asadi et al. tion symptoms (Packman et al. 2010). 2011).

• Intense Medical Treatments • Uncertainty and Loss of Control

The HSCT in the child can be associated with Transplantation should be viewed as a chance medical and psychosocial stressor. The main of hope for a healthy future and long-lasting hap- medical stressors identified to the child are medi- piness for the child. If he/she maintains this posi- cal interventions and treatment side effects. At tive attitude being hopeful about his/her recovery, the same time the psychosocial stressors can be the child can have a positive response from the recognise as missing home or social isolation. treatment and overcoming complications Therefore, the HCST can evoke in the child feel- (Manookian et al. 2014). ings of nervousness, sadness and anger. Support and Fostering Healthy Coping • Isolation Strategies As expected, most children experience a sense of It is widely recognised that physical isolation fear during their HSCT process. This feeling can could contribute to increased depressive symptoms be related to a lack of information or understand- during hospitalisation with factors such as strict iso- ing regarding his/her condition and conditioning lation and specialist care due to decreased immune and transplantation process. Providing clear and functioning potential stressors. During this time, understandable answers to the child’s questions their main concerns are separation from their family about the illness, treatment and prognosis can help members, or even from their toys or possessions, them feel reassured and more relaxed. Information inability to attend school or participate in normal seeking is an important coping strategy for chil- social activities. The common experience of all dren undergoing to HSCT. Developmental status these children is the feeling of loneliness. Reactions and psychological state should be considered to include depression, anger, frustration and attempts enable appropriate communication and provision to ‘overcontrol’ their life, food and hygiene. The of information. isolation period can be perceived as a loss of free- Coping strategies used to address a perceived dom and control and an intrusion on privacy. If iso- medical or psychosocial stressor may change lation is extended, due to problems related to HSCT, over time depending on personal factors and con- children can report declines in social competence text. The child can use several different coping and self-esteem (Packman et al. 2010). strategies which are often categorised: 140 A. Castagna et al.

• Approach (i.e. information seeking) • Loneliness • Avoidance (i.e. distraction or distancing) • Hopelessness • Problem-focused (i.e. problem solving) • Fear of disease recurrence • Emotion-focused (i.e. seeking emotional • Transplant centre relocation support) • Living in two separate households • Commuting between home and transplant Additionally, Bingen et al. (2012) observed centre wishful thinking, distraction, cognitive restruc- • Other family member’s and carer’s turing and social support being used both pre- responsibilities and post-HSCT. • Work-related changes • Lengthy hospital stays Social Support • Parental informed consent for the HSCT Social support is the individual’s perception of procedure positive regard from relationships with others, • Medication compliance the feelings to being loved, being part of a group, • HSCT-related complications reassurance of self-worth and reliable alliance with others (Barrera et al. 2007). Social support During HSCT, parents develop high expecta- is reported to be the most efficacious, for a child tion about a successful outcome and are afraid of undergoing a HSCT, whether this is from family, possible failure. The child's condition can cause friends, teachers, classmates and medical, nurs- parental distress, anxiety and depression. ing and psychosocial providers. It is both instru- Physical, emotional and cognitive exhaustion or mental and emotional and may be provided burnout in parents may adversely affect their directly to the child in the form of hospital visits ability to meet the needs of their child. They or via telecommunication (e.g. video calls, phone could be in extreme crisis and be unable to care conversation or texting, online social networking for their children or perform traditional parental sites and e-mailing). Higher or more positively roles and consequently have feeling of hopeless- perceived social support has been identified to be ness, concern and guilt. Parental psychological associated with positive adjustment, lower dis- reactions may in turn negatively affect the child. tress and higher self-esteem in paediatric patients The psychological load on parents continues undergoing HCST (Barrera et al. 2007). when the child is discharged from the ward. Burnout in mothers and fathers is associated with 8.1.4.2 The Parent Experience of HSCT the child’s number and severity of late effects up Asadi et al. (2011) reported in a qualitative study to 5 years after HSCT (Norberg et al. 2014). It is the Parents’ Experiences of their Children Bone recommended that parents of child that under- Marrow Transplantation. The experience of went HSCT should be followed up and receive HSCT is an unfamiliar, frightening, worrying and specialist psychological support, particularly for stressful experience for the parents of the child those whose child suffers from late effects. undergoing this treatment. Child-centred reasons Common coping strategy amongst families is include: use of social support. Parents’ interactions with their support network can alleviate stress and • Severity of the disease enable parents to adapt. Some parents feel that • Uncertain prognosis communication with family members of other • Complications and risks patients aids in acquiring information and in • Isolation of patients sharing of experiences and helped to take control • Long hospitalisation period of their emotions to reduce fear and become adaptive (Badon and Cesaro 2015). Caregivers Parent-centred reasons include: also attempt to cope by actively participating, • Family and financial pressures engaging in and asking questions pertaining to • Feelings of guilt their child’s medical illness and the procedures 8 Transplantation Through the Generations 141 involved in helping them. Parents who received matched siblings may feel content and proud that cognitive-behavioural stress inoculation training they are able to be a donor, the unmatched sib- in a group format had lower anxiety scores and lings may feel inadequate or rejected and unin- higher positive self-statement scores (Packman volved in the transplant process. Once HLA et al. 2010). They can also increase their coping typing has confirmed a sibling match, the workup strategies by interacting with other families who for most haematopoietic stem cell donors share the same problem. involves determining both the risks to the recipient and the risks to the donor. It is also important Creating a Therapeutic Alliance to consider that these various tests may be over- Parents and the healthcare team need to unite to whelming to the paediatric donor, and the impor- form a therapeutic alliance. Parents should be tance of explaining their necessity cannot be integrated into the multidisciplinary healthcare understated. The workup process may have a sig- team as appropriate. The healthcare team’s expla- nificant impact on the family. In 2010 the nations regarding the transplant process can help American Academy of Pediatrics published a them to better understand their conditions and, policy statement on children as haematopoietic consequently, can alleviate parental anxiety and stem cell donors. Children may ethically serve as fear of uncertainty and help to further reducing donors if five criteria are fulfilled: 1. There is no their emotional burden. medically equivalent histocompatible adult relative who is willing and able to donate; 2. there is 8.1.4.3 Sibling Donor Experience a strong personal and emotionally positive rela- in HSCT tionship between the donor and recipient; 3. there Matched sibling donors are often preferred over is a reasonable likelihood that the recipient will unrelated donors due to decreased risk of compli- benefit; 4. the clinical, emotional andpsychosocial cations. Most family members find the experi- risks to the donor are minimised and are reason- ence of donation as beneficial, despite some able in relation to the benefits expected to accrue concerns about the donation process itself (Pentz to the donor and to the recipient; and 5. parental et al. 2014). Sibling donors actively participate in permission and, when appropriate, child assent the effort to achieve cure for their sick sibling. are obtained. It is also recommended that the They have a dual role; as family members they donor child will have a donor advocate or some experience the difficulties of a life-threatening similar mechanism, with expertise in paediatric illness of one of their siblings. As donors they are development that should be appointed for all exposed to an invasive medical procedure which individuals who have not reached the age of adds anxiety, stress and uncertainty and places majority (Committee of Bioethics 2010). them in a complex situation (Munzenberger et al. The HSCT process can enhance family close- 1999; Williams et al. 2003). When a close rela- ness, improved relationships with the unwell sib- tionship exists between siblings, one can more ling and create a sense of pride and happiness safely assume that the donation will be of psy- about donating (Vogel 2011). Wiener et al. (2007) chological benefit to the donor (Vogel 2011). found that younger donors focus more on the However, sibling donors are at risk of developing pain of the donation and tend to experience low emotional disturbances such as post-traumatic self-esteem, anxiety, and depression. Conversely stress reactions, anxiety and low self-esteem and older sibling donors report lower levels of anxi- can potentially lead to the development of long- ety probably because they are able to think more term distress responses (Packman et al. 2010). globally about the donation process. Attention should be paid to the possibility of Studies of physical aspects and the safety of these issues. During the pre-transplant workup, stem cell collection in paediatric sibling con- potential donors may experience anxiety and fear cluded that it is a safe procedure even in young about the processes used to determine donor eli- children (Pulsipher et al. 2005; Styczynski et al. gibility as well as during the donation process 2012). There are potential physiological risks and itself (Bauk and Andrews 2013). Although side effects of donation with the most common 142 A. Castagna et al. being pain, fatigue and transient changes in the especially amongst nurses and parents, is difficult white blood count, haemoglobin and platelet val- to summarise. However, this triangulation ues. In the immediate days following the dona- involves many mechanisms, roles and functions tion, staff must closely assess the donor for and impact on different aspects of personality evidence of bleeding, infection and other acute and character. complications of the donation procedure. Feeling responsible for the transplant outcome is of nota- 8.1.5.2 Nursing Involvements in Care ble concern for sibling donors. Maladjustment of Children Undergoing HSCT and poor coping in sibling donors may be attributed in part to a lack of information about the Communication with the Child transplant process (Wiener et al. 2007). Undergoing HSCT The nurse can have a significant role in To employ an effective communication, profes- decreasing the sibling donor’s stress and anxiety sionals need to improve their listening and obser- about the impending donation. Providing accu- vation skills and exercise the ability to transmit rate and age-appropriate information about the ideas and feelings to others. impending procedure, the nurse may also help the child prepare for the experience and adapt to Information and Reassurance it more rapidly. This information increases the It is through age-appropriate dialogue that health- predictability of frightening medical procedures, care professionals can explain to the sick child thereby increasing the probability of a less stress- the sense of what is happening, the need for ful experience and a more rapid recovery. The frightening interventions, recognition and mean- nurse can also create opportunities to express ing of fears. The child must know that they will emotion, concerns and questions in order to man- never be left alone and nothing will happen that age anxiety and guilt, involve parents in the was not first controlled or decided by someone donor’s preparation and follow-up to ensure fam- else in whom they are confident (Manookian ily's communication during HSCT and organise a et al. 2014). tour of the hospital and an introduction to staff. The opportunity for the child to be properly informed allows them to become aware of what is happening to him in his life, to have greater 8.1.5 Centred Nursing Care familiarity with hostile hospital setting and be of Patients and Caregiver’s able to work together in their treatment path. Undergoing HSCT Communication about the transplant process between the care staff, child and family can be Psychological and emotional aspects of the pae- further complicated by the different opinions diatric experience are complex and intricate. with respect to what it is to be explained to the Health workers who take care of the sick child sick child. In general, it is preferred to adopt an should be the privileged listeners of the child and attitude that respects the will of the parents, but be receptive to the child's point of view creating this can lead to difficulties when it is the child opportunities to talk. themselves asking or looking for other information. The information, however, allows a reduc- 8.1.5.1 The Relationship Between tion of the perception of pain, an increase in the Nurse, Caregiver and Child child's compliance and a general improvement of The approach of the paediatric team is strongly the quality of life in the hospital (Badon and characterised by interpersonal and communica- Cesaro 2015). The child who reports more free tion methods that are centred on empathic under- expression of emotion in their family in turn standing, smiling, patience and gentleness. The experiences lower levels of distress throughout relationship between nurses and children, but the transplant period. Openness and honesty in 8 Transplantation Through the Generations 143 communication in the family environment can 8.2 Transplantation Through encourage the emotional well-being of child and the Ages: Teenage and Young further promote their resiliency after the HSCT Adults (TYA) procedure is complete (Packman et al. 2010).

Listening Abstract During the ages of 13–24, a person The ability to listen allows us to establish con- will undergoes perhaps the most rapid and forma- structive relations. A real attitude to listening tive changes of their life. The journey of transi- implies the attention, interest, tolerance, under- tioning from child to adult can be severely standing and acceptance of the other. All of these impacted when undergoing hospital treatment are necessary preconditions for the establishment such as a haematopoietic stem cell transplant of an open relationship in which it is easier for the (HSCT) and complicates an already turbulent child to express and give information about him- time. TYA patients present health professionals self. It is useful to encourage the patient to express with a unique set of challenges, and it is impor- themselves freely because, in addition to contain- tant that care settings are designed to address and ing their distress, it is possible for the nurse to bet- respond to the particular needs of young people ter understand the organisation of their personality and their families. and the defences put into place to cope with the situation (Badon and Cesaro 2015). 8.2.1 Introduction Psychological Support Service Psychological support services are well devel- A cancer diagnosis in young people is rare, oped and considered the standard of care in pae- with over 14000 15–24-year-olds diagnosed diatric HSCT settings. Psychological support is across Europe yearly (Stark et al. 2016). It is a configured, therefore, as the accompaniment's growing number; the incidence of cancer in relationship of an entire family system in all this group has increased by 50% in the past 30 phases of the transplant path. The presence of years (Grinyer 2007). In response to this, guid- psychologist with the child who undergoes ance such as that published by the National HSCT: Institute for Health and Care Excellence (NICE) aims to shape services and care to the • Enables meaningful relationships to develop needs of the TYA patient, which spans the ages • Facilitates understanding the illness of the of 13–24 years old (National Institute for child in all its complexity Health and Clinical Excellence 2014). This is • Makes request for help, expressed or implied, in response to research suggesting that this age in view of practical difficulties, organisational, group were receiving inadequate care when relational and emotional that may arise. being treated in the paediatric or older adult setting as they have their own particular needs The intervention must be thought according to (Whiteson (2003). Patients undergoing HSCT age, and even if the parent is always present in require long-term clinical care beyond the the isolation room, one can try to find some pri- acute phase of transplant and will be in regular vate moments between patient and psychologist. contact with transplant clinicians and the mul- The attention to psychological and psychopatho- tidisciplinary team (MDT) for a significant logical aspects is not realised only through spe- amount of time after bone marrow recovery cialised interventions, but it must be realised and discharge from inpatient care. Care must every day by all staff members. Even the nursing be delivered within age-appropriate surround- staff, if trained, may perform work in the role of ings by health professionals experienced in counsellor or coach (Barrera et al. 2007). caring for this group. 144 A. Castagna et al.

8.2.2 Special Indications for HSCT aries of their growing independence. At a time in TYA (AYA) when peers are being afforded greater freedoms, often a cancer diagnosis re-establishes the depen- The most common indication for HSCT in the dency relationship between the young person and TYA age group is in the treatment of malignant their family. Smoking, drinking alcohol, use of haematological diseases lymphoma and acute recreational drugs and engaging in unsafe sexual leukaemia (Transplant 2015). Patients with non- practices can allow the young person to regain Hodgkin’s lymphoma, acute lymphoblastic leu- some control, as can determining how compliant kaemia or acute myeloid leukaemia HSCT will they choose to be with treatment. In the context be considered if high-risk, refractory or relapsed of HSCT, indulging in unsafe behaviours can disease. In the case of Hodgkin’s lymphoma, increase the risk of organ toxicity and infections. guidelines for teenagers indicate avoiding HSCT Failing to comply with supportive medications in the case of successful complete remission such as anti-infectives and immunosuppressives (CR) following first line of chemotherapy as che- increases the morbidity and mortality rate of motherapy alone usually yields successful long- HSCT. As teenagers often focus on short-term term outcomes. However, once a patient requires outcomes if the effects of non-compliance are not second- or third-line treatment, the need for immediately obvious, this can reinforce the HSCT becomes more important (Transplant behaviour. Similarly if there have been immedi- 2015). Standard recommendations are for an ate side effects to therapy, e.g. nausea and weight autologous transplant following successful CR gain, the patient may be less likely to adhere to after second-line treatment. Failure to obtain medical advice. Patients who are compliant to remission at this stage opens up the possibility of treatment are almost three times more likely to allograft, but this would require further discus- have a better outcome than those who are not sions with local MDT. Full-intensity allografts (Taddeo et al. 2008). are more routinely used in the younger adult Gender, socio-economic status and ethnicity patients as opposed to the older population as do not have an impact on whether a patient they tend to not have comorbidities associated adheres to care (Kondryn et al. 2011). Depression with getting older, e.g. heart disease, and as such and lowered self-esteem can increase rate of non- can tolerate stronger conditioning. compliance, as can the perception of the illness A small number of HSCTs are carried out severity. The relationship between the patient and every year for solid tumours. According to British their family can impact on how compliant a Society for Bone Marrow Transplant (BSBMT) young person is with family conflict increasing data, there were 162 transplants carried out on the risk of non-adherence. Young patients who solid tumour patients of any age in 2015 within are treated in specialist young adult ward are the UK, all of which were autografts (BSBMT more likely to be compliant compared to those 2015). The most common solid tumours for who are treated in an adult cancer unit, further which HSCT is indicated includes neuroblas- supporting the development of clinical areas ded- toma, germ cell and Ewing’s sarcoma with clini- icated to the care of the adolescent and young cians using transplants to increase dose intensity adult. This will be discussed further in the (Gratwohl et al. 2004). chapter. Health professionals should be aware of the signs of non-compliance and facilitate an open 8.2.3 Considerations for Care and honest conversation with the patient. Confidentiality should be respected although in 8.2.3.1 Risk-Taking Behaviour the instances where risky behaviour is disclosed, and Non-compliance patients should be made aware if it is necessary to Becoming a teenager can herald a time of risk- inform other members of the team. Healthy life- taking behaviours as adolescents push the bound- style choices should be promoted but within a 8 Transplantation Through the Generations 145 non-judgemental environment. It is important methods have yielded limited success. Embryo that young patients are aware of appropriate collection can be difficult in this age group as boundaries whilst in hospital and local conduct, they are unlikely to be ready to consider their cur- and operational policies must support staff in rent partners as a potential lifelong spouse challenging risk-taking behaviours within the (Levine and Stern 2010). Furthermore there is the care environment (Smith et al. 2012). added issue of time as it can take 2–4 weeks to harvest reproductive material from females. 8.2.3.2 Fertility However female patients should partake in a full Fertility has been covered elsewhere in other discussion about fertility preservation and be chapters, but there are challenges unique to this offered the opportunity to be referred to fertility age group which will be addressed in this section. experts as part of HSCT workup. Total body irradiation (TBI) and high-dose con- Discussions about fertility preservation should ditioning chemotherapy are highly likely to cause take place as early as possible, and parents should infertility. As often the type of transplant for the be included in order to support the teenager in TYA patient is a full-intensity approach, this their decision-making. Psychological input makes the risk of infertility a likely side effect of should be offered, as infertility can be one of the HSCT. If applicable, patients must be advised most impacting aspects of long-term survivor- about the options of fertility preservation as part ship, and there are many cultural, religious and of transplant workup and given the opportunity to social stigmas attached to being unable to bear a explore fertility preservations options although child. Although a difficult topic, in a study by the urgency of the transplant may make this Saito et al. (2005), young male patients indicated difficult. that the process of sperm banking was a positive In a study of TYA patients by Smith et al. one as they found it gave them some hope in the (2007), fertility counselling was only provided to cancer journey, even if the sperm was never used. 36% undergoing treatment for cancer. Barriers to communication include a mutual awkwardness 8.2.3.3 Impact of Treatment between the TYA patient and health professional on the Family Unit when it comes to the topic of fertility. Clinicians Healthcare professionals looking after the TYA can employ a jocular approach to young patients population must also care for the family unit and and find it difficult to broach sensitive topics approach care holistically. During the ages of (Quinn et al. 2009). Patients can feel confused 13–24, young people undergo many develop- and frightened about the potential effects of can- ments in relation to the family unit. They may cer treatment, or they are unable to envisage how still be dependent on their parents, or they them- fertility issues will impact them in the future selves may have their own children and responsi- (Smith et al. 2012). bilities. Care needs to be adapted accordingly. For post-pubertal males, fertility preservation With TYA patients who are parents, often can be achieved through obtaining a sperm sam- children will be babies and preschoolers. Moore ple. Prior to attending fertility sessions, it should and Rauch (2006) described what parents can be clearly explained that the sample is obtained expect from this age group in the context of a through masturbation, so they are prepared for cancer diagnosis; even with age-appropriate the process. Sperm banking can potentially be an explanation, under 5s will have little awareness embarrassing process. Failing to bank a sample of the diagnosis and aims associated with can leave the young person feeling disappointed HSCT. What they will be aware of is the absence and let-down, and it should be reinforced that not of a parent, stress in the household and changes all attempts at sperm banking are successful. to their routine. Rather than understand that these Female fertility preservation is a more com- are caused by illness, the child may believe that plex process. Ovarian stimulation and oocyte col- they are somehow responsible for the absence. lection may be considered, but currently such Parents may also recognise regression in the 146 A. Castagna et al. child’s behaviour, such as bed-wetting in previ- on consenting a minor for stem cell collection in ously toilet-trained children. their 2015 guidelines (Human Tissue Authority Parents of HSCT patients can find their rela- 2015 ). tionship health with their partners placed under There is a significant potential for psychologi- considerable strain. In Long and Marsland (2011) cal impact on those siblings who undergo HLA the authors noted that the needs of the parents tissue typing, regardless of whether they actually were put on hold to prioritise the needs of the turn out to be a match or not. In MacLeod et al. TYA patient. In the case of hospitalisation, paren- (2003) siblings reported feeling as if they had ‘no tal separation places even further strain as there is choice’ about being tested and donating if a decrease in communication, interaction and matched. Reluctance was often not because they closeness between spouses. Reaction to the treat- did not want to help but rather the fear of the pro- ment process varies according to gender. Males cedure. In the case of siblings who were not try to withhold emotion to remain strong for their matched, they described feelings of relief but also families, leaving them feeling quite isolated. To guilt. If they were matched but the sibling died, their partners they can be perceived as cold and donors felt angry and blamed themselves, espe- uncaring. Differences in approach can cause cially in the context of graft failure or graft- emotional distance and feelings of loneliness. versus-host disease. By comparison, siblings in However in some partnerships, going through the Wiener et al. (2008) found that the process of experience of having a child with cancer can donating harboured an increase closeness make the partnership stronger, with spouses between themselves and their siblings and their being viewed as the main source of support. parents. Being able to help gave them a sense of There has been limited research on the effects pride. Response to the process does seem to be of HSCT on the siblings of the recipient. One of linked to whether the transplant was successful or the few studies performed by Pot-Mees and not. A further family stem cell source is the par- Zeitlin (1987) found that siblings developed new ent. In the case of failing to find a suitable donor behavioural problems during and after their through siblings or the register, often parents will brother or sister’s HSCT. The respondents make a motivated stem cell donor. However, as in described feelings of post-traumatic stress disor- the case of the sibling, parents can also be left der, anxiety and low self-esteem as their family with profound feelings of guilt if the transplant model was perceived as ‘abnormal’ and ‘inter- fails (Barfield and Kodish 2006). rupted’. Parents and health professionals should Health professionals have a duty to care for include the sibling in discussions about their the family as a unit. Through the use of multidis- brother or sister, provide them with choices and ciplinary team meetings, staff should be aware of create a safe hospital environment to help them family dynamics. Healthcare professionals adjust to the HSCT experience (Wilkins and should guide patients and their families on appro- Woodgate 2007). priate open communication though needs will Unlike other areas of medicine, family mem- vary depending on the family. For patients who bers may be directly involved in the treatment of are parents of young children, they should reas- HSCT patients by becoming the stem cell donors sure the child that mum or dad’s absence is not and as such a second patient. Siblings are usually their fault and that they have done nothing wrong. the first option for a stem cell source. This can Donors, whether siblings or parents, should be create an ethical dilemma for parents and health- involved in the HSCT process from the start, and care staff, especially if the potential donor is a the complex variables associated with transplant minor. What if the child refuses? What are the success be carefully explored. Members of the limitations of parental decision? What are the MDT, such as psychologists, youth support work- consequences for the child who refuses to donate? ers, school teachers, social workers etc. should be The Human Tissue Authority provides guidance involved early in the journey with patient con- 8 Transplantation Through the Generations 147 sent. Creating a family-friendly space in the clin- 8.2.3.4 Body Image ical environment can encourage children and Side effects of drugs used in the HSCT process siblings to visit. Key workers should be aware of can cause significant physical changes to a support networks and resources locally to refer or patient’s appearance. This is not exclusive to the signpost as appropriate. TYA patient but can be more psychologically harmful as they are at an age where physical appearance is central to their world and when feeling different from peers can have a negative Case Study impact on self-esteem (Smith et al. 2012). Issues A 14-year-old girl was treated in a TYA such as weight gain and alopecia can have a psy- unit for acute lymphoblastic leukaemia. chological impact which is greater compared to From an early point in treatment, it was the older adults. Appearance concerns amongst clear that disease was high risk due to exist- TYA cancer patients have been linked to lower ing cytogenetics and poor response at reas- self-esteem, depression, anxiety, feelings of lone- sessment. She was placed on UKALL 2011 liness and suicidality and decreased treatment Regimen C but experienced complications compliance (Fan and Eiser 2009). including methotrexate encephalopathy Weight loss is an inevitable part of the acute and drug reactions to asparaginase and the and recovery phase of HSCT as patients struggle alternative, erwinase. Treatment was sub- with the gastrointestinal side effects of treatment. optimal. The clinical team decided to test For female patients, weight loss can alarmingly her brother and sister to plan for a sibling seem like a positive aspect of treatment in line allograft when a repeat bone marrow with societies’ perceptions of what is attractive. showed a significant amount of minimal The opposite is true of male patients. It is becom- residual disease after 6 months of treating more normal for young males to try to obtain ment. Her sister was found to be a 10/10 a muscular physic through careful gym and diet HLA match. However her mother struggled regimens. Often newly diagnosed young males greatly with the fact that her ‘healthy’ child are bulky with little body fat. Anecdotally the would be put through procedures, espe- biggest struggle they tend to have is with muscle cially as she was only 10 years old. The wasting aspect of HSCT, in the context of fatigue, younger child was clear on her intention to poor appetite and reduced exercise tolerance. help her sister but did experience distress Research into this area with the TYA population when subjected to blood tests. This exacer- is limited although a study by Rodgers et al. bated the inner turmoil felt by her mother (2010) interviewed TYA patients on their experi- as she worried about the eventual bone ences of nutrition post-HSCT. Participants marrow harvest and openly discussed described abnormal appetites until day 50 post- refusing consent for the procedure in front HSCT, by which point they were able to manage of her 14-year-old daughter, despite know- a small amount of food. Progress continued, with ing that finding an alternative stem cell stark improvement in feeling hungry by day source was unlikely as the patient was from +100. Participants were able to correlate the link a complex ethnic background. With the between improved eating habits and appetite with help of the available psychological team returning to their ‘normal selves’, advising future and activity coordinators at the paediatric patients to have some control over what they eat and TYA centre the patient, her sibling, and portion size rather than being forced into eat- mother and family received separate coun- ing by parents and health professionals. selling, and the resulting harvest was Weight and hair gain is something that not successful. everyone associates with chemotherapy. Often media depictions of cancer patients include 148 A. Castagna et al. gaunt, cachexic figures with alopecia. For patients this age undergoing a HSCT experience social receiving high-dose steroids, for example, in the isolation from their friends and community. This treatment of graft-versus-host disease, a typical is not only due to physical absence from school, side effect includes development of facial swell- university and work but also a difficulty on the ing, known as ‘moon face’ and unwanted facial part of the healthy young person to understand hair. This can drastically alter appearance and be and empathise with the experiences of their devastating for a young person. This can also unwell friend (Thomas et al. 2006). From the per- lead them to become non-compliant to the treat- spective of the survivor of a HSCT, they can find ment with poor consequences for their treatment it difficult to relate to their peers after what they success. have been through. In interviews with Forinder Alopecia is a common and well-known side and Posse (2008), TYA HSCT patients felt they effect of chemotherapy and usually one of the first had a different perspective on life, with material things TYA patients ask about when discussing things and physical appearance not being as treatment. Hair is often very much tied into iden- important as they once were. That said, subjects tity, and the idea of losing it can make some teenag- were conscious of their change in appearance and ers refuse treatment when the idea is initially upset at looking different to those in their social discussed. Youth support workers and nurse spe- network. cialists are excellent at helping to organise a The relationship between the parents and the replacement before hair loss starts to occur (usually unwell adolescent is difficult to navigate. 2 weeks after the start of chemotherapy). There are Necessary increased dependency is at odds with wigs made of real hair which can often be difficult the need for autonomy that is typical at this age. to identify next to the real thing. However a lot of This can lead to direct conflict between the two hair replacement focuses on females, with male parties, especially once the TYA patient has com- patients finding options to be limited. pleted the acute phase of the transplant. A sharp Conditioning regimens containing TBI can difference of priorities can exist between parent impact on the growth of patients who are treated and patient (Grinyer 2009). Research also sug- at a young age, i.e. prepubertal (Leiper 1995). gests that TYA patients may not have fully devel- This is due to the radiation administered to the oped executive function due to regression and hypothalamic-pituitary axis and the resting cognitive development delay which adds to the reduction to the growth hormone. Replacement tension between the parent and patient relation- therapy can aid to reduce further loss of height, ship (Kaufman 2006). but cannot reverse loss. Clinicians need to care- Survivorship is a growing area of research as fully monitor growth of patients to ensure early outcomes from cancer treatment improves. intervention (Lowis 2000). Health professionals and researchers recognise that completion of cancer treatment is the start of 8.2.3.5 Impact on Life a difficult journey of adjustment and transition. Approximately 60% of children and adolescents Clinical staff need to consider the fall out of treat- who are long-term survivors of HSCT experience ment, and patients should be aware that they can late effects, both of the physical and psychologi- and should continue to access support. Treatment cal nature (Forinder and Posse 2008). Fertility within dedicated TYA clinical areas can help and growth issues have been covered already in patients to access peer support which is tailored this chapter, and organ toxicity associated with more to their development needs. HSCT is written about in other sections of this book. There are other ways that HSCT impacts of life which are unique challenges to the TYA 8.2.4 Teenager as a Child vs. Adult patient. For the adolescent and young adult, peers are Under 18s present legal challenges for healthcare an important feature of life. However patients of professionals as the young person must be assessed 8 Transplantation Through the Generations 149 on their ability to make appropriate decisions ‘consenting on behalf of a child’ as the former about their care on an individual basis. In the fol- relates to the concept of a third authority, i.e. the lowing section, issues of consent, confidentiality parent, and is slightly different from informed and guardian roles are discussed. Much of this part consent. As informed consent is an expression of will discuss current legislation within the personal choice, it can only relate to the person UK. Health professionals should refer to local leg- being treated. Authorising treatment is acknowl- islation for further clarity. edging that it is in the best interests of the child. Furthermore the Oviedo Convention requires that 8.2.4.1 Consenting for Treatment the opinion of the minor must still be taken into Informed consent is a cornerstone of medical consideration. Thus the decision-making process practice. Violation of this has legal implications involves three parties: the clinicians, the person for clinicians but more importantly jeopardises with parental responsibility and the child under- the ethical rights of the patient (Bayer et al. going treatment (Nicolussi 2015). According to 2011). In order to satisfy the principles of the Children Act 2004, parental responsibility informed consent, it must be given freely and extends to the child’s parents if married at the with full comprehension. Patients must be pro- time of conception or birth, the child’s father if vided with adequate information in understand- not married to the mother but who features on the able terms. Treatment options should be reviewed, birth certificate or the child’s legally appointed and a discussion about the risks, benefits and guardian or a local authority who has been alternatives to the proposed treatment should take granted a care order in respect of the child. place and be documented. Signing of a consent Scenarios where there are disputes between form is symbolic, representing completion of the parties involved in treatment decisions are rare consenting process. but do occur. This can be between patients and Informed consent is a relatively straightfor- their parents, between health professionals and ward process when concerning over 18s as long the family or between parents to provide more as the individual has capacity. In the UK, patients common instances. A well-known example is between 16 and 18 can consent for treatment but when parents who are Jehovah’s Witnesses refuse may not be able to refuse treatment in the case of blood transfusions on behalf of their child. saving their lives or preventing serious harm. Cultural beliefs should be respected, but bone Under 16s may legally consent if they meet cer- marrow failure can be a life-threatening compli- tain criteria of being Gillick competent. This cation of HSCT. In instances such as this, which principle is based on a case in the 1980s where can be pre-empted, plans should be made about Victoria Gillick took her local authority to court how to deal with the complication before it arises, to prevent them from providing contraception to i.e. the use of erythropoietin as an alternative. her children without her knowledge (Wheeler Unfortunately not every eventuality can be con- 2006). The high court determined that minors sidered, and advice may need to be sought under 16 have the potential to independently con- through legal channels which will provide pro- sent to treatment if deemed competent to do so. tection to the patient, family and the health pro- However it is a good practice to involve the young fessionals concerned. person’s family in the process. In the case of under 18s who are deemed Gillick competent but 8.2.4.2 Communication refusing treatment, it is possible for the decision Regardless of whether a minor is able to consent, to be overturned where it will lead to death or they should still be encouraged to participate in serious injury (Department of Health 2009). discussions about their care, and if they choose to In the case where a minor cannot indepen- attend consultations, information should be dently consent and parental involvement is directed at them. Healthcare professionals should required, the Oviedo Convention recommends give the same time and respect to young people the use of the term ‘authorisation’ rather than as they would do to adult patients. Information 150 A. Castagna et al. should be provided using language that is under- and if the patient is engaging in activities that standable, giving all involved parties the opportu- might put them at risk, e.g. serious addiction and nity to ask questions. Discussions should be self-harming. truthful and open, with consideration given to confidentiality. The information provided should be appropriate to the age of the young person and 8.2.5 TYA Cancer Care in Europe: include a discussion about: A General Review

• Their illness and proposed treatment Across Europe, cancer is the second cause of • The purpose of investigations and treatments death amongst 15–24-year-olds (Gatta et al. and what they involve 2009). Despite this, the services for this popula- • Benefits and risks, including of not having tion remain in the developing stage in compari- treatment son to that of children or older adults. This is a • Who will be responsible for their care strive for change, and an example of this is the • Their right to ask for a second opinion or European Network for Cancer Research in retract consent if deemed capable (GMC Children and Adolescents (ENCCA) programme 2007) which aims to share knowledge and services across the continent. Stark et al. (2016) sum- If is justifiable to keep the above information marised the work across individual countries and from the young person if you think that it will set out guidelines with collaborative aims to: cause them serious harm (this does not include concerns about upsetting them) or if the patient • Not necessarily have agreed age cut-offs set asks you not to tell them, preferring to leave across Europe; rather treat according to the someone else to make the decision for them. needs of their population. Often guardians and young people can strug- • Provide an age-appropriate environment for gle to have honest discussions together as they TYA patients to complete their care, with ser- are afraid of upsetting each other especially in the vices tailored to the needs of the patient and context of sensitive subjects. It should be made family. clear to the young person that they can have con- • Have an active relationship between paediat- sultations on their own. A chaperone may be ric and adult oncologists or a dedicated TYA appropriate, although this could deter the young team, including specialist health professionals person from having a frank discussion. such as nurses, social workers, psychologists, teachers and activity coordinators. 8.2.4.3 Confidentiality • Have a fertility preservation programme. Respecting confidentiality is important in har- • Have a transition programme for those mov- bouring good relations with young people, making from child to TYA services and TYA to ing them feel confident about seeking care and older adult care. advice. If required to share information with par- • Have clinical trials available to the TYA popu- ents or other health professionals, the young per- lation in varying tumour groups. son should be made aware and agree. If they refuse, there are still circumstances where infor- Stark et al. (2016) also summarised progress mation should be disclosed including where it of individual countries in regard to TYA care: would be in the public’s best interest, when it is The UK pioneered the TYA model back in the in the best interests of the young person when 1990s through collaboration between the Teenage they lack capacity and when disclosure is required Cancer Trust (TCT) and National Health Service by law. Examples include if the information (NHS). As such the pathway swell is defined. All would help prevent or prosecute in the case of a TYA patients with a cancer diagnosis must be serious crime (usually against the young person) discussed at a TYA MDT, and those between 13 8 Transplantation Through the Generations 151 and 19 must be treated in a dedicated TYA centre. (Lassaletta et al. 2013). TYA oncologists and The service undergoes yearly peer review, and patients have founded the charity ‘Spanish lead clinicians are at the forefront of specialist Association of Adolescents and Young Adults networks. There is a separate TYA clinical stud- with Cancer’ to create support for young people ies group with the aim of including the availabil- with cancer and push the TYA agenda. ity of trials to this patient group. TYA health In Denmark a TYA project started by nurses professionals have their own UK professional commenced in 2000 at Aarhus University. A membership organisation which provides peer national initiative is also being planned to bring support and sharing of information between ser- together the collective view of young patients, to vices. There are 25 TYA centres across the create TYA-focused unit and to specialise county, and development of such services is dis- treatment. cussed in detail in the next section. In 2013 in the Netherland health professionals In Germany there is separate infrastructure for started a national TYA project dedicated to the paediatric and adult cancer patients with a strict care of 18–35-year-olds and focused on quality age barrier of 18 years separating them. The of life, late effects and fertility. majority of adolescent care is performed within In Portugal that is no national project yet, but paediatric oncology. However practice is chang- in Lisbon a project has commenced to create a ing and a collaborative approach is happening, TYA unit for patients aged between 16 and 25. In with some centres creating TYA-specific MDT other countries, e.g. Belgium, Bulgaria, Czech programmes. Republic, Ireland, Greece, Hungary, Lithuania, In Italy the Committee on Adolescents was Norway, Poland, Romania, Slovenia and Sweden, formed by the Associazione Italiana Ematologia there is no national project yet, but there are some Oncologia Pediatrica in 2010 to ensure TYA can- local projects occurring. cer patients have prompt, adequate and fair access to the best care. Since then two TYA units have been opened. A national task force dedicated to 8.2.6 Development of TYA Cancer teenagers and young adults with cancer was set Units: The UK Experience up in 2013 to push the agenda for TYA care further. It was first recognised that young UK patients In France research by Desandes et al. (2012) had specific needs in the 1950s with the publica- showed that 82% of 15–18-year-olds with cancer tion of the Platt Report (Ministry of Health 1959 were treated in an adult environment and few ). Publication of the Calman-Hine report in 1995 were enrolling clinical trials. This prompted the particularly acknowledged the issues faced by initiation of an improvement plan. Since then young cancer patients. Treating 13–18-year-olds eight TYA units and three specialist centres have in the same units as toddlers or over 18s with the been opened with dedicated teams; improve- elderly fails to provide care that meets their ments have been made to the inclusion of TYA needs. The UK has been at the forefront of devel- patients in clinical trial, and a specific psychoso- oping TYA-specific treatment areas; however, cial programme has been initiated. The Institut age-appropriate care is still not available to all. de France planned to create localised care path- The Teenage Cancer Trust charity was set up ways and has started a national association to over 10 years ago to act as support and advocate focus on cancer care for patients between 15 and for young people facing cancer. Alongside other 25 years old. charity organisations internationally including In Spain in 2011 the Adolescents with Cancer CanTeen Australia, CanTeen New Zealand, Committee was set up by the Spanish Society of LIVESTRONG and SeventyK, they created the Paediatric Haematology; however, a survey in International Charter of Rights for Young People 2014 showed that over 14-year-olds were still with Cancer which states that young people with generally being treated in adult care settings cancer should: 152 A. Castagna et al.

• Receive education about cancer and its During the development stage of a new unit, prevention often patients will be asked for their opinion and • Be taken seriously when seeking medical input into the facilities and design. Use of the attention to ensure that they receive the earli- internet is important in this age group as a means est possible diagnosis and referral for a sus- of staying in touch with normality whilst an inpa- pected cancer tient, so facilities should be provided. Patients • Have access to suitable qualified health pro- should have access to appropriate equipment fessionals with significant experience in treat- including game consoles, music, pool tables etc. ing patients with cancer in this age group Designated recreational areas can provide a space • Access to suitable clinical trials for patients to socialise and relax away from their • Receive age-appropriate support hospital beds. This can also encourage peer sup- • Empowered in making decisions port as patients interact in communal spaces. • Fertility preservation Support for the young person can be gained by • Access to specialised treatment and services having somebody staying with them, and clinical in age-appropriate facilities areas should be able to accommodate. This is • Financial support often possible in paediatric and teenage settings • Long-term survivorship support but can be difficult to provide in adult units. The ethos of TYA care is to approach holisti- The Teenage Cancer Trust was set up over a cally. This is achieved by presenting each new decade ago and works in partnership with the patient at weekly TYA and site-specific MDTs. National Health Service to open inpatient and During TYA MDTs, health professionals from outpatient cancer units, providing education, spe- across the service attend to participate in discus- cialist staff and annual meetings to raise aware- sions about new patients and their planned treat- ness of the issues associated with caring for this ments. All TYA patients, irrespective of place of age group. In 1990 they opened the first dedi- treatment, should be discussed at a TYA MDT to cated unit at the Middlesex Hospital in London ensure that they have the opportunity to receive and currently have 28 units operating across the the correct support. According to (Smith et al. UK. Other European countries have followed 2012) barriers to setting up a TYA MDTs, includ- with the Institut Gustave-Roussy in Paris opening ing time constraints, perceived duplication and in 2003 (Whelan 2003). Development of TYA- resources. However uses of MDTs are thought to dedicated units is down predominantly to initia- improve clinical trial recruitment, outcomes and tives in response to local needs rather than a multi-agency working. general coordinated health policy. As a conse- Due to duration of follow-up post-HSCT, quence there is great variation in the provision of patients may be required to transition as they pass services for TYA patients with cancer across the landmark birthdays. This should be a planned UK. In 2005 the National Institute for Health and process that addresses the needs of TYA patients Care Excellence (NICE) published recommenda- with chronic health problems as they move from tions for health professionals treating teenager child-centred care to the TYA setting or TYA and young adults with cancer. Amongst the care to the adult health system. This can be a dif- guideline was advice about where young people ficult time for patients and their families as they should be treated; under 18s should be treated in leave behind the team that has moved them a principle treatments centre, and those 19 and through the acute phase of the HSCT process and over should be offered a choice about where they with whom they have built up a strong bond. go. Principle treatment centres are designed to Planning may take a number of months and offer expert medical care, an age-appropriate should be approached sensitively. The process environment, psychosocial support and access to can be helped by patients visiting the new units a multidisciplinary team. and good communication between all parties. 8 Transplantation Through the Generations 153

8.2.7 Summary logical malignancies are increasing, yet the majority of our experience is with patients under • TYA cancer patients include those aged the age of 65. between 13 and 24 years old. Older patients however represent a very het- • Often HSCT indications in this age group are erogeneous group with respect to overall health for malignancies including refractory or status; some individuals stay fit, whilst others are relapsed leukaemia and lymphoma. frail or become fragile suddenly. • There are unique challenges facing this age group In order to help healthcare professionals decide when diagnosed and undergoing treatment. on the best treatment option for their older patients, • One significant challenge is the impact that a geriatric assessment (GA) ( Extermann et al. 2005) cancer diagnosis has on the family unit espe- can identify unknown medical, functional, cogni- cially in the younger siblings providing the tive and social issues, making it possible to plan stem cell. early interventions. Although GA still requires • Even when considered a minor, patients do prospective validation in larger cohorts, this still need to be assessed for competence and assessment is able to predict survival and toxicities afforded the same respect as adult patients. and to detect unknown geriatric problems. • Partnership between the NHS and charities A substantial percentage of older adults have such as the Teenage Cancer Trust can provide more difficulties processing and remembering an age-appropriate environment for patients information than younger ones. It is important to and their families. make sure that also older adults understand their • There is still much work to be done across disease, the prognosis and the treatment plan to Europe to ensure each patient is getting care make an informed decision. Therefore, it is that is responsive to their needs. essential to assess cognitive functioning and in case of mild cognitive impairment that the information is tailored to reflect the individual’s 8.3 Transplanting the Adult needs. and the Older Adult: Nursing Most healthcare professionals working in hae- Considerations matology settings are not trained in geriatrics. The aim of this section is to describe GA, to provide information about the increasing prevalence Abstract Older people are usually identified by of certain risk factors (impaired cognitive func- their chronological age, and persons aged 65 tion, medication non-adherence) and how patient years or over are often referred to as ‘elderly’ information can be adjusted to the needs of older (WHO 2010). The median age at diagnosis of patients. patients with acute myeloid leukaemia (AML), myelodysplastic syndromes (MDS), chronic Keywords Older patients • Fragile • lymphatic leukaemia (CLL), multiple myeloma Geriatric problems • Geriatric assessment • (MM) and non-Hodgkin’s lymphoma (NHL) is Patient information over 65 years old (Eichhorst et al. 2011; NCI 20003; Palumbo and Anderson 2011; Sekeres 2010; Smith et al. 2011; Siegel et al. 2015). Most 8.3.1 Differences Between Older of these haematological diseases are not curable and Younger Patients unless an allogeneic or autologous haematopoietic cell transplantation can be performed. The incidence of acute myeloid leukaemia Currently the indications for and subsequently (AML), myelodysplastic syndromes (MDS), the use of haematopoietic cell transplantation as chronic lymphatic leukaemia (CLL), multiple a treatment option in older adults with haemato- myeloma (MM) and non-Hodgkin’s lymphoma 154 A. Castagna et al.

(NHL) increases with age, with the majority of social issues, making it possible to uncover patients being over 65 years of age (Eichhorst potential problem areas and plan early interven- et al. 2011; NCI 20003, Palumbo and Anderson tions. Although GA still requires prospective 2011; Sekeres 2010; Smith et al. 2011; Siegel validation in larger cohorts, and in the transplant et al. 2015 ). Most of these haematological dis- setting (Elsawy and Sorror 2016), this assess- eases are not curable unless the appropriate allo- ment is able to predict survival and toxicities geneic and/or autologous haematopoietic cell (Artz et al. 2006; Palumbo et al. 2015) and to transplantation is performed. detect unknown geriatric problems, making it Chronological age is becoming less of a bar- possible to plan early interventions and to influ- rier to reduced-intensity conditioning in alloge- ence treatment decisions (Kenis et al. 2013). neic haematopoietic cell transplantation (HCT), and as a result, HCT in the older adult population is increasing. However the majority of experi- 8.3.2 Geriatric Assessment ence with stem cell transplantation remains amongst younger adults. GA strategies need to be implemented early on in the patient pathway in order to facilitate decision- Older age is still associated with: making in relation to the optimal approach to • Pharmacokinetic and pharmacodynamic treatment. It can assist in identifying patients changes most likely to benefit from standard induction • An increased risk of toxicities and infectious and post-remission therapies, as well as in the complications from chemotherapeutic agents consideration of performing a HCT. To deter- • An impaired immune system mine the best treatment for the patient, GA is • A high prevalence of comorbid conditions and needed to systematically uncover medical, func- an overall worse performance status tional, cognitive and social issues, which may compromise the treatment. Table 8.2 provides an These factors may result in higher risks of overview of domains and tools commonly used. non-relapse death after both autologous and allo- Domains are assessed by means of commonly geneic HCT (Artz and Chow, 2016; Mamdani used tools to measure functional status, cognitive et al. 2016). function, nutritional status, comorbidities, poly- Older patients represent a very heterogeneous pharmacy and socio-economic status. Some use group in terms of health and functioning; as this in combination with a short screening tool to whilst some individuals remain fit, others are detect vulnerability. An appropriately trained frail or become fragile suddenly. healthcare professional can perform the assess- More than half of adults aged over 65 have ment, and in some cases this may be a nurse. GA three or more medical problems (Boyd et al. instruments aid in identifying potential problems; 2012) and may be taking multiple medications, however, when the problem is identified as being making care more complex. severe, a thorough assessment is needed to under- In older patients, therapeutic decisions are stand the cause. In order to optimise the outcomes widely based on the patient’s age, general health, of the older patient, a geriatric intervention or the disease features, as well as the patient’s per- referral may be necessary, for example, to the sonal wishes, and clinical judgement. However, geriatrician, dietician, physiotherapist, social even amongst older patients with a good perfor- worker or psychologist. mance status, geriatric impairments are reported A full GA can be time-consuming and burden- (Extermann et al. 2005). In order to help health- some for HCP who are not trained in the evalua- care professionals (HCP) work with patients and tion of older adults. The use of more simplified caregivers to decide on the best treatment option, screening tools like the Vulnerable Elders Survey GA can be used to objectively evaluate patients, (VES) (Saliba et al. 2001) and G8 screening tool identifying medical, functional, cognitive and (Soubeyran et al. 2011) (see Table 8.2) can be 8 Transplantation Through the Generations 155

Table 8.2 Comprehensive geriatric assessment domains and commonly used tools, and screening tools Domain Tools Reference Functional status Performance Status (PS) Karnofsky and Burchenal (1949), and Mor et al. (1984) Activities of Daily Living (ADL) Mahoney and Barthel (1965) Instrumental Activities of daily Living (IADL) Graf (2008) Self-reported number of falls Peeters et al. (2010) Comorbidities hematopoietic cell transplantation comorbidity Sorror et al. (2005) index (HCT-CI) Polypharmacy comprehensive drug review Geriatric syndromes Mini mental State Examination (MMSE) Folstein et al. (1975) Geriatric Depression Scale (GDS-15) Almeida and Almeida (1999) Nutrional status Malnutrition Universal Screening Tool (MUST) Stratton et al. (2004) Simplified Nutritional Assessment Questionnaire Kruizenga et al. (2005) (SNAQ) Mini Nutrional Assessment Short Form (MNA) Guigoz (2006) Screening tool Vulnerable elders survey Age Saliba et al. (2001) Self-rated health 6 physical function limitations 5 IADL/ADL items G8 Screening tool Appetite, Weight loss, BMI Soubeyran et al. (2011) Mobility Mood and cognition Number medications Patient-related health Age categories employed in an initial appraisal, identifying those ping, cooking and managing finances, which are who would benefit most from a more detailed and required for independent living. complete GA. Evaluation of gait difficulty and self-reported number of falls may also be useful when looking 8.3.2.1 Functional Status at functional status. Problems may be caused by An important determinant of frailty is func- fatigue, muscle weakness, dizziness or neuropa- tional status, including Karnofsky’s perfor- thies induced by cancer or its treatment and can mance status (PS) (Karnofsky and Burchenal cause significant mortality and morbidity. 1949; Mor et al. 1984), the activities of daily living (ADL) (Mahoney and Barthel 1965) and 8.3.2.2 Vision and Hearing the instrumental activities of daily living (IADL) Impairments (Graf 2008). The PS is utilised routinely in HCT Many older adults have either a visual impair- and is a global estimate of the overall health of ment, a hearing impairment, or both. There is evi- patients according to their doctor. The ADL dence of an association between hearing measures the level of independence or depen- impairment and cognitive decline amongst older dence of patients and, in terms of limitations to adults (Valentijn et al. 2005). An evaluation of self-care, mobility and being able to walk and visual and hearing acuity of any patient should be continence status. undertaken during the physical assessment. The IADL describes the more complex ADLs Where possible, hearing and visual impairments necessary for living in the community and should be corrected, so that elders can function assesses the competence in skills such as shop- better, promoting greater independence. 156 A. Castagna et al.

8.3.2.3 Comorbidity and Polypharmacy Assessment of cognitive function is included Typical older adults have multiple comorbidities. as a domain in GA. In addition, the Mini-Mental For HCT, comorbidity can be assessed by using State Examination (MMSE) is widely used as a the haematopoietic cell transplantation comor- screener for cognitive impairment and for demen- bidity index (HCT-CI) introduced by Sorror et al. tia in older persons (Folstein et al. 1975) . in 2005, as an evaluation of organ dysfunction for potential HCT recipients. The HCT-CI was 8.3.2.5 Geriatric Syndromes developed from the historical Charlson comor- Geriatric syndromes include dementia, depres- bidity index (Charlson et al. 1987). sion, delirium, osteoporosis, falls and fatigue. Due to existing comorbidities, the older Specific geriatric syndromes can be assessed patient is often taking multiple medications – with instruments such as the MMSE and the each with their own side effects, interactions and geriatric depression scale (GDS-15) (Almeida contraindications. Polypharmacy, (defined as an and Almeida 1999). The MMSE assesses to excessive number of medication ( ≥5)), is some- which degree the person is alert, oriented and times further increased by medications which can able to concentrate and perform complex mental be bought over the counter without prescription. tasks and affective functions and detects signs of Some of these medications may interact with pre- dementia (Folstein et al. 1975; Sattar et al. 2014). scribed cancer treatments or even supportive The geriatric depression scale (GDS-15) medications such as immunosuppressive agents searches for signs of depression (Sheikh and that are used following HCT. A comprehensive Yesavage 1986; Almeida and Almeida 1999). drug review is strongly advised before initiating The presence of dementia and/or depression is therapy and then regularly throughout the associated with a negative impact on survival patients’ treatment pathway to maintain accurate (Pallis et al. 2010). records of concomitant drugs and ensure avoidance of potentially inappropriate medications. 8.3.2.6 Medication Adherence During HCT it is imperative that patients adhere 8.3.2.4 Cognitive Functioning to the prescribed treatment. Non-adherence leads Although cognitive decline is acknowledged to to poorer health outcomes, such as increased increase with age, significant variability is noted incidence of transplant-related morbidity and amongst the older population (Greene and mortality, higher cancer recurrence rates and Adelman 2003). They define mild cognitive shorter survival (Puts et al. 2014). impairment as ‘deficits in memory that do not Older age has not been identified as a risk fac- impact on daily functioning’. tor for non-adherence, unless the older adult him- However, consequences of even mild cognitive self perceives insufficient social support. For impairment are significant because these patients older adults, certain factors are known to impact may have more difficulty understanding the risks upon medication non-adherence. These include and benefits of treatment and also adhering to factors relating to the healthcare system and the complex cancer treatment regimens. It should be treatment team: remembered that a diagnosis of cognitive impairment does not necessarily mean that the patient is • High cost of medication whilst patient income incapable of making decisions and consenting. is low Most patients are still able to understand the risks • Incomplete insurance coverage and benefits of treatment and of being involved in • Lack of coordinated care research. It is important that researchers do not • Individual factors such as misunderstanding automatically exclude patients with cognitive of instructions, intentional choice of medica- impairment from treatment but that every effort is tion and non-adherence to accommodate the made to ensure that patients are fully informed in individuals’ lifestyle and daily activities (Van order to be able to give their consent. Cleave et al. 2016) 8 Transplantation Through the Generations 157

Whilst there is no screening tool currently • Social companionship available for non-adherence in gero-oncological • Informative support patients, there are several existing medication adherence scales available to assess patients’ Everyone needs everyday support in a certain adherence to medication (Lam and Fresco 2015). way. The type and amount of support needed will depend on the individual and also the phase of the 8.3.2.7 Nutritional Status illness and treatment. Consideration should also Nutritional deficiency and malnutrition are com- be given to the well-being of the caregiver as the mon in older adults. The presence of weight loss quality of life and quality of care of the patient and/or anorexia points towards malnutrition, also depend upon this factor. which increases vulnerability to illness. In order to determine nutritional status, screening instru- 8.3.2.9 Decision-Making ments like the Malnutrition Universal Screening Older persons may have grown up in a health- Tool (MUST) (Stratton et al. 2004) or Simplified care culture where decision-making was more Nutritional Assessment Questionnaire (SNAQ) paternalistic. As a result, this may either lead to (Kruizenga et al. 2005) are available. In all these lower requests for information by the patient or screening instruments, unintentional weight loss to a risk of poor overall communication. For in a short time is a fixed-item parameter to evalu- most young patients, the decision and desire to ate malnutrition. In order to diagnose malnutri- be transplanted are often clear. For older tion, the Mini Nutritional Assessment (MNA) patients however, the decision is often far less (Guigoz 2006) can be used. The MNA assesses: obvious, and the choice to proceed to HCT is a complex one (Randall et al. 2016). Patients • Decline in food intake might think they are ‘too old’ for HCT or be • Weight loss, mobility concerned whether they can find an available • Neuropsychological problems caregiver and whether they have enough money • Body mass index for extra costs incurred or that it will impair • Number of medications taken per day their quality of life (Randall et al. 2016). • Patients’ assessment of their health status Medical information about the general process compared with others their own age and outcomes of the transplant, donor sources, medications, timelines, and risks and benefits of A multidisciplinary approach to nutrition the procedure are usually provided after induc- assessment, care planning, intervention and eval- tion therapy has been successful. However, uation in HCT patients should be advocated older people have more difficulties processing where possible, with the involvement of health- and remembering information than younger care professionals such as dieticians and nutrition ones (Posma et al. 2009), and cognition may specialist teams in collaboration with the medical have been affected further by the chemotherapy and nursing team. that has been given (Williams et al. 2016). It is important, therefore, to provide education about 8.3.2.8 Socio-economic HCT, which is gradual and repeated during Social support, persons’ general living conditions induction and, afterwards, presented using plain as well as availability and adequacy of caregivers language, empowering the older patient to make should be an integral part of GA. There are differ- the decision about transplant (Randall et al. ent types of support, such as: 2016). 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Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Early and Acute Complications and the Principles of HSCT 9 Nursing Care

Elisabeth Wallhult and Barry Quinn

Abstract Haematopoietic stem cell transplantation (HSCT) generally includes preparative or conditioning regimes containing chemotherapy and/or radiotherapy in high doses. These regimens, as well as other treatments before and after HSCT such as immunosuppressive drugs to prevent graft versus host disease (GvHD) (see Chap. 11), may affect the patient’s organs and tissues and may cause both acute and long-term complications. In the evolving field of stem cell therapies, some complications that traditionally have been regarded as early complications are now, due to changes in preparative regimens and choice of stem cell source, sometimes seen later in the post-transplant out-patient setting. The complications covered in this chapter generally occur within 100 days post HSCT and are thus classified as early complications. Two of the most common early complications are oral complications/mucositis and sepsis. Some other relatively rare complications are also covered here: haemorrhagic cystitis (HC), endothelial damage (ED) syndromes including engraftment syndrome (ES), idiopathic pneumonia syndrome (IPS), diffuse alveolar haemorrhage (DAH), transplant-associated microangiopathy (TAM) and sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD). For all complications, recommendations for prevention and principles for nursing care are presented since careful nursing monitoring, prompt intervention and care may have an influence on patients’ morbidity and mortality.

E. Wallhult (*) Section of Hematology and Coagulation, Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden e-mail: [email protected] B. Quinn Woking and Sam Beare Hospices, Surrey, UK e-mail: [email protected]

© EBMT and the Author(s) 2018 163 M. Kenyon, A. Babic (eds.), The European Blood and Marrow Transplantation Textbook for Nurses, https://doi.org/10.1007/978-3-319-50026-3_9 164 E. Wallhult and B. Quinn

Keywords Oral complications • Mucositis • Sepsis • Haemorrhagic cystitis SOS/VOD • Endothelial damage syndromes

Table 9.1 Oral complications of HSCT include 9.1 Oral Care in Transplantation Oral mucositis Xerostomia Oral infections Oral graft versus host disease Ulceration Trismus 9.1.1 Introduction Taste changes Halitosis Bleeding Dry lips Mindful of the many developments in the field of Pain Dental decay HSCT aimed at improving survival and quality of Osteonecrosis Fibrosis life, the correct and consistent approach to man- Leading to difficulties in eating, sleeping and talking and aging oral care problems still remains a challenge a reduction in quality of life in many transplant settings across Europe. There is much evidence to show that rather than taking a proactive approach to this aspect of care, many opportunity for infection to flourish, and in par- clinicians simply react to oral complications once ticular putting the severely immunocompro- they occur with a sometimes inconsistent and mised patient in the HSCT setting at risk of anecdotal approach. sepsis and septicaemia. Oral problems and damage may be temporary OM and oral problems in the HSCT setting or permanent resulting in a significant health bur- (Table 9.1) can be expected to occur in as many den for the individual while making substantial as 68% of patients undergoing autologous HSCT demands on limited healthcare resources. and 98% of patients undergoing allogeneic HSCT However, oral complications are not always inev- (Filicko et al. 2003; Bhatt et al. 2010). With the itable, and much can be done to reduce or mini- increasing use of targeted drug therapies and mise the severity of symptoms by taking a more approaches in the cancer and haematology set- proactive approach to this aspect of care. Working ting, problems in the oral cavity will increase and as a multidisciplinary team with the patient at the become even more of a challenge (Quinn et al. centre of care and treatment plan, the early detec- 2015). tion of potential and actual problems and treatment can help to reduce oral problems and prevent interruptions to treatment while maxi- 9.1.3 Key Principles of Treatment mising patient safety and comfort (National Cancer Institute 2013). All treatment strategies aimed at improving mouth care are dependent on four key principles: accurate assessment of the oral cavity, 9.1.2 Oral Mucositis (OM) individualised plan of care, initiating timely preventative measures and correct treatment Oral mucositis (OM) has been defined by (Quinn et al. 2008). The assessment process Rubenstein et al. (2004), Al-Dasoogi et al. should begin prior to HSCT by identifying all (2013) and others as the inflammation of the the patient risks most likely to increase oral mucosal membrane, characterised by ulceration, damage. Each patient needs to be assessed in which may result in pain, swallowing difficul- relation to the following risk factors that may ties and impairment of the ability to talk. The put them at higher risk of oral complications mucosal injury caused by OM provides an during treatment: 9 Early and Acute Complications and the Principles of HSCT Nursing Care 165

• Pre-existing dental problems 9.1.5 Care of the Oral Cavity • Prior treatment • Older patients and females (at higher risk of Care of the oral cavity is central to helping to pre- oral damage) vent and/or reduce oral complications during and • History of alcohol and/or tobacco use after treatment. The oral care team in the HSCT • Poor nutrition and hydration setting includes dental professionals, dietician, • Supportive feeding (nasogastric, PEG, RIG) nurse, doctor and pharmacist. The support pro- • Supportive therapies (opiates diuretics, seda- vided by the team along with good communica- tives, oxygen therapy – may cause dryness) tion and the patient at the centre of all care plans is central to maintaining patient’s oral health. Patients about to commence HSCT should All patients should be provided with clear undergo dental assessment by a specialist (Elad instructions and encouraged to maintain good et al. 2015). This is to establish general oral health oral hygiene. Education should also include status and identify and manage existing and/or potential oral complications to enable patients to potential source of infection, trauma or injury. Any identify and report these early (Clarkson et al. identified dental problems should be corrected 2011; Quinn et al. 2015). All patients should before starting treatment regimen. Some patients receive written information, as well as verbal will need regular dental follow-up following treat- instruction, about oral care as part of the preven- ment. A further baseline assessment of the oral tion and treatment of oral changes. mucosa should be taken as close to the administra- Good nutrition is vital in helping to fight tion of the first treatment dose as possible. infection, maintain mucosal integrity, enhance The oral cavity should be assessed by trained mucosal tissue repair and reduce exacerbation of healthcare professionals using a recognised existing mucositis. Issues that may affect nutri- grading system to ensure accurate monitoring tion such as loss of appetite, taste changes and and record keeping. The tool chosen should con- dysphagia should be addressed. tain both objective and subjective elements. The There are certain foods that can damage the assessment should include changes to the oral oral mucosa; this may include rough, sharp and mucosa, the presence or absence of pain and the hard foods and should be avoided. Spicy, very patient’s nutritional status (Quinn et al. 2008). salty and acidic foods may cause mucosal irrita- Assessments should be completed daily dur- tion but may be preferred or tolerated by some ing HSCT and at regular intervals posttreatment patients. to monitor for complications. Patients can be Brushing of teeth, gums and tongue should be encouraged to assess their own mouth using a performed two to four times a day preferably patient-reported tool and to report any changes after meals and before going to bed (Peterson they notice or experience to the transplant team. et al. 2015). Soft-bristled toothbrush (manual or electric) is recommended to prevent injury to the oral mucosa and must be rinsed thoroughly with 9.1.4 Inspecting the Oral Cavity water after each use. If the mouth is painful or patients cannot open their mouths fully, soft oral • Clinical tools: good light source, gloves, sponges may be used. tongue depressor and dry gauze To prevent infections, the toothbrush should • Patient in convenient and comfortable be stored with the brush head upwards and not position soaked in disinfectant solution. These should also • Use valid and reliable assessment instrument be monitored for evidence of fungal/bacterial which is easy to interpret colonisation. In order to protect the enamel, non- • Oral sites to be evaluated (cheeks, lips, soft abrasive toothpaste containing mild fluoride palate, floor of mouth, tongue) (1000–1500 ppm) should be used. 166 E. Wallhult and B. Quinn

Daily interdental cleaning with brushes may • Educate and encourage self-reporting of any reduce plaque formation between the teeth oral changes (Sambunjak et al. 2011). However, the use of • Good and regular oral hygiene including gar- interdental cleaners should be used with caution gling to remove any unwanted debris for patients with thrombocytopenia or clotting • Interdental cleaning disorders. • Fluoride toothpaste/foam/gel/tray After each meal, dentures must be rinsed. • 0.9% sodium chloride/saltwater rinse Thorough cleaning by brushing with soap and • Early nutritional intervention water should be performed at least twice a day. • Cryotherapy/sucking ice chips during melpha- Dentures should be cleaned, dried and stored in a lan infusion closed container overnight (Duyck et al. 2013). • Consider oral rinses (Caphosol®, Benzyda The goal of using mouthwashes may include mine®) oral hygiene, preventing/treating infection, • Mucosal protectants/barrier rinses licenced to moistening the oral cavity or providing pain use as a preventative measure/reduce pain relief. As a minimum to keep the mouth clean, (Mugard®, Episil®) bland gargles and rinses with water, normal saline • Anti-infective prophylaxis (0.9% NaCl) and saltwater are recommended at • Palifermin least four times a day (Lalla et al. 2014; Quinn • Low-level laser therapy et al. 2015). Some patients will require assistance; it may be necessary for healthcare professionals to per- 9.1.7 Anti-infective Prophylaxis form/support oral care through rinsing with normal saline (0.9% NaCl) (Elad et al. 2015), with or While good oral hygiene is fundamental, anti- without suction. fungal and antiviral treatments will be prescribed Lubricants, lip balm or lip cream may be used to reduce infections in patients in the transplant to moisten the lips. setting. Patients should receive an antifungal Patients should maintain adequate hydration agent given orally or intravenously. Antiviral and drink water frequently to keep the mouth prophylaxis should also be given. The choice of moist. Several factors could contribute to dryness drug will be dependent on local policies/ such as oxygen therapy and supportive care medi- guidance. cations (e.g. antidepressants, antihistamines, seda- tives and opioids). To keep the oral mucosa moist, regular sipping or spraying water may help. Use of 9.1.8 Treatment of Oral saline sprays and mouthwashes as well as use of Complications saliva substitutes may be used. There is anecdotal evidence that fresh pineapple chunks may also All treatment plans should be based upon the help stimulate saliva but should be used with cau- grading of oral damage and patient reports; these tion as their acidity could irritate the oral mucosa may include the following. and affect the teeth (Lalla et al. 2014). 9.1.8.1 Mild/Moderate Mucositis/Oral Complications 9.1.6 Prevention of Oral Mucositis • Once oral damage develops, patients should be supported to continue oral care. The choice of prevention regimens should be • Frequency of oral rinsing may be increased. guided by evidence-based or expert opinion inter- The aim is to keep the oral surfaces clean and ventions, working with the individual patient and moist (Elad et al. 2014). the potential risk of oral mucositis which may • Check for oral infections, swab and treat include the following (adapted Quinn et al. 2015). appropriately. Review of antifungal treatment, 9 Early and Acute Complications and the Principles of HSCT Nursing Care 167

local or systemic, should be administered if patient by some of these oral care products. required (Watson et al. 2011). Institutions can offer a range of mouthwashes • Dexamethasone containing gels may be used selecting the most appropriate for the clinical for aphthous lesions. situation and the patients trying out which one • Consider mucosal protectants (Quinn et al. works best for them. Generally spoken, topical 2015). antibacterial substances are not recommended. • Dietary requirements should be assessed and The use of oral rinses, topical gels or films can be foods causing discomfort avoided. individually considered. Any with sufficient • Swallowing problems, malnutrition and safety and positive experiences can be used: weight loss should be monitored and patients Caphosol®, Mugard®, Oralife®, Gelclair® and given support/advice. Adjustments to food Episil® are just a few of them. consistency, methods of intake, food fortifica- For systemic pain medication, it is useful to tion and methods of intake should be assessed, follow a step-by-step increase, with the aim of support and education offered to patients. Use the patient becoming pain-free within 24 h. It can of supplement drinks, PEG, RIG or nasogas- be helpful to monitor the efficacy of pain medica- tric feeding should be considered (Quinn et al. tion with pain assessment tools. Institutions 2015). should follow a standardised pattern of pain med- • Fluid intake should be assessed and route of ication following the WHO recommendations administration of pain relief continually moni- where applicable. tored. General health problems should also be In severe mucositis, the use of opiates with the assessed (swallowing of tablets, decreased optimal application route should be considered. blood sugar levels and decreased blood pres- The best route of application depends on many sure, decreased renal function leading to over- individual and setting factors and may be oral, dosing of substances). subcutaneous, intravenous or transdermal with • Patients will need adequate pain medication patches. Patients may require a combination of including topical and systemic analgesia such slow-release and fast-acting drugs. Patient con- as paracetamol, codeine, morphine rinses, trolled analgesia should be considered. Careful Benzydamine mouthwash, trimecaine and monitoring should include pain relief and any lidocaine. Patients should be offered educa- potential side effects, and including family tion on use and possible side effects including members may prove helpful to obtain a wider numbness of the oral mucosa. view of how well the patient copes outside the treatment unit. 9.1.8.2 Severe Mucositis/Oral Complications 9.1.8.3 Treatment of Specific Oral • Increase pain medication following patient Complications needs • Increase nutritional support Bleeding from OM • Increase oral rinses and care Continue mouth gargling. Tranexamic acid has been widely used in oral surgery, and gargling/ When oral damage progresses, closer moni- swishing with tranexamic acid (500 mg) as a toring and support for patients is required. An mouthwash may be worth considering (Watson important aspect of care is to control the pain et al. 2011). thereby helping the patient to continue food and fluid intake, communication and sleep. Xerostomia (Dry Mouth) For topical treatment the use of topical analge- As this may be due to or increased by concurrent sics can be intensified. There is insufficient evi- mediation, a review of the patient’s medications dence that many products reduce the severity of is needed and if possible adjustments made. mucositis but comfort can be provided for the Patients should be encouraged to increase sip- 168 E. Wallhult and B. Quinn ping of fluids. Artificial saliva, viscous solutions supervised to address longer-term and late and gels to protect and moisten the mucosa complications. should be considered; patients should be counselled on correct application. In chronic radiotherapy-related xerostomia, pilocarpine 9.1.10 Conclusion should be used. The principles presented here are intended as a Trismus (Spasm of the Jaw Muscles) support and in no way should replace clinical deci- This is a common side effect during and post sion-making related to the particular patient and high-dose radiotherapy. Patients should be given clinical situation. Depending on the severity of helpful exercises, and the team may consider oral complications and the impact on the patient, mechanical devices to help alleviate the problem. the team will need to review the plan of care.

Graft Versus Host Disease (GvHD) Acknowledgement European Oral Care in Cancer Group Oral damage may be a hallmark of graft versus (EOCC). host disease (GvHD) in patients following allogeneic stem cell transplantation, and the presence of lichenoid hyperkeratotic plaques (diagnostic 9.2 Sepsis and Principles sign), gingivitis, mucositis, erythema, pain, xero- of Care stomia and ulcers may indicate GvHD. Kuten- Shorrer et al. (2014) suggest that solutions of 9.2.1 Introduction dexamethasone or other steroids are used as first- line treatment; second-line may include solutions The increased risk of infections in patients under- of steroids in combination with other immuno- going haematopoietic stem cell transplantation suppressant drugs. (HSCT) is well known, and infection is a leading cause of morbidity and mortality. HSCT patients are particularly at risk, especially during the neu- 9.1.9 Posttreatment Care/ tropenic period following the conditioning treat- Follow-Up ment. In HSCT patients, signs and symptoms of sepsis may be subtle and difficult to recognise Oral damage in the HSCT will require several due to neutropenia or other complications of the weeks/months to heal, and patients need continu- transplant procedure. Preventive measures should ing support and care during this period. Advice be applied, but vigilance and close monitoring of and support by suitably qualified health profes- the patient, strong team collaboration and imme- sional should continue during this period. Support diate action will allow for prompt and appropri- to manage side effects including pain and the ate management of septic patients. gradual reduction of analgesia is extremely important. Chronic side effects may include dental decay, 9.2.2 Definition of Sepsis trismus, fibrosis, lymphedema, chronic xerostomia and chronic pain and will require careful There are multiple definitions and clinical criteria management. All patients should be individually for sepsis. The terms below are all terms for assessed and appropriate care and treatment severe infection where bacteria may or may not given. Follow-up care should be planned and be identified in blood cultures. 9 Early and Acute Complications and the Principles of HSCT Nursing Care 169

• Sepsis which particularly profound circulatory, cellular • Severe sepsis and metabolic abnormalities are associated with a • Septicaemia greater risk of mortality than with sepsis alone. • Septic syndrome The table below has limited clinical diagnostic • Septic shock relevance but is a schematic description of the evolution from systemic inflammatory response According to the Third International Consensus system (SIRS) to septic shock (Table 9.2). It is Definitions for Sepsis and Septic Shock (Sepsis-3) worth noting that the symptoms of SIRS will not (Singer et al. 2016), sepsis can be defined as: delineate between SIRS and sepsis itself, and A life-threatening condition caused by aberrant and since many of the signs and symptoms may be dysregulated host response to infection. The patho- present in HSCT patients, an individual assess- biology is still not completely known but the diver- ment, including other examinations as well, needs gent infection response injures the body’s own to be performed for the diagnosis of sepsis. tissues and organs and causes organ dysfunction. The consequence of the inflammatory That is also what differentiates sepsis from infec- response and evolution of sepsis is called the sep- tion in general. Septic shock is a subset of sepsis in sis cascade and is illustrated in Fig. 9.1.

Table 9.2 Evolution from SIRS to septic shock Term Definition Signs and symptoms Systemic inflammatory The body’s response to different Fever (>38 °C) or hypothermia (<36 °C) response system (SIRS) severe clinical insults, which may or Pulse rate > 90 beats/min may not be infection Respiratory rate > 20/min WBC >12 x109/L or <4 ×109/L or >10% bands

Sepsis Systemic inflammatory response SIRS symptoms caused by infection Evidence of infection

Severe sepsis Sepsis with hypoperfusion or acute Sepsis with:Increased lactate level organ dysfunction or hypotension Mental changes, Saturation < 90% Decreased urine output Increased liver function tests levels Reduced platelet levels Abnormal coagulation parameters Systolic blood pressure < 90 mmHg

Septic shock A subset of severe sepsis with Severe sepsis with:Vasopressor requirement hypotension despite adequate fluid Serum lactate level > 2 mmol/L (>18 mg/dL) resuscitation and with presence of At least two of the following quick Sequential perfusion abnormalities that may [sepsis-related] Organ Failure Assessment include lactic acidosis, oliguria or (qSOFA) clinical criteria: alteration of mental status Respiratory rate of ≥22/min Altered mental status Systolic blood pressure ≤ 100 mm Hg 170 E. Wallhult and B. Quinn

* Oedema Capillary * Decreased urinary output leak Microvascular * Tachycardia, with an initially bounding injury pulse which will then become weaker * Increased respiratory rate Inflammatory Hypotension response

Vasodilatation Decreased Hypovolemia renal blood flow

Poor tissue perfusion

Tissue hypoxia Release of oxygen and with anaerobic lactate for metabolism metabolism causing metabolic acidosis

Fig. 9.1 The sepsis cascade starts with an inflammatory microvascular injury and vasodilation. The vasodilation response that will cause microvascular injury, vasodila- will also cause decreased renal blood flow. The hypovole- tion and tissue hypoxia. The microvascular injury will mia will cause poor tissue perfusion causing tissue lead to capillary leak resulting in oedema, decreased uri- hypoxia with anaerobic metabolism. In this process oxy- nary output, tachycardia, with an initially bounding pulse gen and lactate are released for metabolism and thus caus- which will then become weaker, and an increased respira- ing metabolic acidosis (E-learning package Sepsis and tory rate. Hypotension is another symptom caused by both Sepsis Six http://sonet.nottingham.ac.uk/, 2017)

9.2.3 Risk Factors (aGvHD). Indwelling catheters such as peripheral cannulas, central lines, urinary catheters and In the early phase of HSCT, i.e. day 0 to day pyelostomy catheters are a potential port of entry +100, the main risk factors for infections are for microorganisms into the blood stream. (Rovira et al. 2012): 9.2.3.3 Depressed T- and B-Cell 9.2.3.1 Neutropenia Function A longer period of neutropenia can be expected Allogeneic transplant is always followed by in allogeneic than in autologous transplant. The long-lasting immunodeficiency. Conditioning stem cell source also affects the length of the treatment may include T-cell depleting agents neutropenic period where peripheral blood and even non-myeloablative regimens cause lym- (PBSC) has an expected neutropenic phase of phodepletion with prolonged periods of immune about 2 weeks, bone marrow (BM) 3 weeks and incompetence. Donor type and degree of histocom- cord blood (CB) 4 weeks. patibility (human leukocyte antigen (HLA) match) Myeloablative conditioning (MAC) treatment are other factors that influence the time to immune will cause a longer neutropenic phase than reconstitution. Immunosuppression for GvHD pro- reduced intensity conditioning (RIC). phylaxis is necessary in allogeneic HSCT and will delay immune reconstitution (Toubert 2012). 9.2.3.2 Barrier Breakdown All kinds of barrier breakdown will increase the 9.2.3.4 Presence of Acute Graft Versus infection risk and mucositis occur in almost all Host Disease (aGvHD) transplant patients.Skin breakdown can be caused Need for immunosuppressive treatment will by, e.g. drugs and acute graft versus host disease increase the risk for infections. 9 Early and Acute Complications and the Principles of HSCT Nursing Care 171

Mucosal or skin barrier breakdown further 9.2.5 Diagnosis and Management increases the risk. Early recognition and treatment is vital for a suc- 9.2.3.5 Poor General Status cessful outcome of sepsis. Temperature, pulse, If the patient is not in remission at HSCT, there is blood pressure, respirations and saturation (vital a greater risk for infection and sepsis. signs) should be frequently monitored. Signs of Comorbidity, such as diabetes, is another risk infection are not always obvious, but if the patient factor. has a temperature ≥38.0 °C, cultures should be taken, i.v. antibiotics and i.v. fluids started or increased and oxygen therapy initiated. The goal 9.2.4 Strategies for Sepsis is always to start antibiotic treatment within 1 h Prevention from detection of fever (Swedish “Pro Sepsis” Programme Group Sepsis 2015). This is some- The most important action to prevent infections times referred to as “the golden hour” (or “door acquired by exogenous organisms is good hand to needle time” for patients admitted from out- hygiene performed correctly. All clinical staff side the hospital) and is the most critical period in should also wear a uniform that is clean and short the patient’s survival from sepsis. sleeved. Protective isolation during the neutrope- Recognising sepsis can be a challenge in nic phase is recommended, and the patient should HSCT patients during the immediate posttrans- not be in contact with any staff or visitors with plant period where often a plethora of symptoms symptoms of infection. For prevention of endoge- are present but also after discharge, in the outpa- nous infections, oral hygiene and skin care to tient setting, since some symptoms are rather maintain the mucosal and skin barrier and use of unspecific. Other than fever, chills or rigouring, prophylactic antibiotics are the most important feeling unwell or different (without clear expla- actions. Correct handling of any indwelling cath- nation), changes in behaviour or mental changes, eters is also a key nursing responsibility in infec- feeling faint or changes in skin tone can indicate tion control. sepsis. An increased respiratory rate can be seen Other areas where infections can be pre- even if saturation is normal. An increased pulse vented are air and water quality, food hygiene and lowered blood pressure may be noted. Some and the environmental cleaning. Environmental patients may not develop fever, and hypothermia, cleaning includes medical equipment as well. i.e. <36 °C, can also be a sign of sepsis. If an out- For more detailed guidance on infection control, patient with symptoms that could be sepsis- see Chap. 7. related reports a normal body temperature, it Routine surveillance screening for infection by should be checked again in the clinic with a reli- bacterial and/or fungal cultures, i.e. blood, urine, able thermometer and correct method. Diarrhoea faeces, swabs from nasopharynx and central line and vomiting are frequently seen in sepsis but can insertion site and serum galactomannan blood test, easily be mistaken for gastroenteritis, mucositis may allow for earlier identification and implemen- or acute graft versus host disease (aGvHD). tation of therapy, although the benefit of such rou- Diffuse or local pain, e.g. in the abdomen, is tines can be discussed (Nesher et al. 2014). Regular common. Falls are often secondary to sepsis par- monitoring of blood tests such as full blood count, ticularly in elderly patients. Any of these indices electrolytes, urea and/or creatinine and C-reactive need prompt and thorough assessment. protein (CRP) may assist in detecting any changes The concept of the Sepsis Six has been devel- that could indicate infection. oped as a guide to prioritise interventions in patients Prophylactic antibiotics, e.g. fluoroquino- where sepsis is suspected (Daniels et al. 2011). lones, antifungal and antiviral medication, will be used in most HSCT patients, at least during the 1. Oxygen therapy neutropenic phase. 2. Blood cultures 172 E. Wallhult and B. Quinn

3. I.v. antibiotics treatment has been initiated, the patient must be 4. Fluid resuscitation continually monitored to determine the effect of 5. Serum lactate treatment or worsening of the condition. This 6. Assess urine output (may require catheteri- includes vital signs, fluid balance including sation) weight and assessment of identified and/or potential infection sites (mouth, skin, any indwelling When sepsis is suspected, all cultures should be or tunnelled catheter, urine, stools, etc.), mental taken prior to commencing antimicrobials, if possi- status, signs of bleeding, pain and general appear- ble (Rhodes et al. 2017). Cultures should be taken ance and well-being. from central lines, wounds, nasopharynx, urine and Antibiotics should be delivered with strict faeces. It is also sensible to consider peripheral i.v. adherence to the prescribed time schedule. cannulae as a possible source of infection. Despite Antipyretics should be avoided since they may conventional practice to collect blood cultures at a mask fever but may under certain circumstances fever spike in order to increase the chances of be used to alleviate patient discomfort and pain. detecting bacteraemia, there is so far no data to sup- Laboratory tests results will guide the need for port this principle (Kee et al. 2016). Testing could electrolyte replacement and blood product trans- include polymerase chain reaction (PCR) virology fusion that may be ordered prophylactically or in (e.g. for cytomegalovirus (CMV) or Epstein-Barr case of bleeding. Cultures may need to be virus (EBV)) and screening for fungus (e.g. oral repeated to confirm infection and/or response to swab), depending on symptoms and suspected treatment. Oxygen should be administered as microbial agent. For the procedures for diagnosis of needed to ensure adequate saturation (i.e. ≥94%, central line-associated bloodstream infections or 88–92% for patients with chronic obstructive (CLABSI), please see Chap. 4. Laboratory tests pulmonary disease (COPD) (Royal College of should be taken to monitor electrolyte status, organ Physicians 2012)). If the patient’s condition function, blood count and signs of infection. worsens and organ support such as assisted venti- A site of infection may not always be identified. lation or haemodialysis is required, the patient If a source of infection is confirmed, or strongly may need to be prepared for transfer to the inten- suspected, applicable actions should be taken, e.g. sive care unit (ICU). wound care or removal of peripheral i.v. needle Extra psychological support is important for with signs of thrombophlebitis (Schorr et al. 2014). both the patient and family. Educating the patient Upon initiation of antimicrobial treatment, a and the carer about the condition and actions broad-spectrum antibiotic is usually used. taken or planned will prevent unnecessary worry- Depending on the results of the cultures performed, ing and enable them to alert the staff about symp- the chosen drug may need to be changed later. toms or changes. Information and education may Fever and infection will affect the blood count also facilitate mental preparedness if the condi- and frequently cause platelet consumption why tion worsens and a higher level of care, ICU, is transfusions may be necessary. needed. Patients with sepsis are likely to need additional nursing care such as assistance with oral 9.2.6 Nursing Considerations care and personal hygiene. It is important to and Care ensure that the patient’s and caregivers’ information, education and support needs are met. On Early recognition and intervention are achieved discharge from the hospital, we need to ensure by frequent monitoring of the patient’s vital signs that the patient and their caregiver are aware of and general condition and paying attention to when, why and how to contact the clinic or hos- subtle changes that should be promptly reported. pital that they have a fever thermometer at home, As described above, immediate action is know when to take their temperature and are required at the first indication of sepsis. When aware of the level that constitutes a fever. 9 Early and Acute Complications and the Principles of HSCT Nursing Care 173

9.3 Haemorrhagic Cystitis scope. To be confirmed as microscopic haematuria, two positive samples on consecutive days are 9.3.1 Introduction needed. The haematuria can be visually detected (macroscopic) as red urine at levels as low as Haemorrhagic cystitis (HC) is sometimes seen in 1 mL blood per litre urine. The visible blood does haematopoietic stem cell transplantation (HSCT) however not necessarily correspond to the degree patients and can on its own or by subsequent of blood loss through the urine. Red urine may complications cause significant morbidity and also have other causes which will not be described even death. here. Cystitis is the term used to describe inflammation of the bladder. The inflammation can be 9.3.2 Definition caused by an infection or as a reaction to certain drugs or radiation therapy. According to NCI Dictionary of Cancer Terms, it The following symptoms may be seen in all is defined as “A condition in which the lining of types of cystitis: the bladder becomes inflamed and starts to bleed. The blood can be seen in the urine. Symptoms • Urinary urgency and frequency include pain and a burning feeling while urinating, • Burning or stinging with urination or right feeling a need to urinate often, and being unable to after control the flow of urine. Haemorrhagic cystitis • Pain, dysuria (painful urination), lower may be caused by anticancer drugs, radiation ther- abdominal or supra-pubic pain apy, infection, or being exposed to chemicals, such • Nocturia, when sleep is disturbed twice or as dyes or insecticides” (NCI Dictionary of Cancer more at night due to a need to urinate Terms 2016 https://www.cancer.gov/publications/ • Urinary incontinence dictionaries/cancer-terms?cdrid=695987). • General feeling of illness Haematuria can be symptomatic or asymptomatic. It can be described as microscopic (not visible to the eye but detected on a dipstick and in the 9.3.3 Incidence microscope) or macroscopic (red urine or visible blood or clots) (Table 9.3). Normally about 1 mil- Reported incidences of HC after HSCT range lion erythrocytes are excreted daily in the urine. between 5% and 70% depending on risk factors This is equal to one to three erythrocytes per high- and use of preventive measures or not, but most power field (magnification ×400) under the materials describe an incidence between 5% and microscope. Haematuria is defined as abnormal 30%. presence of blood in the urine, i.e. more than three erythrocytes per high-power field in the micro- 9.3.4 Pathogenesis

Table 9.3 Haematuria is graded as follows The pathogenesis leading to HC is not completely Grade Haematuria findings known but is likely to be multifactorial. The onset is I Microscopic seen either early, within the two first weeks after II Macroscopic start of conditioning treatment, or late, more than 2 III Macroscopic with clots weeks after HSCT. Conditioning treatment with IV Requiring instrumentation for clot evacuation chemotherapy, irradiation, cytopenia, viral infec- Leading to urinary retention Requiring surgical intervention tions due to immunosuppression and alloimmune May also include elevated creatinine levels and reactions (immunisation by development of anti- renal impairment bodies in response to an antigen, i.e. a protein from Droller et al. (1982). a donor, e.g. by receiving HSCT or transfusion) may 174 E. Wallhult and B. Quinn all contribute to HC in the posttransplant period. host can be viral infection. Viral particles are fre- Higher incidence of late-onset HC in HSCT with quently identified from the urine of HSCT recipi- unrelated donors, older patients, and in patients with ents. Of these, reactivation of the polyoma BK graft versus host disease (GvHD) and thrombocyto- virus (BKV) is the commonest and most consis- penia does support the conclusion that the pathogen- tent risk factor for HC following HSCT, as the esis is multifactorial (de Padua Silva 2010). virus is almost invariably present in the urine of patients with HC (Leung et al. 2005). The dam- 9.3.4.1 Drug-Related HC aged urothelial cells provide a milieu for viral rep- Early-onset HC is usually a direct and immediate lication. Immunosuppression leads to viral effect of the conditioning treatment. Conditioning reactivation and causes viruria. However, the therapy for HSCT often contains one or more exact pathogenetic link between BKV and HC alkylating agent. Cyclophosphamide, ifosfamide, remains enigmatic. Other viral agents such as busulfan, melphalan and thiotepa are among the adenovirus, cytomegalovirus (CMV) and other most commonly used drugs in conditioning regi- polyomaviruses similar to BKV may also but less mens and the major drug-related cause of often cause HC. HC. Use of other alkylating agents and etoposide Alloimmunity after engraftment by attack may also increase the risk of HC. When cyclo- from donor lymphoid cells against infected uro- phosphamide or ifosfamide is metabolised in the thelial cells has not been confirmed as causing body, it produces a metabolite called acrolein. HC but may be an additional potential factor for Acrolein will cause direct toxicity to the inner development of this complication. lining of the urinary tract, the urothelium. The degree of damage is dose dependent, and the toxicity may increase with previous or concomitant 9.3.5 Diagnosis radiation therapy and if busulfan is included in the conditioning regimen together with cyclo- The diagnosis of HC is confirmed by the pres- phosphamide. The time of duration that acrolein ence of haematuria and symptoms of cystitis tak- is exposed to the bladder also contributes to the ing into account risk factors such as: degree of damage. For cyclophosphamide, the maximal concentration of active metabolites is • Age (older patients) reached after 2–4 h of oral or intravenous admin- • Chemotherapy (particularly cyclophosphamide- istration. Most of the cyclophosphamide, 35–80% or ifosfamide-containing regimens) of the dose, is excreted in the urine as metabo- • Irradiation lites, and up to 20% is excreted as intact drug • Immunosuppressive drugs (anti-thymocyte (Hassan and Ljungman 2003). In patients with globulin (ATG), cyclosporine (CyA), corticos decreased renal function, particularly in severe teroids) cases, decreased renal excretion may result in • Cytopenia increased plasma levels of cyclophosphamide • Thrombocytopenia and its metabolites. This can cause increased tox- • Infection icity. The following substances may also increase • Myeloablative conditioning the concentration of toxic metabolites, possibly • Unrelated donor through inhibited breakdown or decreased renal • Mismatched donor excretion: allopurinol, cimetidine, hydrochloro- • GvHD thiazide and HIV protease inhibitors. • Viruria (presence of virus in the urine) in particular with BKV, adenovirus and CMV 9.3.4.2 Nondrug-Related HC When HC occurs more than 2 weeks after HSCT, In order to confirm microscopic haematuria, a common cause in the immunocompromised two positive urine samples on consecutive days 9 Early and Acute Complications and the Principles of HSCT Nursing Care 175 are needed. Urinary tract infection (UTI) should fort. All assessments mentioned above should be confirmed by urine culture for bacteria and be performed at least every 6 h. Informing the PCR-testing for virus. Yet, a diagnosis is occa- patient about the treatment and treatment goals sionally derived from the exclusion of alternative as well as the importance of reporting any causes. symptoms of HC will help ensure that appropriate actions and early intervention can be applied without delay. 9.3.6 Prognosis For patients receiving cyclophosphamide- or ifosfamide-based regimens, the drug mesna In most cases of chemotherapy-induced HC (sodium 2-mercaptoethanesulfonate) can be with pre-engraftment onset and in polyomaviru- used as pharmacological prophylaxis, although ria, the condition is self-limiting and the prog- the additional benefit in the HSCT setting has nosis is good. If the viruria is caused by not been scientifically proven in comparison adenovirus, the prognosis is worse with the risk with hyperhydration and forced diuresis. of progression to systemic adenovirus infection. Mesna binds to the toxic metabolite acrolein In these cases early pharmacological interven- and forms a non-toxic compound. By addition with antiviral drugs, e.g. cidofovir, is tional actions mesna also reduces the forming recommended. of acrolein in the urine. The drug itself has low toxicity (Mesna Summary of Product Characteristics 2017 (SPC) [in Swedish]). 9.3.7 Prevention of Chemotherapy In HSCT conditioning with cyclophospha- (Cyclophosphamide/ mide, the recommended dose of mesna accord- Ifosfamide)-Induced HC ing to the Summary of Product Characteristics (SPC) is 20% of the cyclophosphamide dose and Hyperhydration with forced diuresis, i.e. 3 L/ the first mesna dose should be administered m2/24 h with the goal of a diuresis of >250 mL/h, immediately prior to the cyclophosphamide. during and until the day after administration of Subsequent doses will then be given at 3, 6, 9 an alkylating agent is the most important pre- and 12 h after administration of cyclophospha- ventive action. If the diuresis is insufficient, mide (totalling 120% of the cyclophosphamide diuretics should be administered. The forced dose). It is important to adhere to the timing of diuresis will not just dilute the urine but shorten mesna doses in order to ensure efficacy of the the time of duration for acrolein exposure to the treatment. Mesna treatment should be continued bladder and thus prevent the toxic effects. during the cyclophosphamide treatment period During the days of hyperhydration, the patient plus the time predicted for the metabolites to shall be closely monitored for fluid balance, reach non-toxic levels. This will usually occur including weight, at regular intervals. An elec- between 8 and 12 h after completed cyclophos- trocardiogram (ECG) should be taken, and phamide administration. This treatment schedule approved, prior to start of treatment, and vital for mesna may however vary according to condi- signs (blood pressure, pulse, oxygen saturation tioning regimen and doses as well as to patient and respiratory rate) should be checked individual factors. throughout the day in order to ascertain circula- An example of a checklist to be used during tory stability. Electrolytes and renal function high-dose cyclophosphamide treatment is should be monitored by blood samples and enclosed. electrolyte substitution given where required. A BK virus-induced HC may be prevented by need for potassium substitution is not uncom- the administration of quinolones (e.g. ciproflox- mon. The patient should also be assessed for acin) (Dropulic and Jones 2008). Although qui- any urinary or low abdominal pain or discom- nolones are not strictly antiviral, fluoroqui 176 E. Wallhult and B. Quinn nolones are capable of inhibiting the helicase or likely attributable to adeno- or BK virus. activity of BKV large T antigen (TAg) protein, Decreased immunosuppression could be consid- which seems to be crucial for separation of the ered in particular in cases of relapsing viral cys- double-stranded DNA genome during replica- titis. Note that anticoagulants such as tranexamic tion of the virus (Umbro et al. 2013). There is acid and aminocaproic acid are contraindicated currently no consensus regarding this prophy- in HC due to risk of clot formation and laxis because many patients with BKV do not retention! develop HC. The fact that there is a general Another type of treatment that has proven increase of multidrug-resistant microorganisms effective is hyperbaric oxygen (Savva-Bordalo makes the use of this prophylaxis a matter for et al. 2012). The patient then receives 100% oxy- careful consideration. gen in a hyperbaric chamber but limited access to hyperbaric chambers, and the likely need and inability for the patient to move to another treat- 9.3.8 Treatment ment unit often makes this intervention less of an option. The first intervention will be hyperhydration with forced diuresis to prevent clot formation. HC is usually painful and analgesia should be 9.3.9 Nursing Aspects administered. If the patient is thrombocytopenic, a higher threshold level for platelet transfusion During treatment with hyperhydration, the same and intensive platelet support should be applied, need for close monitoring and assessments as in in particular in haematuria grades III– the prophylactic setting applies (see above). IV. Catheterisation and bladder irrigation with Assess the need for platelet transfusion prior to 0.9% sodium chloride (normal saline) may be catheterisation as well as after. Blood transfu- necessary to prevent clot obstruction. Catheter sions may also be necessary with significant insertion should be performed so that the risk of blood loss. Standard monitoring for signs of additional injury to the urothelium is minimised. infection, injury, pain, clot formation and other Treatment with bladder instillation of various potential complications from the urinary cathe- compounds such as formalin, alum, silver nitrate, ter is important. In cases of bladder irrigation sodium hyalonurate, prostaglandins, GM-CSF, keeping the fluids for irrigation at ambient tem- fibrin glue, cidofovir, ciprofloxacin or ribavirin perature may alleviate discomfort. Complications has been reported as effective, but experiences of the irrigation can be prevented or minimised are still limited (Carreras 2012). If obstruction by close monitoring and recording of fluid bal- occurs, cystoscopy can be performed. Selective ance. It is also important to maintain patient embolisation of bladder arteries and catheterisa- comfort by adequate pain management and gen- tion of both ureters to rest the bladder are actions eral nursing interventions such as comfortable that can be taken in severe cases. Cystectomy positioning and assistance with personal hygiene. remains the last resort if all other treatment The need for information and psychological sup- attempts fail. port should be observed for both patient and In addition to actions mentioned above, treat- family. ment with systemic administration of palifer- Since in particular viral HC may occur after min, oral oestrogens and recombinant FVIIa discharge from the hospital, careful assessment may be used (Carreras 2012). Systemic antimi- of any signs and symptoms related to the urinary crobial drugs, e.g. cidofovir, ciprofloxacin and tract and that may indicate viral infection is just ribavirin, can be started, if the HC is confirmed as important in the outpatient setting. 9 Early and Acute Complications and the Principles of HSCT Nursing Care 177

NB! Patient ID: Administer mesna at ordered intervals

Assessments for treatment with high dose 2 g/m2 or 4 g/m2 cyclophosphamide (Cy)

Date: Date: time: time: 12.00 ECG 00.00 Blood Pressure

Blood Pressure Pulse Pulse Saturation Saturation (Weight) Administer diuretics if urine output Weight Urine output <1500 mL After 1st day: Urine output Administer diuretics if urine output (after 1st day) <1500 mL

Serum Sodium Serum potassium Serum creatinine

time: time: 18.00 Blood Pressure 06.00 Blood Pressure Pulse Pulse Saturation Saturation Weight Weight Administer diuretics Administer diuretics if urine output if urine output Urine output <1500 mL Urine output <1500 mL

Serum Sodium Serum Sodium Serum Serum potassium potassium Serum Serum creatinine creatinine

9.4 Sinusoidal Obstruction referred to as SOS/VOD hereafter. Of the early Syndrome/Veno-Occlusive complications that are considered to be of vascu- Disease lar endothelial origin, this is the most described. There are diagnosis and severity criteria 9.4.1 Introduction (McDonald et al. 1984, 1993; Jones et al. 1987; deLeve et al. 2009; Mohty et al. 2016), although Sinusoidal obstruction syndrome (SOS) is also the EBMT criteria proposed in 2016 (Mohty known as veno-occlusive disease (VOD) and is et al. 2016) is expected to be further validated, 178 E. Wallhult and B. Quinn and there is approved treatment available. Careful When cells and debris accumulate in this space, monitoring of HSCT patients allows early detec- the sinusoids become narrower. Due to the sinu- tion of SOS/VOD. Treatment can then be started soidal damage, endothelial cells can dissect off without delay, ultimately improving patient out- and embolise further downstream thus contrib- comes. From pre-transplant assessment to medi- ute to the narrowing. The damage also leads to cal management and overall care of the patient, an increase in the expression of tissue factor nurses thus have an essential role to play as part (TF) and plasminogen activator inhibitor-1 (PAI- of a multidisciplinary team (Wallhult et al. 2017). 1). This coagulopathy causes an increase in clot There are specific differences between the formation and a decrease in the breakdown of clinical presentation of SOS/VOD in adults clots. The deposition of fibrin and the clot for- versus in children which has not been reflected mation will contribute to the narrowing of the in the older diagnosis and severity criteria. For sinusoids and may ultimately lead to hepatic this reason, EBMT has also developed a clas- sinusoidal obstruction. The result is SOS/VOD sification for diagnosis and severity criteria which is characterised by obstruction of the for SOS/VOD in paediatric patients sinusoids, portal vein hypotension and reduced (Corbacioglu et al. 2017). The information hepatic venous outflow. Severe cases can prog- presented below is related to adults. For the ress to multi-organ dysfunction (MOD)/multi- paediatric population, please see original arti- organ failure (MOF) and death. cle and/or the VOD learning programme on SOS/VOD usually develops before day +21 the EBMT website. (Veno Occlusive Disease after HSCT with a peak incidence around day 12, (VOD) Learning Programme 2017 http://www. but about 15–20% of the SOS/VOD cases have a ebmt.org/Contents/Nursing/Materials/ late onset, after day +21. LearningProgrammes/Pages/default.aspx.)

9.4.3 Incidence and Prognosis 9.4.2 Definition and Pathogenesis Although relatively rare, SOS/VOD is one of the When drugs used in haematopoietic stem cell main causes of non-relapse, transplant-related transplant (HSCT) conditioning regimens are mortality. A mean incidence of 14% (Coppell metabolised in the liver, it results in toxic metab- et al. 2010) has been reported, but it varies with olites being produced by the hepatocytes. The the diagnostic criteria, depending whether the metabolites trigger the activation, damage and Seattle (McDonald et al. 1984, 1993) or the inflammation of the endothelial cells lining the slightly stricter Baltimore criteria (Jones et al. sinusoids (sinusoids being small capillary-like 1987) have been used. It will also depend on risk blood vessels in the liver). This trigger mecha- factors including intensity of conditioning regi- nism can start as soon as the conditioning treat- men and type of transplant. After allo-HSCT with ment is administered. The activated sinusoidal myeloablative conditioning (MAC), the incidence endothelial cells release inflammatory cytokines, is approximately 10–15%, but if reduced intensity chemokines and the enzyme heparanase which conditioning (RIC) is used, the incidence is <5%. break down the extracellular matrix that sup- This is the same incidence as for auto-HSCT. ports the structure of the sinusoids. The endothe- Early-stage SOS/VOD, mild SOS/VOD, may lial cells are then forced to round up, and gaps not be particularly well-recognised since the form between the cells. The gaps allow for red symptoms are subtle, may not require treatment blood cells, white blood cells and other cellular and spontaneously resolve within a few weeks. debris to exit through these gaps in the sinusoid Unrecognised SOS/VOD may however progress, walls into the space of Disse. (The space of sometimes very rapidly, into moderate or severe. Disse is the perisinusoidal space that is located Severe SOS/VOD is associated with MOD/MOF between the endothelium and the hepatocytes.) and a mortality rate of 84%. 9 Early and Acute Complications and the Principles of HSCT Nursing Care 179

9.4.4 Risk Factors 9.4.5 Diagnosis

The risk factors for SOS/VOD can be divided Despite the fact that diagnostic criteria were devel- into patient- and disease-related and transplant- oped in the 1980s and have been used in clinical related risk factors (Mohty et al. 2015). As men- practice and research studies, it is often hard to tioned above, the risk factors, as well as the identify early or mild cases of SOS/VOD before it clinical presentation of SOS/VOD, differ between progresses to a more severe form. Some reasons the adult and the paediatric population, and the are lack of sensitivity and specificity of the crite- risk factors presented here are related to adults. ria, the dynamic manifestations that makes defini- The patient- and disease-related risk factors tion of the condition hard and that early signs and are: symptoms often are subtle and makes differentiation from other transplant complications difficult. • Older age Given the poor prognosis of severe SOS/VOD, it is • Decreased performance status (Karnofsky however vital to identify mild cases before they score <90%) progress to moderate, with signs of hepatic injury • Metabolic syndrome and requiring more aggressive intervention, or fur- • Female receiving norethisterone (gestagen) to ther progress to severe SOS/VOD with MOD/ postpone menstruation period MOF. The most recent diagnostic criteria pro- • Genetic factors (GSTM1 polymorphism, posed by EBMT (Mohty et al. 2016) are the same C282Y allele, MTHFR 677CC/1298CC as the Baltimore criteria (Jones et al. 1987) for haplotype) classical SOS/VOD with onset within the first • Thalassemia 3 weeks after HSCT, but if SOS/VOD develops • Disease status beyond CR2 after day +21, elevated serum bilirubin level is not • Refractory disease or relapse always seen, why a modified version of the criteria • Hepatic-related risk factors (Cirrhosis, hepatic can be used for diagnosis of late SOS/VOD fibrosis, active viral hepatitis, transaminases (Mohty et al. 2016) (Table 9.4). The EBMT crite- (AST and ALT) >2.5 of the upper limit of nor- ria will also better capture the dynamic manifesta- mal (ULN), serum bilirubin >1.5 ULN, coag- tions of the disease and thus facilitate an early ulopathy (deficit of anti-thrombin (AT) III, diagnosis as well as a more accurate assessment of tissue plasminogen activator (t-PA) and resis- severity. Treatment can then be started at a stage tance to activated protein C), elevated ferritin with greater chance for treatment response. level, iron overload, previous abdominal or Differential diagnoses will need to be excluded hepatic irradiation, use of hepatotoxic drugs by assessing risk factors, symptoms and lab tests and previous use of gemtuzumab ozogamicin since liver dysfunction can also be seen in sepsis, and inotuzumab ozogamicin. It can be noted viral infection, graft versus host disease (GvHD) that SOS/VOD has been reported after inotu- and iron overload and as a side effect from many zumab ozogamicin treatment also in non- of the drugs used in the HSCT setting. In addition transplant patients.) to the signs and symptoms required for diagnosis haemorrhagic complications, thrombocytopenia The transplant-related risk factors are: with platelet refractoriness, pulmonary dysfunction, renal dysfunction and encephalopathy are • Unrelated donor “late” signs that can be seen in more severe cases • HLA-mismatched donor of SOS/VOD. Further it is worth noting that all • Non-T-cell-depleted graft symptoms are also observed in other conditions • MAC and that many other complications may coexist • Conditioning regimen with busulfan and/or with SOS/VOD. Examples of differential diagno- TBI sis for classical symptoms of SOS/VOD are listed • Second HSCT in Table 9.5. 180 E. Wallhult and B. Quinn

Table 9.4 SOS/VOD diagnosis criteria

Original Seattle Modified Seattle Baltimore Criteria EBMT Criteria for adults (2016)4 Criteria (1984) criteria (1993)2 (1987)3

Presentation Presentation Bilirubin ≥2 mg/dL Classical SOS/VOD Late onset before Day 30 before Day 20 (~34 µmol/L) in the first 21 days SOS/VOD >21 days post-HSCT post-HSCT before Day 21 post- post HSCT post HSCT HSCT with Bilirubin ≥2 mg/dL (~34 µmol/L)

Classical SOS/VOD and at least two of two of the and at least two of and two of the OR of the following: following: the following: following: Jaundice Bilirubin >2 mg/dL Hepatomegaly Painful SOS/VOD (~34 µmol/L) hepatomegaly confirmed by liver biopsy OR two or more of the following:

Hepatomegaly Hepatomegaly Ascites Ascites Bilirubin ≥2 mg/dL and right upper or right upper (~34 µmol/L) quadrant pain quadrant pain of liver origin

Ascites ± Unexplained Weight gain ≥5% Weight gain >5% Painful unexplained weight gain of >2% from baseline hepatomegaly weight gain baseline due to fluid accumulation

Ascites Weight gain >5% AND Hemodynamical or/and ultrasound evidence of SOS/VOD

1McDonald et al. (1984) 2McDonald et al. (1993) 3Jones et al. (1987) 4Mohty et al. (2016)

When SOS/VOD is diagnosed, it is impor- 9.4.6 Prevention tant to classify the severity grade in order to intensify the monitoring and identify patients The first strategy for prevention is to be aware of that will need therapeutic intervention. The pre-existing risk factors and try and eliminate them EBMT severity grading criteria (Mohty et al. as far as possible and potentially establish support- 2016) stress the importance of taking the time ive or treatment measures prior to transplant. The since the appearance of the symptoms into patient- and disease-related risk factors, including account. A rapid progression of symptoms, and hepatic, are often difficult or impossible to change, in particular bilirubin kinetics (the rate of but the transplant-related risk factors should be increase) with a doubling time of 48 h, should carefully considered in the pre-transplant setting. be classified as a more severe grade than if No proven medical prophylaxis exists but symptoms develop more slowly over several sodium heparin, prostaglandin E1, ursodeoxycho- days (Table 9.6). lic acid and low molecular weight heparin have 9 Early and Acute Complications and the Principles of HSCT Nursing Care 181 been tried, although data about effectiveness 9.4.7 Treatment remains inconclusive (Carreras 2012, 2015). Defibrotide, approved for treatment of severe As soon as SOS/VOD is suspected, supportive SOS/VOD, has also been used as prophylaxis therapy should be initiated. In mild cases of SOS/ (Dignan et al. 2013), and one randomised study in VOD, close monitoring to detect progression and children has shown a reduction in SOS/VOD inci- supportive management is often sufficient. dence (Corbacioglu et al. 2012). The monitoring should include:

Table 9.5 SOS/VOD symptoms • Daily weight Symptom Also observed in • Fluid intake and output Jaundice Biliary infection • Abdominal girth Cholestasis • Blood tests including urea and electrolytes Acute GvHD • Assessment of all sites for bleeding Cyclosporine • Assessment of pain source and level Drug or TPN injury Haemolysis The supportive management consists of: Hepatomegaly and Congestive heart failure ascites Fungal infection • Restricting fluid intake EBV lymphoproliferative disease • Avoidance of hepatotoxic drugs if possible Pancreatitis • Diuretics Portal vein thrombosis • Analgesia Rapid weight gain Congestive heart failure • Blood products Renal failure • Electrolytes Sepsis syndrome • Comfortable positioning Capillary leak syndrome • Psychological support Eisenberg (2008)

Table 9.6 New EBMT criteria for severity grading of a suspected SOS/VOD in adults Very severe – MOD/ Milda Moderatea Severe MOFb Time since first clinical >7 Days 5–7 Days ≤4 Days Any time symptoms of SOS/ VODc Bilirubin (mg/dL) ≥2 and <3 ≥3 and < 5 ≥5 and < 8 ≥8 Bilirubin (μmol/L) ≥34 and <51 ≥51 and < 85 ≥85 and <136 ≥136 Bilirubin kinetics Doubling within 48 h Transaminases ≤2 × normal > 2 and ≤5 × normal >5 and ≤8 × normal >8 × Normal Weight increase < 5% ≥5% and <10% ≥5% and <10% ≥10% Renal function <1.2 × baseline at ≥1.2 ≥1.5 and ≥2 × baseline at transplant and < 1.5 × baseline <2 × baseline at transplant or others at transplant transplant signs of MOD/MOF Patients belong to the category that fulfils two or more criteria. If patients fulfil two or more criteria in two different categories, they must be classified in the most severe category. Patients weight increase≥ 5% and <10% is considered by default as a criterion for severe SOS/VOD; however, if patients do not fulfil other criteria for severe SOS/VOD, weight increase ≥5% and <10% is therefore considered as a criterion for moderate SOS/VOD Abbreviations: EBMT European Society for Blood and Marrow Transplantation, MOD multi-organ dysfunction, MOF multi-organ failure, SOS sinusoidal obstruction syndrome, VOD veno-occlusive disease aIn the case of presence of two or more risk factors for SOS/VOD, patients should be in the upper grade bPatients with multi-organ dysfunction must be classified as very severe cTime from the date when the first signs/symptoms of SOS/VOD began to appear (retrospectively determined) and the date when the symptoms fulfilled SOS/VOD diagnostic criteria 182 E. Wallhult and B. Quinn

For more details about nursing interventions and/or spiders should always be included in see below. abdominal assessment. For nurses trained in pal- The only curative treatment for SOS/VOD is the pation and percussion for ascites, bulkiness, liver drug defibrotide. Defibrotide protects the endothe- margins and size these assessments should also lial cells, reduces inflammation and restores be performed. thrombo-fibrinolytic balance (Richardson et al. Sclera and skin should be assessed for bleed- 2013). The recommended dose is 6.25 mg/kg body ing/bruising and discoloration (jaundice). weight administered as a 2-h, i.v. infusion every 6 h Knowledge of the relevant reference ranges of (to a total dose of 25 mg/kg/day). Recommendation daily laboratory values, particularly liver for treatment duration is at least 21 days but should enzymes, serum bilirubin, blood count, electro- continue until the symptoms and signs of severe lytes, urea and serum creatinine will enable early VOD resolve. Defibrotide is generally well toler- detection of significant change or trend in values ated (Keating 2014) but should not be used with since nurses are likely to take blood samples and products that affect platelet aggregation, e.g. non- see the results first and can alert medical steroid anti-inflammatory drugs (NSAIDs), antico- colleagues. agulant therapy or other products that increase the All findings should be precisely documented risk of bleeding. and any changes promptly reported. This is especially important in patients identified as high risk as early detection of SOS/VOD may affect the 9.4.8 Nursing Aspects overall outcome. If SOS/VOD is suspected, the monitoring It is important to perform a risk assessment con- should be intensified and adequate vascular sidering the risk factors mentioned above and to access established. In addition to standard lab take baseline measurements including defining a tests, coagulation parameters should be per- threshold of >5% for weight gain or what level formed daily. If possible, hepatotoxic drugs and pattern of weight gain that represents a clini- should be avoided and diuretics and pain medica- cal concern. Most baseline measurements will be tion administered as needed. Electrolyte replace- standard for HSCT patients, but in patients at ment may be necessary, and in case of high risk for SOS/VOD, assessments of abdomi- thrombocytopenia or bleeding, blood products nal girth, right upper quadrant (RUQ) pain and will be administered. If fluid restriction is inspection of sclera should be added. enforced, it is important to know the smallest vol- Standard daily monitoring should include tem- umes that can be safely delivered. perature, pulse, blood pressure, respiration rate and The patient may also need assistance to be saturation. One of the most important daily moni- comfortably positioned. toring aspects is an accurate fluid balance including When SOS/VOD has been diagnosed, the sup- intake, output and weight since fluid imbalance is portive care and monitoring will be further inten- one of the earliest signs of SOS/VOD. A fluid sified including assessing for failure in respiratory, retention which does not respond to diuretics repre- cardiac and renal function. Defibrotide treatment sents an early sign of endothelial damage. will most likely be started, and patients in need When performing abdominal girth measure- for ventilatory support should be prepared for ment, it is advised to use a marked line for place- transfer to the intensive care unit (ICU). ment of the measuring tape and to choose one Patients should be informed and educated to position (i.e. sitting/standing/lying) for the notify the staff of any signs and symptoms that patient, to be used consequently. Abdominal dis- may need closer monitoring or intervention. In comfort, tenderness, pain (in particular RUQ case SOS/VOD is diagnosed, both patient and pain) and inspection for collateral circulation family will need reassurance and support. 9 Early and Acute Complications and the Principles of HSCT Nursing Care 183

9.5 Other Early Complications around the time of neutrophil recovery, i.e. when of Endothelial Origin the absolute neutrophil count (ANC) increases to ≥0.5 × 109/L, which is why the complex process 9.5.1 Introduction of engraftment may also play a role in activation of endothelial cell damage. The activation of the A number of early complications to haematopoi- endothelial cells leads to further damage and etic stem cell transplantation (HSCT) seem to be inflammation by the release of pro-inflammatory initiated by damage to the vascular endothelium. cytokines. Since the incidence of vascular endo- The most well defined and well described of these thelial syndromes is higher after allogeneic trans- complications is sinusoidal obstruction syndrome plantation, alloreactivity (the immune response (SOS)/veno-occlusive disease (VOD) described to non-self cells) is considered to play a role in in a separate section of this chapter. Other syn- activation and damage of endothelial cells. dromes in this group have been named engraftment syndrome (ES), diffuse alveolar haemorrhage (DAH), idiopathic pneumonia syndrome (IPS) 9.6 Engraftment and transplant-associated microangiopathy Syndrome (ES) (TMA). The similarities in their clinical manifestations and the lack of established diagnostic cri- 9.6.1 Definition teria often make determination of incidence and differential diagnosis difficult (Soubani and ES usually occurs after auto-HSCT although Pandya 2010; Afessa et al. 2012). Although many described in allo-HSCT as well, in particular times mild and with spontaneous recovery, these when reduced intensity conditioning (RIC) and complications also share the risk for progression cord blood (CB) have been used. to multi-organ failure (MOF)/multi-organ dam- Due to lack of diagnostic criteria, the term ES age (MOD) resulting in a poor outcome. has been used as synonymous with capillary leak Ongoing research and efforts for better char- syndrome (CLS), auto-aggression syndrome, acterisation and treatment indicate that there will peri-engraftment respiratory distress syndrome be future changes in terminology and diagnostic (PERDS), aseptic shock syndrome and autolo- criteria, as well as interventions, for the early gous graft versus host disease (AGVHD). HSCT complications mentioned here. Although there are differences, their common denominator is that they share some or all symptoms that have been attributed to ES. 9.5.2 Pathogenesis Engraftment is defined as when the number of neutrophils in the patient’s blood rises to an abso- Several factors in the HSCT setting activate the lute neutrophil count (ANC) of ≥0.5 × 109/L. endothelial cells that line the blood vessels. Peri-engraftment can be defined as the period Contributing factors are the conditioning treat- within 5 days of neutrophil engraftment. ment and use of other drugs such as granulocyte colony-stimulating factor (G-CSF) and calcineurin inhibitors (CNI), e.g. cyclosporine-A, and 9.6.2 Incidence and Prognosis microbial products translocated through mucosal barriers. The result is that fluid and proteins leak Due to the diagnosis difficulties, there is no reli- out of tiny blood vessels and flow into surround- able incidence figure and numbers between 10% ing tissues. If unrecognised, this may lead to dan- and 70% have been reported. There is also a lack gerously low blood pressure and subsequently of survival data. Most cases are mild and respond MOF and shock. The symptoms often appear well to corticosteroid therapy, but ES may progress 184 E. Wallhult and B. Quinn and lead to transplant-related mortality and Table 9.7 Engraftment syndrome criteria decrease in overall survival. Patients who require Major Non-infectious fever New fever (> 38°C) mechanical ventilation has a poor prognosis. criteria without documented infection or without response to anti-infectious 9.6.3 Risk Factors treatment Skin rash Maculopapular A number of potential risk factors related to exanthema in >25% patient characteristics, disease, previous treat- of body surface area Pulmonary oedema Confirmed by X-ray ment, conditioning treatment, stem cell source or CT, and supportive drug treatment have been reported, Without signs of but there is a lack of consensus which can in part infection, cardiac be contributed to the lack of diagnostic criteria. failure or pulmonary embolism Changes in HSCT practices with new drugs and Minor Weight gain >2.5% from alternate stem cell sources may impact the risk criteria baseline factors in the future. Hepatic dysfunction Bilirubin ≥2 mg/dL Among the risk factors described are: (34μmol/L) or transaminases • Female gender (ASAT/ALAT) ≥2 times increase from • Advanced age baseline • No or little prior chemotherapy Renal dysfunction Creatinine ≥2 times • Previous use of bortezomib and lenalidomide increase from in multiple myeloma patients baseline • Cord blood transplantation Transient Without other cause encephalopathy • CD34+ cell number and engraftment rate Diarrhoea ≥2 liquid stools per • G-CSF treatment day without • Amphotericin treatment documented • Cyclosporine (CyA) treatment infection • Auto-HSCT for amyloidosis, multiple myeloma, POEMS (polyneuropathy organo- Table 9.8 Spitzer and Maiolino criteria megaly endocrinopathy monoclonal protein and skin abnormalities) syndrome and auto- Spitzer criteria Maiolino criteria immune diseases Symptoms 3 major or Non-infectious 2 major and fever and 1 minor 1 minor 9.6.4 Diagnosis Timing relative Within 96 h 24 h before or at engraftment after any time after There are two tools to aid diagnosis of ES; the Spitzer (2001) and the Maiolino et al. (2003) diagnostic criteria. The clinical manifestations before (for patients with POEMS) to 7 days after are divided into major or minor clinical criteria engraftment, and in cases with more severe (Table 9.7), but Maiolino only has one major cri- symptoms, the early symptoms may have been teria, non-infectious fever. The timing of symp- overlooked, why the clinical criteria sometimes toms relative engraftment also differs between could be used regardless of appearance of symp- the two, where Maiolino has a stricter timeframe toms in relation to time for engraftment (Chang from 24 h before to any time after neutrophil et al. 2014). C-reactive protein (CRP) is not used recovery compared to Spitzer’s 96 h after for diagnosis in either criteria, but a sudden and (Table 9.8). However, in some patients others significant increase in the CRP level has been have described onset of symptoms from 7 days found to support the diagnosis. 9 Early and Acute Complications and the Principles of HSCT Nursing Care 185

9.6.5 Prevention 9.6.7 Nursing Aspects

Early recognition of signs and symptoms is the Daily nursing assessments are critical in early most important aspect since there is no stan- detection and diagnosis of all complications to dard prophylaxis for ES, although there is evi- HSCT. The patient’s general well-being should dence that corticosteroids may prevent this be assessed, and listed below are the nursing complication. assessments that should be carried out frequently, the findings that could indicate ES and actions that can be taken in order to detect or rule out the 9.6.6 Treatment ES diagnosis (Table 9.9). All findings should be

Before treatment is initiated, other diagnoses such Table 9.9 Nursing assessments and actions as infection, drug rash, diarrhoea associated with Assessment Action infection or medication and intravenous Temperature Monitor frequently, and in cases of (i.v.)-related fluid overload should be excluded. fever ≥38 °C, obtain cultures from Broad-spectrum antibiotics should be used until blood, urine, stools or other infection is ruled out (Cornell et al. 2015). If cul- suspected sites of infection and keep the patient comfortable tures are negative, symptoms remain after 48–72 h Pulse and blood Monitor frequently in order to of antibiotic treatment and other etiologies can be pressure detect, e.g. circulatory symptoms excluded, corticosteroid treatment can be initiated. of fluid overload, infection and Methylprednisolone in doses of 1–3 mg/kg/ pulmonary dysfunction day i.v. are recommended until symptoms begin Respirations and Monitor frequently, and if saturation symptoms of pulmonary to subside. Response to treatment is usually dysfunction, e.g. dyspnoea, seen within 2–3 days. Corticosteroids could tachypnoea, change in breathing then be switched to oral administration and pattern, chest pain or cough, are should be slowly tapered. Early intervention present, a chest X-ray or pulmonary CT scan may be with steroids prevents progression to more performed. In order to ensure severe manifestations, and in the vast majority adequate oxygenation, (80%) of patients, there is then complete reso- administration of oxygen therapy lution in less than 6 days. In cases with no may be necessary response to steroid treatment after 72 h, biop- Weight and fluid Assess the patient’s weight daily balance and perform calculation of fluid sies of affected organs may be necessary. If balance at least once daily to note biopsies are performed for evaluation of diar- any trends. If oedema, ascites or rhoea, the findings may not be able to distin- other symptoms of fluid retention guish from GvHD. This does however not occurs diuretics should be administered as ordered exclude ES since overlap and coexistence with Skin Perform assessment at least daily GvHD is possible. If a biopsy supports the ES and note any rashes. If a rash is diagnosis treatment with additional immune detected, review the patient’s suppressants should be started and continued medication chart for medication that may cause drug rash until response. If the result of the biopsy is an Jaundice and yellow sclera are alternative diagnosis, the patient should be signs of liver dysfunction and treated accordingly. bilirubin levels should be checked In addition to pharmacological treatment sup- Stools Monitor frequency and consistency portive care with i.v. fluids, with electrolyte sup- and obtain cultures and test for Clostridium difficile in cases of plement as needed, and oxygen therapy may be diarrhoea in order to rule out necessary depending on the symptoms. infection. Pale stools are a sign of In cases of encephalopathy or severe ES with liver dysfunction and bilirubin MOF, plasma exchange may be considered levels should be checked (Yeoung-Hau and Syed 2014). (continued) 186 E. Wallhult and B. Quinn

Table 9.9 (continued) IPS also includes a subset of diagnoses of pri- Assessment Action mary lung injuries classified according to the Lab tests Be alert to any trends or changes in anatomical sites of inflammation. They can either ANC, bilirubin, transaminases and be related to the pulmonary parenchyma (e.g. creatinine and to result of cultures acute interstitial pneumonitis and acute respira- Mental status Assess regularly for confusion, tory distress syndrome (ARDS)), the airway lethargy, headache, visual disturbances, aphasia and note any endothelium (e.g. bronchiolitis obliterans syn- changes drome (BO)), the vascular endothelium (e.g. dif- Patient Educate the patient about signs and ferent forms of ES (PERDS, CLS)) or be information and symptoms of ES and explain why unclassifiable. Other less frequent non-infectious education it is important to report any PCs have also been identified. None of these enti- symptoms without delay. Explain actions taken in diagnosis and ties will be described here. management of ES and provide emotional support to both patient and family 9.7.2 Incidence and Prognosis Thoele (2014) PCs are common in HSCT recipients and a major cause of morbidity and mortality. IPS is more documented and any abnormalities promptly often seen in patients undergoing allogeneic reported to the treating physician. HSCT with a mean estimated incidence of 1–10% If steroid treatment is started, the patient (6% in auto-HSCT) (Chi et al. 2013). The overall should be assessed for possible side effects such outcome is different between auto- and allo- as hyperglycaemia and insomnia. Blood glucose HSCT recipients, and where IPS in patients that should be monitored daily. have undergone auto-HSCT usually has a favourable prognosis, the mortality is 60–80% in the allo-setting (Carreras 2012). IPS has a progres- 9.7 Idiopathic Pneumonia sive nature, and patients with progression to Syndrome respiratory failure and need for mechanical ventilation have a very poor prognosis with 95% 9.7.1 Definition mortality.

Pulmonary complications (PCs) are the leading cause of patients’ admission to intensive care unit 9.7.3 Risk Factors (ICU) after HSCT. PC can be divided into infectious or non-infectious. One of the non-infectious For IPS the following risk factors have been iden- PCs is idiopathic pneumonia syndrome (IPS). tified (Diab et al. 2016): For the purpose of this chapter, IPS will be defined and described according to the definition • Older age by the American Thoracic Society (Panotskaltsis- • Low performance status (Karnofsky score) Mortari et al. 2011) as “an idiopathic syndrome of • High-intensity conditioning regimen pneumopathy after HSCT, with evidence of wide- • Total body irradiation (TBI) spread alveolar injury and in which an infectious • Allo-HSCT etiology and cardiac dysfunction, acute renal fail- • Acute graft versus host disease (aGvHD) ure or iatrogenic fluid overload have been • Malignant disease excluded”. The alveolar injury is a result from the release of proinflammatory cytokines during Pre-transplant pulmonary function abnormali- engraftment increasing alveolar permeability and ties have also been associated with early respira- causing diffuse alveolar or interstitial infiltrates. tory failure and mortality (Chien et al. 2005). 9 Early and Acute Complications and the Principles of HSCT Nursing Care 187

9.7.4 Diagnosis prevent progression of pulmonary dysfunction (Elbahlawan et al. 2016). The most common signs and symptoms are fever, non-productive cough, rales, dyspnoea, tachypnoea and low saturation with an increasing need 9.7.6 Treatment for oxygen support. The diagnosis will be based on alveolar injury Beyond supportive care, there is no proven treat- confirmed clinically, radiologically and/or func- ment for IPS. In auto-HSCT patients, corticoste- tionally. X-ray will reveal diffuse pulmonary infil- roids can be effective, but this is usually not the trates. Infection must have been ruled out by case for allo-transplanted patients, irrespective of negative cultures and tests in bronchoalveolar steroid dose. Studies with etanercept, a TNF-α- lavage (BAL) or lung biopsies (Zhu et al. 2008), binding protein, given in combination with corti- and there should be no evidence of cardiac dys- costeroids have reported improved pulmonary function, acute renal failure or treatment-related function in patients with IPS following alloge- fluid overload. It is however considered possible neic HSCT and may be considered (Carreras that some cases of IPS may be caused by an uniden- 2012) although a small but later study (Yanik tified underlying infection since infections may et al. 2014) could not confirm the benefit of this lack typical signs and symptoms in the neutropenic treatment. patient. The IPS diagnosis can thus be supported by lack of improvement despite broad-spectrum antibiotics and other antimicrobial drugs. 9.7.7 Nursing Aspects The typical onset will be around day +20, but IPS may also present later after HSCT, why it is The close monitoring and daily nursing assess- important to be alert for this complication also ments that apply for all HSCT patients should be after discharge from the hospital, in the outpa- employed. Depending on risk factors, extra tient setting. attention may be needed to early and subtle There are no standard guidelines for diagno- symptoms of pulmonary dysfunction, such as sis and evaluation of PC after HSCT, but the decrease in saturation, shortness of breath and course of illness should be considered when dif- cough. Monitoring of daily weight and fluid bal- ferential diagnoses are to be excluded. When ance, with administration of diuretics if neces- symptoms occur, IPS may rapidly progress to sary, will prevent and rule out fluid overload. pulmonary dysfunction requiring mechanical Several different tests and examinations may be ventilation. performed to establish or rule out the diagnosis of IPS. Sputum cultures and laboratory tests, such as polymerase chain reaction (PCR) for 9.7.5 Prevention mycoplasma, and serum galactomannan for Aspergillus may need to be obtained, and chest For patients at risk for IPS, careful consideration X-ray or computed tomography (CT) scan per- of treatment options pre- and posttransplant such formed to rule out infection. In case a BAL, with as avoiding conditioning with TBI or high- or without transbronchial biopsy, will be per- intensity regimens and choice of GvHD prophy- formed, information to the patient and prepara- laxis may be beneficial. Monitoring of pulmonary tion prior to the procedure as well as support function and symptoms after transplantation will both before and after and post procedure moni- enable prompt intervention. toring is important. The BAL may add substan- In patients with decreased lung function prior tial discomfort, in particular to an already to HSCT and suspected lung injury in the post- seriously ill patient. Other lung function tests transplant setting, close collaboration with pul- may also be repeated, for comparison with pre- monary specialist or the intensive care team may transplant results. 188 E. Wallhult and B. Quinn

When corticosteroids are administered, the 9.8.2 Incidence and Prognosis blood glucose levels should be followed daily and the patient should be informed of and An approximate incidence of around 5% up to assessed for other side effects, e.g. insomnia. 20%, with a mortality rate ranging between 50% Oxygen therapy may need to be administered and 100%, has been reported for DAH in HSCT and noninvasive positive pressure ventilation recipients (Afessa et al. 2002; Majhail et al. 2006; necessary. Respiratory difficulties generate anxi- Carreras 2012). The incidence is similar between ety, and the patient should be offered psycho- auto- and allo-HSCT. logical support as well as assistance with The implication of prognostic factors has not positioning and breathing techniques and exer- been well studied, but early-onset DAH (within cises. Medication for anxiety may be necessary. the first 30 days after transplant) in patients Referral to a physiotherapist, respiratory thera- undergoing auto-HSCT has a favourable pist or other staff with expertise in pulmonary prognosis. diseases should be made for advice on tools and exercises that may help the patient to maintain pulmonary function and prevent worsening of 9.8.3 Risk Factors the condition. If the condition shows no signs of improving, Risk factors for the development of DAH in the patient should be prepared for transfer to the HSCT recipients include: ICU. Identification of patients at risk, prompt inter- • Older age vention to signs and symptoms of pulmonary • Total body irradiation (TBI) dysfunction and close collaboration within the • Myeloablative conditioning (MAC) regimens team will increase the chances of a positive • Acute graft versus host (aGvHD) disease outcome.

9.8.4 Diagnosis 9.8 Diffuse Alveolar Haemorrhage Dyspnoea, dry cough and fever are the most common complaints. Haemoptysis is rarely observed 9.8.1 Definition in HSCT recipients. Hypoxemia may be present and diffuse or focal interstitial or alveolar infil- Diffuse Alveolar Haemorrhage (DAH) is a non- trates can be found on chest X-ray or computed infectious pulmonary complication associated tomography (CT) scan. With such findings, bron- with haematopoietic stem cell transplant (HSCT) choscopy with BAL and transbronchial biopsy is and other causes (Park 2013). It is differentiated indicated although performing these invasive from idiopathic pneumonia syndrome (IPS) tests in patients with severe illness, and unstable through confirmation of pulmonary haemor- respiratory status is a challenge. rhage by bronchoscopy and bronchoalveolar The diagnosis is based on BAL findings which lavage (BAL). The bleeding can be either insidi- become progressively more blood stained, indicat- ous, causing a gradual pulmonary dysfunction, ing blood in the alveoli. Other causes, such as heart or a more acute bleeding into the alveolar space. failure and fluid overload, should be excluded. Damage to the alveolar-capillary barrier from Infection needs to be ruled out by obtaining rele- conditioning treatment and the engraftment pro- vant cultures. Presence of hemosiderin-laden mac- cess with recovery of neutrophils leads to entry rophages in BAL fluid is not diagnostic for DAH of blood into the alveolar space. but may support the diagnosis. 9 Early and Acute Complications and the Principles of HSCT Nursing Care 189

It is often very difficult to differentiate DAH rate and saturation should be assessed together from IPS and the ES form of respiratory distress with temperature and other standard assessments. (PERDS). IPS is more common in allo-HSCT, If cough is noted, this should be reported to the after engraftment, and does not respond to corti- team and the treating physician. Cultures and costeroids and has a more progressive nature. In blood tests may be necessary to rule out infec- PERDS the majority of patients do not have BAL tion. Cultures should be performed according to findings becoming progressively bloodier. signs and symptoms, but screening cultures can The mean onset of DAH has been reported on be collected to possibly enable detection of occult day 24 after transplant and 6 days after absolute infection. The patient’s circulatory status and neutrophil count (ANC) recovery. fluid balance should be controlled by monitoring pulse, blood pressure, weight and input and output. 9.8.5 Prevention The patient should be instructed to report all symptoms, and if BAL and lung biopsy will be Reversal of some risk factors, e.g. choice of con- performed, patient information and support ditioning treatment, may be possible, but other- throughout the whole procedure is vital. wise no prophylaxis exists. Administration of transfusions, oxygen therapy and non-invasive ventilation should be performed 9.8.6 Treatment as ordered and since dyspnoea and other breathing difficulties are associated with a great deal of High-dose corticosteroids, using methyl prednis- anxiety patient support, sometimes with pharma- olone in doses of 250–500 mg every 6 h for 4–5- cological treatment, is crucial. Proper positioning days followed by slow tapering, is considered together with breathing exercises using appropri- first-line treatment even if efficacy can be ques- ate breathing technique may alleviate some tioned. With early diagnosis and treatment with discomfort. steroid therapy, respiratory failure can often be During high-dose corticosteroid treatment, prevented. Noninvasive ventilation may decrease blood glucose should be monitored, and it is mortality although the majority of patients with important to be alert to steroid-related changes in DAH require mechanical ventilation, and sepsis the patient’s mental status. and MOF/MOD will cause death in a large proportion of patients (Rabe et al. 2010). Other pharmacological therapies, as well as 9.9 Transplant-Associated plasma exchange, have been tried for treatment of Microangiopathy (TAM) DAH. Recombinant factor VIIa (rFVIIa) has been administered and achieved temporary control of 9.9.1 Definition bleeding. Tranexamic acid or the TNFα-inhibitor etanercept have been used in addition to cortico- Transplant-associated microangiopathy (TAM) is steroids but have not proved to be effective. also known as haematopoietic stem cell trans- Transfusion of platelets and red blood cells plantation (HSCT)-associated thrombotic micro- (RBC) may be necessary. angiopathy (TA-TMA). In this text, the term TAM is being used. TAM is characterised by microangiopathic haemolytic anaemia with 9.8.7 Nursing Aspects schistocytes (fragmented red blood cells) and thrombocytopenia from platelet consumption. Patients need frequent monitoring for early detec- These symptoms are due to endothelial dysfunction of any pulmonary symptoms. Respiration tion causing small vessels thrombosis in the 190 E. Wallhult and B. Quinn microcirculation. TAM is a multi-visceral disease (GvHD), infections (e.g. cytomegalovirus (CMV) most often affecting the kidneys, but pulmonary, and fungal infections) and unrelated donor trans- gastrointestinal and central nervous system plant (in particular if mismatched) are all consid- (CNS) involvement can also be seen. Complement ered risk factors or triggers for TAM, although system dysregulation plays an important role in reported data is conflicting (Nadir and Brenner the severity of TAM. Defects in the complement 2012; Rosenthal 2016). system lead to formation of the lytic complex C5b-9. This complex can be detected in blood, and an increased level will support the TAM 9.9.5 Diagnosis diagnosis. TAM usually has an onset between 1 and 2 months after HSCT but can be seen both earlier 9.9.2 Incidence and later. Several slightly different criteria for diagnosis The incidence will vary with the criteria used to of TAM are being used (Sahin et al. 2016). See diagnose TAM. In retrospective data, the inci- adapted Table 9.10. The diagnosis is difficult but dence is approximately 4% in auto-HSCT, 7% can be confirmed with a biopsy tissue sample has been reported in allo-HSCT (Carreras 2012), although this invasive test may not always be an whereas one prospective study has shown an inci- option for the seriously ill HSCT recipient. TAM dence close to 40% (Jodele et al. 2015). has clinical similarities with idiopathic thrombotic Conditioning intensity, myeloablative (MAC) thrombocytopenic purpura (TTP), and laboratory versus reduced (RIC), has not shown any differ- testing for the von Willebrand factor regulator ence in incidence in allo-HSCT. ADAMTS13 can be performed to support the diagnosis. In classical TTP, there is a severe deficiency, while no significant decrease of ADAMTS13 is 9.9.3 Prognosis seen in TAM (Graf and Stern 2012). Renal TAM should be suspected if the patient As with many early complications in HSCT requires higher doses of antihypertensives than prompt recognition of early signs and symptoms would be expected considering the situation and with early diagnosis and intervention will concomitant and/or nephrotoxic medication. increase the chances of a positive outcome. Cases Example of a differential diagnosis is virus- of mild TAM where calcineurin inhibitor (CNI), related nephropathy. e.g. cyclosporine, tacrolimus and sirolimus, is the Symptoms such as tachycardia, chest pain cause generally have a good prognosis if CNI can and hypoxemia should lead to suspicion of lung be discontinued. If TAM is not related to CNI involvement and pulmonary hypertension. The treatment, the prognosis is worse due to lack of diagnosis can be supported by findings of car- effective treatment options. Exact figures for diomegaly on chest X-ray, pericardial effusion mortality rate are difficult to establish, but in on transthoracic echocardiography and blood patients with TAM and multi-organ involvement, tests. the mortality is as high as >90%. Patients surviv- Intestinal TAM presents with the same symp- ing TAM are as a consequence at greater risk for toms as acute GvHD (aGvHD), abdominal pain, chronic kidney disease (CKD) and hypertension diarrhoea, vomiting and gastrointestinal bleeding. later on. The symptoms can also be mistaken for infectious colitis, but in TAM the cause of the bleeding is ischemia in the bowels due to the microangiopa- 9.9.4 Risk Factors thy. In addition to the general diagnostic criteria, specific criteria for gastrointestinal TAM have Use of total body irradiation (TBI) in condition- been proposed. Besides the clinical symptoms, ing treatment, CNI, graft versus host disease X-ray findings with signs of ileus and thick 9 Early and Acute Complications and the Principles of HSCT Nursing Care 191

Table 9.10 TAM diagnostic criteria

Blood and Marrow Transplant Clinical Trials Network toxicity committee International Working Group consensus definition for 1 Definition for TMA Probable TMA Diagnostic Criteria for TA-TMA TMA (BBMT 2005 ) 2 (Haematologica 2007 ) (Transplantation 20103) (Blood Rev. 20154) Tissue biopsy confirming microangiopathy or criteria below 1 Peripheral Blood Smear with >4% shistocytes in peripheral >4% shistocytes in peripheral LDH above Upper Limit of RBC fragmentation and ³ 2 blood blood Normal (ULN) shistocytes per high power field

2 Concurrent increase in LD Thrombocytopenia <50 x109 /L Concurrent increase in LD Proteinuria on random or decrease of 50% from analysis with ³ 30 mg/dL baseline 3 Concurrent renal Sudden and persistant increase in Thrombocytopenia <50 x109 /L Hypertension dysfunction (doubling of LD or decrease of 50% from serum creatinine from baseline baseline) an/or neurologic dysfunction without other explanations

4 Negative DAT and IAT Decrease in Hgb concentration Negative DAT and IATThrombocytopenia <50 x109 /L or increase in RBC transfusion or decrease of 50% from requirement baseline 5 Decrease in serum haptoglobin Decrease in serum haptoglobin Hgb below Lower Limit of Normal (LLN) or anaemia with transfusion requirement 6 Absence of coagulopathy Shistocytes in peripheral blood or microangiopathy on tissue specimen 7 sC5b-9 above ULN

1+2+3: Consider diagnosis of TAM and monitor very closely 2+7: If present at diagnosis poor outcome is apprehended. Consider active treatment. 1Ho et al. (2005) 2Ruutu et al. (2007) 3Cho et al. (2010) 4Jodele et al. (2015)

mucosal wall and endoscopy with mucosal ero- sary. CNI concentration in blood, lactate sions and haemorrhages are included in the gas- dehydrogenase (LD or LDH) and serum creati- trointestinal TAM diagnostic criteria, but the only nine should be closely followed, i.e. two to three definite diagnostic test is a biopsy tissue sample. times/week, with laboratory testing. Additional As a result of generalised vascular injury in blood tests with peripheral blood smear, hapto- TAM, polyserositis with pericardial and pleural globin and direct and indirect antiglobulin tests effusion and ascites can occur. It can easily be (DAT and IAT) should be performed if an increase mistaken for GvHD, but where GvHD more sel- is seen in CNI, LD and creatinine levels. dom is associated with microangiopathic anaemia, proteinuria and hypertension, these symptoms are common in TAM. 9.9.7 Treatment

There is currently no established treatment for 9.9.6 Prevention TMA but supportive measures should always be taken. Traditionally the first step is to discontinue No specific prophylaxis exists, so vigilant moni- CNI, despite paucity of evidence for this action. toring of clinical signs and symptoms is neces- It is also important to treat infections, GvHD and 192 E. Wallhult and B. Quinn hypertension. Changing to other GvHD prophy- for proteinuria and the patient instructed about laxis and use of antimicrobial drugs should be what abnormal findings and symptoms to look based on a risk-benefit assessment where, for for and to notify staff of any discomfort including example, nephrotoxicity is considered. signs of gastrointestinal bleeding. If invasive Administration of diuretics may be necessary to tests such as biopsies are to be performed, proper treat fluid and sodium retention due to steroid preparation and support is vital. treatment. Vasodilators and renin-angiotensin If pharmacological treatment with eculizumab antagonists may also be used to treat is started, serum level concentration needs to be hypertension. followed. Treatment with rituximab and defib- It is recommended to restrict platelet transfu- rotide should be administered as ordered, and the sion in microangiopathic disease, but this is often patient should be monitored accordingly for impossible due to the need to prevent bleeding effect and side effects. complications. Since the onset of TAM can occur after dis- A potential treatment for TMA is eculizumab. charge from the transplant unit, it is important to Eculizumab stops the complement-activating be observant to symptoms and consider this diag- cascade preventing formation of C5b-9. This nosis even in the outpatient setting. leads to hampering of the intravascular haemolysis. Eculizumab has shown effect when started early after diagnosis (Jodele et al. 2015). References Monitoring for effect by following serum concentration levels is important, and dose adjust- Afessa B, Tefferi A, Litzow MR, et al. Outcome of ments may be necessary to reach and maintain Diffuse Alveolar Hemorrhage in Hematopoietic Stem Cell Transplant Recipients. Am J Respir Critical Care the desired therapeutic levels and effect. Med. 2002;166:1364–8. Originally Published in Press In a small number of cases, successful treat- as https://doi.org/10.1164/rccm.200208-792OC on ment with rituximab and other monoclonal anti- September 25, 2002. bodies has been reported. Afessa B, Abdulai RM, Kremers WK, et al. Risk factors and outcome of pulmonary complications after Treatment attempts have also been made with autologous hematopoietic stem cell transplant. defibrotide at the same dosing as approved for Chest. 2012;141(2):442–50. https://doi.org/10.1378/ treatment of severe sinusoidal obstruction syn- chest.10-2889. drome/veno-occlusive disease (SOS/VOD) but Al-Dasoogi N, et al. Emerging evidence of the patho- biology of mucositis. Support Care Cancer. with variable results. 2013;21:3233–41. Total plasma exchange (TPE) has been tried Bhatt V, Ventrell N, et al. Implementation of a stan- due to the clinical similarities between TAM and dardised protocol for prevention and management TTP, but where TTP can be successfully treated on oral mucositis in patients undergoing haemato- poitiec stem cell transplant. J Oncol Pharm Pract. with TPE, it is not recommended for TAM due to 2010;16(3):195–204. poor response rates. Carreras E. Chapter 11: Early complications after HSCT. In: Carreras E, Gluckman E, Masszi T, editors. EBMT-ESH handbook on haematopoietic stem cell transplantation. 6th ed. Genova: Forum Service 9.9.8 Nursing Aspects Editore; 2012. p. 176–94. Carreras E. How I manage sinusoidal obstruction syn- Careful assessments will facilitate early diagno- drome after haematopoietic cell transplantation. Br J sis of, or ruling out, TMA and thus improves the Haematol. 2015;168:481–91. https://doi.org/10.1111/ bjh.13215. First published online 17 November 2014. outcome. Close monitoring of vital signs and Chang L, Frame D, Braun T, et al ngraftment syndrome being alert to any changes or trends is standard. after allogeneic hematopoietic cell transplantation pre- Keeping track of fluid balance and weight is dicts poor outcomes. Biol Blood Marrow Transplant. equally important. Blood pressure should be kept 2014;20:1407–17. https://doi.org/10.1016/j. bbmt.2014.05.022. below 140/90 in adult patients (Jodele et al. Chi AK, Soubani AO, White AC, et al. An update on 2015). The patient’s urine should be monitored pulmonary complications of hematopoietic stem cell 9 Early and Acute Complications and the Principles of HSCT Nursing Care 193

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Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Supportive Care 10 S. J. van der Linden, M. E. G. Harinck, H. T. Speksnijder, Teija Schröder, Ien Schlösser, Vera Verkerk, Micheala van Bohemen, A. M. Rusman-Vergunst, J. C. Veldhuijzen, and W. J. A. Quak

Abstract Hematopoietic stem cell transplantation (HSCT) care is highly complex. This chapter focuses on the aspects of supportive care required following HSCT. Assessment tools are key component of nursing practice and are necessary for planning and providing patient-centered care. HSCT care must be planned, implemented, and evaluated and is underpinned by collaboration with the entire multidisciplinary healthcare team. With supportive care following HSCT, we ultimately aim to improve the quality of life of our patients in the posttransplant period. Supportive care extends beyond symptom management and includes social, psychological, and spiritual care. The needs of the patient are multifactorial and can be complex, considering multiple issues at the e time and involving multiple disciplines.

S. J. van der Linden (*) • M. E. G. Harinck I. Schlösser • V. Verkerk • M. van Bohemen A. M. Rusman-Vergunst • J. C. Veldhuijzen • W. J. A. Quak Erasmus MC, Rotterdam, The Netherlands e-mail: [email protected]; [email protected] H. T. Speksnijder, MSc, RN Hogeschool, Utrecht, The Netherlands T. Schröder, MA, RN Helsinki University Hospital for Children and Adolescents, Helsinki, Finland

© EBMT and the Author(s) 2018 197 M. Kenyon, A. Babic (eds.), The European Blood and Marrow Transplantation Textbook for Nurses, https://doi.org/10.1007/978-3-319-50026-3_10 198 S. J. van der Linden et al.

Throughout supportive nursing care, our clinical competence is critical and is complemented by experience, knowledge, and awareness.

Keywords Supportive care • Assessment • Early warning scores • Oral care • Nutrition Allied health professionals • Transfusion • Physiotherapy • Spiritual care Complementary therapies • Music • Touch • Massage • Pediatric

10.1 Nursing Assessment instruments enable measurable and objective care delivery. Highly complex nursing care is essential for the disease- and treatment-related health problems of patients with hematological diagnoses (Kluin- 10.2 Pain Assessment Nelemans and Tanasale-Huisman 2013). The diagnoses within hematology are diverse but gen- In certain hematological diseases such as lym- erally associated with a specific set of symptoms. phoma or multiple myeloma, patients experience Hematological diseases can be broadly divided pain as a result of the compression of the lymph into malignant and nonmalignant hematological nodes or bone destruction. In some cases, patients diseases. The underlying hematological disease are reluctant to report symptoms of pain to their and cumulative effects of previous therapy can attending physicians in case this is interpreted as influence the degree and range of side effects and a poor treatment response. It is imperative to symptoms experienced following HSCT condi- consider both verbal and nonverbal signs and tioning therapy. These effects can manifest as symptoms of pain to complete a comprehensive physical complaints such as fatigue, fever, infec- assessment. tion, and bleeding and can result in complex ill- The bedside nurse is well placed to assess ness necessitating specialist care and treatment. their patient and explain the importance of ade- Psychological concerns are common and can fre- quate pain management using pharmacological quently manifest as low-level anxiety and depres- and supportive measures. Improving the patient’s sion and less often as features of significant comfort will enable them to better tolerate treat- trauma. As a key element of the multidisciplinary ment and improve their experience. team, nurses are ideally placed to identify and In the HSCT setting, pain is most commonly assess symptoms due to illness or treatment at an experienced as a result of mucositis, but patients early stage. HSCT nurses have extensive knowl- will also report other pain such as bone pain edge that contributes to treatment optimization. associated with GCSF, abdominal pain due Assessment is undertaken frequently to reflect to diarrhea, or general discomfort with fluid the dynamic nature and rapidly changing clinical accumulation. picture and will take into account the patient’s Not all reported pain symptoms or discomfort vital signs, blood results, and symptoms as well is treated in the same way. By explaining to our as knowledge of their baseline physical function. patients the possible cause of the pain and the By taking the medical and social history of the treatment for it, we can also help to manage their patient into consideration, we can increase our expectations of the analgesia and other supportive awareness of the potential care problems that interventions. We should inform our patients of may arise. The understanding and assimilation of the common side effects of analgesia like drows- information derived from these sources in con- iness and constipation and ways of reducing junction with standardized assessment tools and these effects. 10 Supportive Care 199

When assessing pain, a standardized tool • If the patient is immobile for long periods, should be applied to ensure consistency across pain can increase. The nurse should assess patients and between assessments. A compre- pressure area risk and consider offering a hensive evaluation of the pain, location, charac- pressure area mattress and/or gel cushion to teristics, onset, duration, frequency, severity of increase comfort and reduce pressure area pain, and exacerbating and relieving factors deterioration. should be included. This assessment should be • In addition to pharmaceutical pain relief, com- supported by the patient’s nonverbal reactions plementary care can also be offered to reduce such as facial expression, pallor, tempo of pain: heat-cold packs, relaxation by music speech, body position, etc. as well as their vital therapy, distraction, or gentle massages (if signs. possible with low thrombocytes). According to Kluin-Nelemans and Tanasale- Huisman (2013), a nurse can give the patient information and tips and tricks in the field of pain relief to the patient: 10.3 The Role of Early Warning Scores • Check to what extent the pain is present on performing her/his daily routine (getting up, Adult going to the shower, or getting dressed). The Observing vital signs is a crucial task in the use of a pain scale can give insight to the care of the HSCT patient. The patient’s condi- extent of pain the patient endures. Ask the tion can change dramatically in a short period patient how she/he scores the pain from 0 (no of time due to treatment and illness. Various pain) to 10 (maximum pain). If analgesia is measuring instruments allow us to monitor vital administered, you can monitor the effect by functions. The modified early warning score reassessing the pain score. (MEWS) shows when values of vital functions • Consideration of pretreatment with analgesia deviate and indicates when intervention is before starting the daily routine may permit required. the patient to move independently or with The MEWS (Subbe et al. 2001) scores various more comfort. items (Table 10.1): • Nonsteroidal anti-inflammatory drugs (NSAIDs) should not be prescribed for the • Heart rate HSCT patient. These can cause diminished • Blood pressure (systole) function of the thrombocytes and kidney dam- • Breath rate age and complicate the monitoring of • Temperature infections. • Awareness (AVPU score)

Table 10.1 Modified early warning score Score 3 2 1 0 1 2 3 Systolic blood <70 71–80 81–100 101–199 ≥200 pressure (mmHg) Heart rate (bpm) <40 41–50 51–100 101–110 111–129 ≥130 Respiratory rate <9 9–14 15–20 21–29 ≥30 (bpm) Temperature (°C) <35 35–38.4 ≥38.5 AVPU score Alert Reacting to Reacting to Unresponsive voice pain Subbe (2001) 200 S. J. van der Linden et al.

In addition, decreased urine production, dysfunction and increases the probability of SaO2 < 90% with adequate O2 therapy, and the reversing existing organ failure by delivering nurse’s awareness or “gut feeling” give increased timely and appropriate organ support. The value to existing scores (Ludikhuizen et al. modified early warning score (MEWS) may 2012). If the score is moderately elevated, it is contribute to this early recognition and prompt advisable to monitor the vitals more often and to referral to ICU. inform the attending physician. When the score When the patient is well enough to return to the increases, continuous monitoring is necessary, HSCT unit, fear of relocation may occur. This can and evaluation from an emergency intervention happen because the continuous monitoring of vital team or a medical emergency team should be functions ceases and the ward environment is very requested. These teams are available in most different from that of the intensive care. The HSCT centers and usually consist of a doctor patient may experience stress and anxiety and and an intensive care unit (ICU) nurse/emer- should be prepared at ICU for the transfer to the gency nurse. HSCT unit taking into account the psychological effect of relocation to both patient and family HSCT and Intensive Care The outcomes of (Coyle 2001). HSCT patients have been greatly improved over recent decades due to new therapies and Pediatric improvements in supportive care. An ICU As noted by Agulnik et al. 2016, hospitalized admission is sometimes necessary to treat life- oncology and HSCT patients are a high-risk pop- threatening situations that can arise following ulation with frequent clinical decline requiring HSCT. unplanned PICU transfer and high mortality Reasons for admission might include: rates. Complications developed by these patients, such as sepsis and respiratory failure, are known • Respiratory failure secondary to infection to have better outcomes with earlier identification • Sepsis requiring intensive support and management. • Multi-organ failure It is important to know the normal vital signs • Renal dysfunction in children in different ages. That is the basis • Complications such as graft-versus-host dis- which helps to recognize the early warning ease after allogeneic stem cell transplant signs in children. The use of the pediatric early warning system (PEWS) scores in clinical prac- Treatment in the ICU consists of: tice is a new concept (Murray et al. 2015). In reference to Agulnik et al. (2016), PEWS has • Mechanical ventilation been implemented in many pediatric institu- • Support of vital functions tions. Their study demonstrates that the PEWS • Treatment of sepsis/septic shock tool is valid in identifying pediatric oncology • Continuation of chemotherapy and HSCT patients requiring unplanned PICU transfer. Over the past 20 years, the survival of the The use of PEWS scores as an assessment hematology patient on the ICU has been tool has the potential to quantify the severity greatly improved, with reductions in mortality of illness in children. It is hoped that this by 40–60% (Netters et al. 2010; Ven van der results in facilitating early identification of et al. 2009). When a hematological patient is patients at risk for clinical deterioration and admitted to ICU early in their course, the prompt intervention to avoid the need to trans- chance of survival is greater (Peigne et al. fer to a higher level of care (Murray et al. 2009). Early admission reduces further organ 2015). 10 Supportive Care 201

10.4 Nutritional Assessment

The malnutrition universal screening tool (MUST) is a validated screening tool for recognition and treatment of malnutrition. The MUST form must be filled in accurately upon admission, asking for length/height, weight, and weight loss and whether the patient has no food intake for several days. The HSCT patient often has a reduced dietary intake during and following conditioning therapy, but this is often not considered at the time of Fig. 10.2 Bioelectrical impedance analysis (BIA) (Photo admission. credit https://www.habdirect.co.uk/bodystat) Sometimes weight loss is difficult to assess due to fluid gain. It is not possible using conven- ferent hand tightness measurements during the tional methods to determine what proportion of course of treatment, it can be determined muscle or fat components account for the weight whether the patient’s muscle function increases loss. or decreases. The measuring instruments deployed to obtain A bioelectrical impedance analysis (BIA) (see information about muscle function and muscle Figs. 10.2 and 10.3) is a tool measuring the resis- mass are the hand clamp and the bioelectrical tance that the body provides for an alternating impedance analysis (BIA). current of 50 kHz. The fat-free mass is calculated The hand clamping force gauge (see using a formula incorporating the resistance, Fig. 10.1) can be used to measure the maximum length, weight, gender, and age. With this mea- crushing force. The maximal squeezing force of surement we can assess whether a patient with the hand gives a good estimate of the peripheral weight loss has lost muscle mass and/or fat mass. muscle function and is related to the total amount Determining the fat-free mass with the BIA is of muscle mass in the body. Hand force depends not reliable if there is an abnormal hydration on age and gender. It can also be influenced by status. other factors, such as disease. By obtaining dif-

10.5 The Role of Allied Health Professionals

In the care of the HSCT patient, collaboration between different supporting disciplines is of great importance. Not only is medical and nursing care essential, but body, mind, and psychosocial care is necessary to facilitate the patient’s recovery. Allied healthcare professionals (AHP) are essential members of the multidisciplinary team (MDT) and include:

• Dietician Fig. 10.1 Hand dynamometer (Photo credits www.nutri- • Physiotherapist tionalassessment.azm.nl) • Occupational therapist 202 S. J. van der Linden et al.

10.6.1 Through the Treatment with Intensive Chemotherapy, There May Be the Following Nutritional Problems

10.6.1.1 Reduced Resistance to Infection Following intensive chemotherapy, the patient has reduced tolerance due to neutropenia and/or increased intestinal permeability. In neutropenia, the number of white blood cells decreases signifi- voltage cantly, resulting in the so-called aplasia with an Sensing Electrodes increased risk of infection. The patient is neutropenic if the neutrophil granulocytes (subdivision of the leukocytes) are less than 0.5 × 109/l. An increased permeability of the intestinal wall is caused by intensive chemotherapy damaging the Impedance gastrointestinal mucosa. As a result, pathogenic bacteria (bodily bacteria or bacteria from the diet) can enter the bloodstream (sepsis or blood poisoning). The patient has an increased risk of infection due to the reduced resistance. If the patient is expected to be neutropenic for longer than 7–10 days after chemotherapy, antimicro- Current Injection Electrodes bial prophylaxis may be given because of the high risk of infection. In some centers, the patient Standard placement of electrodes for whole-body impedance measurements. may commence this prophylaxis (selective intestinal contamination, SDD) at the time of condi- Fig. 10.3 BIA resistance (Photo credit http://www.nutri- tioning therapy. These specific antibiotics select tionalassessment.azm.nl/algoritme+na/onderzoek/ lichaamssamenstelling/bia.htm) out the patient’s own aerobic, potentially pathogenic intestinal flora and remove them. To prevent food-mediated infections, the Hygiene Nutrition Directive or “neutropenic • Wound or tissue viability nurse diet” or “clean diet” guidelines are implemented. • Pain nurse or specialist This directive is usually followed from the start • Spiritual worker of conditioning therapy until discontinuation of • Social worker the SDD or neutrophil recovery. The National • Counselor/psychologist Consultation Dietitian Hematology and Stem • Consultative psychiatric nurse (CPN) Cell Transplantation in the Netherlands has writ- • Psychiatrist ten the Hygiene Nutrition Directive, which is the basis for all hospitals in the Netherlands. There are small differences between several hospitals.

10.6 Principles of Nutritional 10.6.1.2 Food Aversion, Taste Support and Smell Changes, and Bad Taste in the Mouth Patients undergoing HSCT experience intensive Intensive chemotherapy, as well as other medica- treatment with chemotherapy, sometimes in com- tions such as antibiotics and antifungal agents, bination with total body irradiation (TBI). adversely affects the senses of taste and smell. 10 Supportive Care 203

The influence of the disease itself can also affect tis are busulfan, etoposide, melphalan, and meth- taste, and taste may be reduced and/or there may otrexate. Mucositis can occur in the mouth and be increased sensitivity to all flavors and smells. throat (orally) and in the rest of the gastrointesti- Aversions to specific foods, enhanced flavor or nal tract (gastrointestinal). taste sensation, or a bad taste (metal, cardboard, Oral mucositis can vary widely from sensitive or sand flavor) are frequently reported. Sometimes, gums (mucositis grade 1), the patient is often able the taste perception does not match the taste to eat everything, until blisters and ulcerations in memory. Patients may also be more sensitive to the mouth, and then the patient has even difficulty odors and can find that many foods or products drinking sips of water (mucositis grade 4, accord- like perfume or cleaning agents smell unpleasant. ing to the WHO scale). Good oral hygiene is very important to limit complications associated with 10.6.1.3 Nausea and Vomiting oral mucositis. Mucositis usually occurs Cytotoxic treatment is often associated with 4–10 days after the conditioning and lasts about complaints of nausea and vomiting. Highly 2–3 weeks. As soon as the leukocytes start to rise emetogenic cytotoxic agents used in HSCT to normal values, the mucositis heals rapidly. regimes include carmustine and cyclophospha- In severe mucositis, oral nutritional intake is mide; moderately emetogenic are busulfan (iv usually inadequate, and the patient is recom- Busilvex), cytarabine, and (high-dose) melpha- mended for nutritional intervention. Gastric feed- lan. Nausea and vomiting can occur indepen- ing with a tube through the nose (tube feeding) is dently. Medication to reduce nausea and vomiting preferred over parenteral nutrition, because it is (antiemetics) and hydration infusions are given physiologically more natural and reduces the risk and often adjusted. Nausea and vomiting after for intestinal atrophy. The main contraindication chemotherapy can occur acutely (4–24 h) and is of tube feeding is the risk of bleeding due to often severe. The symptoms may also occur later ulcerations in the gastrointestinal tract. (2 or several days to sometimes a few weeks after Insertion of a nasogastric feeding tube is safe the chemotherapy). There is usually no associa- when there is mucositis grade 1 or 2 and if there tion between vomiting and the type of diet used. are sufficient platelets (at least 40 × 109/l). As the patient undergoes multiple chemotherapy Otherwise the patient first needs platelet trans- cycles, anticipatory vomiting may occur. In this fusion for placement of the tube. When the case, vomiting occurs prior to the treatment in severity of the mucositis is too great to intro- response to previous chemotherapies and is trig- duce a tube, parenteral nutrition is the remaining gered by memory, experience, smell, taste, and option. sometimes visual cues. Diarrhea, due to gastrointestinal mucositis, is a common complaint following conditioning 10.6.1.4 Reduced Appetite and Early therapy. It is important to pay attention to dietary Satiety (Full Feeling) fiber, electrolytes, and hydration. Patients with Intensive chemotherapy, as well as other medica- severe watery diarrhea have reduced nutritional tions, infections, and fever, can cause a reduced absorption through the gut, and parenteral nutri- appetite and feeling of early satiety or fullness. tion may be indicated. As a result, a reduced dietary intake may occur, When the patient is discharged from the hospi- which may adversely affect the nutritional state. tal after HSCT, dietary intake is often still not optimal and particularly after allogeneic mye- 10.6.1.5 Mucositis (See Oral loablative conditioned (MAC) stem cell trans- Complications Section plantation. The patient often reports a dry mouth, for Further Information) nausea, vomiting, and early satiety. These patients Mucositis (oral and gastrointestinal) frequently often need nutritional monitoring and support for occurs after conditioning therapy. The grade some time in the outpatient setting. Additionally, depends on the type of chemotherapy. these patients often have increased energy Chemotherapies that are associated with mucosi- demands due to the treatment, and further 204 S. J. van der Linden et al.

interventions may need to be considered such as Plasma is administered to help correct coagu- tube feeding at home to limit further weight loss lation factors. The indication for plasma transfu- and restore nutrition. sion is usually based on PT/APTT and fibrinogen In general, following autologous HSCT there content in the blood. are less complications and infection-related prob- In summary, the indication for transfusion is lems. However, following allogeneic HSCT it based on the clinical situation of the patient and takes several months for the immune system to laboratory diagnostics. being to recover, and these patients are susceptible to infections for quite some time. In addition, Blood Groups and Pre-transfusion the immune system is suppressed with medica- Investigations tion to prevent graft rejection and to prevent or In order to select the correct blood product for a treat GvHD. patient, the determination of the ABO and Rhesus blood group is necessary. For transfusion of platelet concentrates and plasma, this is sufficient. In addition to the ABO and Rhesus blood group sys- 10.7 Transfusion tems, there are many more systems such as Duffy, Kidd, and MNS. For the administration of eryth- Introduction rocytes, it is important to screen the patient prior Blood transfusion is an essential element of sup- to every transfusion for irregular antibodies in portive care for many hematological disorders, addition to the ABO and Rhesus blood groups. and HSCT recipients will almost always require These antibodies are usually not naturally present transfusion support during aplasia. Importantly, in the blood but can be acquired at each preg- HSCT recipients will usually require product nancy and may increase with chronic transfusion irradiation to prevent transfusion-associated need. Depending on the number and type of anti- GvHD (tGvHD). This section covers general body, it may be difficult to find the appropriate information on blood transfusion. Please refer to erythrocyte concentrate. Following allogeneic your local and national transfusion directive or stem cell or cord blood transplantation, the stem policy for further details. cell donor blood group(s) as well as recipient blood group should also be taken into account. Blood Products and Indication For example, in case of double cord blood trans- Different types of blood products can be transplantation, up to three different AB0 blood groups fused: erythrocyte concentrate, platelet concen- may need to be taken into account. In case of trate, and plasma. The most commonly used emergency and if there is no time for determining blood product is erythrocyte concentrate (Sanquin a blood group, erythrocytes with blood group “O 2016). Erythrocyte concentrate is administered in negative” must be administered. Blood group O severe anemia, where insufficient hemoglobin negative is the universal donor for erythrocytes. reduces oxygen transport capacity. There may be Platelet antibodies such as the HLA (human acute anemia, for example, due to bleeding, or leukocyte antigen) antibodies may also need to chronic anemia, for example, due to a chronic be considered. These antibodies may develop disease. after prior transfusions and/or pregnancy. Platelet concentrate is administered to correct Sometimes HLA antibodies result in no or low thrombocytopenia to prevent or treat bleeding. increment after platelet transfusion. For these The indication for administration of prophylac- patients, platelet donors are selected as the best tic platelets depends on the patient’s condition possible match with the patient at HLA level. and whether the patient requires a higher circu- This is an intensive process, and sometimes only lating platelet count to treat, limit, or prevent a very small number of platelet donors are identi- bleeding. fied for a particular patient. In these cases, it may 10 Supportive Care 205

Table 10.3 Symptoms that may indicate possible transfusion reaction Mild Moderate Serious Temperature rise >1 or <2 °C Moderate clinical decline Severe clinical impairment during during transfusion transfusion Urticaria Cold shivering Dyspnea Itch Temperature rise >2 °C Respiratory insufficiency Exanthem/erythema Hypotension/shock Low back pain Vademecum (2017) take longer than usual to obtain platelets for the phoma. Only thrombocyte and erythrocyte blood patient, and in an emergency, “random donor” products can be irradiated. platelets may be prescribed until the matched platelets become available. For plasma transfu- Transfusion Reactions sion, only the ABO blood group is important. Although today’s blood products are very safe, a Note: Blood group AB is the universal donor. In patient sometimes experiences side effects from plasma, the Rhesus blood group does not need to transfusion. The table below (Table 10.3) shows be considered since the Rhesus blood group is on the symptoms of a possible transfusion reaction the membrane of the erythrocyte. that may occur during and up to several hours It is known that some drugs can interfere with after transfusion. the accuracy of pre-transfusion investigations in Acute transfusion reactions may be caused by the laboratory. An example of this is daratu- administration of an incorrect blood product, vol- mumab (monoclonal Ab anti-CD38). It is there- ume overload, or bacterial or viral contamination fore important, upon request of serological of the transfused product. In addition, there may testing, to provide the laboratory with all relevant be an unexpected reaction from the patient. If medical information and transfusion history, transfusion symptoms are observed during a including transplantation, pregnancy, previous transfusion reaction, the transfusion should be serious transfusion reactions, and the use of rele- discontinued immediately and the doctor should vant medication such as fludarabine (purine be alerted. Always leave intravenous access in analog). situ and then follow the instructions of the physician. It is very important to inform the blood Processed Blood Products transfusion laboratory about the possible transfu- Sometimes blood products need to be processed. sion reaction so that the cause can be investi- In addition, erythrocytes and platelet concen- gated. This may prevent a transfusion reaction at trates need to be irradiated and may be washed in a subsequent transfusion. some cases. Erythrocytes and platelets are In addition to acute reactions, blood transfu- washed in the case of previous severe anaphylac- sions can create long-term effects. For example, tic transfusion reaction or in a patient with IgA if a patient gets a lot of erythrocyte concentrates deficiency. When washing blood products, the over a longer period of time, developing iron plasma proteins are removed as far as possible. In overload can lead to increased iron stores in plasma this operation is not possible. Erythrocytes organs such as the heart, liver, and kidneys caus- and platelets are irradiated to damage the T cells ing severe damage. This process occurs because in the blood product, preventing these T cells erythrocyte concentrate contains iron, and the from causing transfusion-associated graft-versus- body does not have a system to break this excess host disease in patients with risk factors such as iron down and remove it. However, this can be HSCT, anti-thymocyte globulin (ATG), alemtu- treated by monthly venesection when the blood zumab and fludarabine use, and Hodgkin’s lym- counts have normalized after HSCT and if the 206 S. J. van der Linden et al. hemoglobin is not sufficient, by medication such and Huber 2008; Cramp and Byron-Daniel 2012; as Exjade or Desferral. Knols et al. 2005; Spence et al. 2010; Speck et al. 2010). Hemovigilance In the time period before and after the HSCT, Hemovigilance is the systematic monitoring of a specialized oncology physical therapist can be side effects and adverse incidents throughout the useful to advise, coach, and support exercise donor to patient transfusion chain, as well as (under supervision). By remaining mobile, com- anything that contributes to safer and more effec- plications can be prevented and the effects of the tive use of blood products. In this context, hospi- treatment can be optimized. Depending on the tals report transfusion reactions and incidents to phase in which the patient is, the physical thera- their National Hemovigilance Organization. pist will set goals (by using the “shared decision Annually, serious transfusion actions are reported model” with the patients). The goal can be to to the EU by the National Hemovigilance stay at the same level during the treatment or Organization. improve condition before, during, or after treatment. Conclusion Due to the long hospitalization in isolation For a safe blood transfusion, it is important that the and the side effects from treatment, exercise can correct indication is stated. The laboratory must be a challenge. Most patients are not permitted to have all relevant medical information to select the leave their room, so providing apparatus such as correct blood product. The nurse must verify: light weights, exercise bands, or static bikes can be helpful. The patient’s condition changes day 1. The transfusion prescription to day, so the physical therapist will need to 2. The identification of blood product adjust the expectations to ensure they remain 3. The patient and must always be performed by realistic. It is important not to force exercise to two nurses maintain safety and prevent strain or injury.

In addition, the patient must be observed closely during transfusion and the doctor notified 10.9 Psychological/Spiritual Care immediately of symptoms of possible transfusion reaction. The blood is an organ, and blood transfusion is an organ transplant which requires max- Introduction imum care. Psychosocial issues can lead to such a loss of energy that patients become dependent on their partner or caregivers. This is further compounded 10.8 Physiotherapy and Exercise by fatigue. In addition, physical symptoms such as pain can enhance the sense of dependence. Over the last years, several clinical trials have Reduced appetite, insomnia, and side effects of contributed to the growing body of evidence medication can cause depressive feelings, while showing the beneficial effects of exercise in can- anxiety and fear can contribute to restlessness, cer patients and also in the field of HSCT. Exercise forgetfulness, nausea, and tension. It is important interventions at different time points during and to regularly evaluate these patient’s care needs after HSCT can improve physical performance, and any additional care or aftercare requirements. quality of life, symptom control, and fatigue. However, it is still not possible to give a clear • Patients often experience fear and powerless- advice regarding the best type, intensity, start, ness feeling a loss of control over the disease and duration of an exercise program (Steinberg and its consequences. It is important to explain et al. 2015; Wiskemann et al. 2015; Wiskemann factual information about the diagnosis and 10 Supportive Care 207

treatment procedures, possible side effects, and relatives). Physical problems continuously inter- practical guidance to improve understanding. act with the psychological state. The enduring • Patients often experience the stages of mourning nature of many physical problems demands a (denial, anger, negotiation, and acceptance) and huge amount of resilience. This section describes react in their own way to their diagnosis. They the emotional impact of HSCT therapy and the may also experience these emotions during their importance of integrated care, with a focus on the transplant. Anxiety, sadness, powerlessness, role of the psychologist or consultative psychiat- and/or a disturbed body image can cause dys- ric nurse (CPN) and on the role of the bedside function, and it is essential to support the patient HSCT nurse. to reduce fear and/or discuss their feelings. Emotional problems such as depression and Enabling a social network around the patient fear of relapse may occur and impact adversely will provide a vital source of support both dur- on the patients’ quality of life (QOL) (Syrjala ing and after hospitalization. Prompt referral to et al. 2012). Emotional concerns are frequently a psychologist or possibly a consultative psychi- referred to as psychological distress, which has atric nurse (CPN) or a psychiatrist may be nec- been defined in Distress Management Version I essary for those patients with a history of (Practice Guideline Oncology of National psychological issues, in those who appear Comprehensive Cancer Network (NCCN) 2002) unable to cope emotionally, or where there are as “a multi-determined unpleasant emotional any concerns for psychological well-being. experience of a psychological (cognitive, behav- • Patients with younger children or grandchildren ioral, emotional), social, and/or spiritual nature are advised to discuss their diagnosis and treat- that may interfere with the ability to cope effec- ment with them. There are different information tively with cancer, its physical symptoms, and its materials aimed at children of different ages. treatment.” • Within the family unit, there may be a change “Distress extends along a continuum, ranging in the role of the patient or family members. from common feelings of vulnerability, sadness, Offering a social worker can be helpful in and fears to problems that may become disabling finding support to manage these changes. such as depression, anxiety, panic, social isola- • Through diagnosis and treatment, patients can tion, and spiritual crisis” (NCCN 2002). develop low self-esteem. The treatment may This description gives sufficient reason to affect their physical appearance in a way that organize an interdisciplinary team of caregivers makes them feel uncomfortable. Tips on per- around this special patient group. “Meeting the sonal care should be discussed. There are sev- needs of a patient requires the multiple compe- eral organizations that can assist in counseling. tences that many caregivers from different pro- Advise the patient and provide them with fessions will have to share in order to offer the resources and signposting where possible. best quality of comfort and care. It is a common • Finding a trusted person or talking with other practice in which each team member will incul- patients can help the HSCT patient in discuss- cate his own competencies. This is the essence of ing her/his feelings or fears. Patients should be interdisciplinary” (Porchet 2006). Braamse, psy- directed to relevant patient associations prior chologist at Vrije Universiteit, Amsterdam to commencing HSCT treatment. (VUmc), wrote her doctoral thesis about psychological aspects of HSCT in patients with hematological malignancies (2015). Hematological Basic Information of Psychological Care malignancies as well as treatment procedures are for the HSCT Recipient associated with impairment in patients’ Beside the physical impact of the HSCT treat- QOL. According to the World Health Organization ment, there is great impact on the whole psycho- (WHO), QOL reflects a subjective concept, social well-being of the patient (and their defined as an “individual’s perception of their 208 S. J. van der Linden et al. position in life in the context of the culture and • Physical condition value systems in which they live and in relation to • Sleeping pattern their goals, expectations, standards and concerns” • Influence on relationships and work (WHO 2017). Impairments are caused by the • Communication with caregivers original disease, prior treatment, and intensive conditioning therapy. Certain subgroups of The CPN gives psychoeducation on various patients have more difficulties adjusting to their topics, for example, coping, loss of control, and disease and treatment and consequently experi- loss of social roles. The screening includes some ence a more impaired health-related QOL post- questions which indicate if there is a risk of psy- transplant compared with other patient subgroups. chiatric decompensation or other increasing Suffering from (chronic) GvHD leads to prob- problems. The CPN discusses the assessment lems with overall QOL and physical well-being. outcome and possible needs with the patient as Braamse (2015): “Other subgroups that are at well as helpful resources. Extra support by the risk for worse psychological and social function- allied health professionals or other disciplines ing are female patients, patients receiving low may also be suggested. social support and patients experiencing pre- When there is preexistent psychopathology, a transplant psychological distress.” This is consis- special care plan will be described in collabora- tent with other research (Hill et al. 2011; Nordin tion with the physician, the psychiatrist, and et al. 2001) on psychological and social function- nurses from the ward. The CPN writes the con- ing in cancer patients. Receiving low social sup- clusions and advice in the patient record. port had been shown to increase the risk of During the hospitalization of these patients, depression and anxiety. Braamse (2015) indicates the CPN visits them for a brief consultation and that most HSCT patients were not in need of observes how the patient is coping. This is an active interventions to improve psychological informal way of counseling. CPNs take part of distress: most patients chose watchful waiting the weekly interdisciplinary meeting to discuss instead of a special online intervention program the complex cases with the nurses and other dis- or additional psychological care. Braamse (2015) ciplines. The main goal of the meeting is to give concluded that a discrepancy appears to exist practical advice about the communication and between symptoms patients report in the year structuring the daily nursing care. The meeting after transplantation and their need for additional also functions as a mechanism for supporting care: it seems that a substantial number of patients each other in our work with this patient group, who report emotional problems after auto-SCT which has great impact on all caregivers. do not engage in help-seeking behavior.” This The experience of the CPN is that many HSCT highlights the great resilience of patients going patients after hearing the news about their diagno- through all different aspects related to undergo- sis have a “rollercoaster experience.” At this point, ing a HSCT and their strength to cope with it there is often less time to think about the impact of without additional professional help. therapy options due to the pressure to commence therapy. In the weeks between chemotherapy with Role of the Consultative Psychiatric Nurse for its (side) effects and waiting for HSCT, patients the HSCT Patient A consultative psychiatric often begin to consider their dilemma and con- nurse (CPN) visits the HSCT patients in the out- template their situation. Meanwhile, their physi- patient clinic, during the “waiting zone” before cal condition is improving, and they are afraid of admission. The patients are screened by protocol losing this as they begin their HSCT journey. which asks them to share their experiences about: Most patients share their experience (while they visit the CPN in the out-clinic setting) about the • Hearing the diagnosis two emotional pathways: realizing that it is a pos- • Treatment sibility that they can die and trying to stay strong • Impact on different aspects of life and positive toward the treatment. They lose their 10 Supportive Care 209 innocence toward staying in isolation and dealing During his hospitalization he had some diffi- with lots of physical problems. Last but not least, culty with the ward routine such as waking up they struggle with their social role and how to early in the morning and was unfriendly toward manage the loss of or changes to it. the nurses. His mother was very concerned, so Patients report many examples of when they she stopped working. She visited her son daily felt understood by their doctors and nurses. But and remained by his bedside for the entire visit many patients also report experience of misun- even when his girlfriend arrives. derstandings and difficult and complicated com- He had fever for several days and mucositis munication with caregivers. requiring opioid administration, and he experi- Deweirdt and Vincke (2008) stated how enced nightmares due to analgesia. His thoughts patients report the importance of a family mem- and reactions were slower and at night, he became ber being allowed to stay for rooming-in while more anxious. He couldn’t eat normally. the patient was anxious. For the patient it is In this case the CPN can help the nurses with important that their caregivers provide basic, per- coordinating the communication and the daily rou- sonal attention, inserting in their experience, tine and to observe for the signs of confusion or hal- their concerns, and their irritations. lucinations that might occur despite his young age. The phase of recovery varies between patients. Some of them have the feeling of being elderly or Case Two aged. Others use their first energy to spend time Women B, 44 years old, acute myeloid leukemia at work or with friends, which can affect home (AML). relationships and partner interaction. She has a known bipolar personality diagnosis HSCT patients are frequently readmitted for which she is prescribed lithium. Lithium has because of infections, GvHD, or other complica- a specific therapeutic range and must be closely tions. After a long stay in the hospital, each new monitored through lithium blood levels. Nurses readmission can add an enormous psychological on general wards are often uncertain about the burden. It is understandable that patients some- care of patients with a psychiatric diagnosis and times lose courage. In some cases, patients speak about their own (communication) tools and skills. about their boundaries being further threatened It is understandable that they are unsure about by the treatment. They find it difficult to discuss their observations because behavior change can because the doctor did so much good work and occur as a result of the HSCT and existing psy- can mean that they don’t want to refuse further chopathology. The patient and the CPN can work treatment. It can be the role of the CPN to help together to process this and support the ward patients communicate their wishes. team in the care of these patients. The Collaboration Between a CPN and In these cases the patterns of reaction on the Hematology Nurses on the HSCT Wards changed psychosocial situations are very under- Case Examples for This Population standable. Patients are not doing things wrong, but sometimes their reactions or behavior may not Case One have a positive effect on recovery. For each case it Patient A, male, 21 years old, non-Hodgkin lym- is important that the HSCT nurses use their own phoma (NHL). observations to contribute to patient care. Relapsed NHL (initially diagnosed aged 16). In the nursing practice, it can be helpful to He is a student and living independent near the consider the following: campus. He has a steady relationship for a year, but because of his treatment and functional decline, • Does the patient really understand the need to he has moved back home to live with his mother. strictly follow a set medication regime after His parents are divorced and don’t communicate SCT? well. He enjoys online gaming until late at night • How is the hygiene at home in relation of and subsequently wakes up late in the morning. infection risk? 210 S. J. van der Linden et al.

• In normal life enjoying food impacts on qual- Coolbrandt (2005) noticed the active role of the ity of life. How can the nurse help their patient nurses in the recovery story of HSCT patients. with the difficulties they experience around Like their medical counterparts, nurses contrib- food? ute to the positive story and support patients in • Diarrhea caused by GvHD has various effects their therapy. Nurses protect the positive story by on the psychological well-being of the patient. advising what the patient might expect. When How can you help to support? things are going badly, they intervene by explain- • The pattern of activities changes significantly ing the situation. Sometimes, it is appropriate to in comparison with normal life, and the hospi- normalize a situation and the patients feel less tal room and environment can inhibit mobility. panic. Nurses give positive feedback; patients • The sleep pattern and routine are disrupted told that it helped them when the nurses are opti- because of intravenous therapies which can mistic. Nurses give comfort when they reassure stimulate the need of going to the toilet. Other that symptoms will resolve, and they identify contributing factors are worrying about the solutions improve symptoms. Nurses are often diagnoses and social impact in their lives. searching for the balance between “realistic hope • Some patients do not understand their treat- and hopeful realism.” This study of Coolbrandt ment regimen, either due to preexistent loss of (2005) is followed by a study in the same ward cognitive functioning, dementia, low IQ, or the about the way hematology nurses care for HSCT sheer complex nature of their therapy. This can patients through the most difficult part of treat- cause increased anxiety and loss of control. ment (Deweirdt and Vincke 2008). We already • Self-image is often a concern: roles and rela- know, but this study confirms the great impor- tionships change rapidly, and often there are tance of an empathic attitude and expertise. This feelings of being “on hold,” at the sideline. empathic attitude is characterized by understand- • How do we facilitate intimacy and address ing what the patient is going through, willingness sexual functioning concerns? to adjust the schedule if necessary for the patient, and to pay attention to the person behind the Nurses understand that body and mind con- patient. The shown expertise, that nurses can nor- tinually interact, and they need to develop skills malize concerns and complications, creates con- to structure and interpret their observations. They fidence in the collaboration between patient and should discuss this in multidisciplinary meetings caregivers. and consider appropriate interventions. Nurses Psychologist Braamse (2015) learns that for need to be taught how to use evidence-based some patients, there’s often no immediate solu- tools that assess and address this aspect of care. tion for the problems. Patients have to go through The patient is the best source of information the situation – and they know that very well. about the impact of their concerns, coping in nor- They don’t expect their nurses and relatives to mal healthy life and what might help them at that wear their burden. Patients know that the isola- moment. To promote self-management and tion is inherent of their illness and treatment. But shared decision-making, it is necessary that they still need the presence from caregivers and nurses are aware of the diverse resources and how close relatives or to feel them nearby. In this way, to use them in their own work setting. Even when they can feel the autonomy to choose their own there are many professionals involved in a way of coping with the situation. That autonomy patient’s care, it does not necessarily follow that is often affected by the disease and treatment. they will work in a multidisciplinary manner. Nurses can always reflect on themselves with Interdisciplinary working is time demanding: the following basic questions: time for meetings, dialogue, and questioning teamwork (Porchet 2006). • What do I observe? Coolbrandt (2005) wrote a thesis about keep- • What do I signal? ing and losing courage, a qualitative research in • Which interventions can I do? HSCT patients at Gent University Hospital. • What do I report in the dossier? 10 Supportive Care 211

• Who can I ask for extra support? patients (workshop). For this patient group, most And activities take place in the patient room. • Which attitude is needed? Do I have it? Some of the creative activities that we offer • Which knowledge is needed? Do I have it? include mosaic, jewelry making, painting, draw- • Which skills do I need? Do I have them? ing, mandala, knitting, and crochet. Special cre- • What do I need from my colleagues? ative volunteers help and provide the patient with • Who can I ask for counseling and coaching creative material. Also workshops can provide when I need it? special creative activities like (dry)flower arranging and seasonal workshops. These questions can help you to go back to A creative activity provides the patient with a your nursing base when the complexity of the welcome distraction to get through the day. It cases makes you problematize things too much. also helps to keep the mind of negative things, When you feel powerless because of the multiple and it is a way to make something nice for their problems, you don’t have to forget that your pres- loved ones. ence is also an intervention. Social Activities Patients regularly stay for long periods of time during their treatment. Some of the patients don’t have a big social network and 10.10 Therapeutic Interventions, are at risk of becoming lonely during their stay. e.g., Complementary An initiative “life well-being and relaxation” has Therapies, Music, Touch, special “social” volunteers that visit the patients and Massage on a regular basis. The volunteers work with a cart that is filled with all kinds of magazines. In some countries there are well-being and relax- With that cart the volunteer visits every patient on ation departments for the oncologic patients. The the ward. They make contact with new patients, goal is to provide the patients with a wide range hand out magazines, and tell what can be offered of recreational activities and with that maximize to them during their stay. They make extra time to their well-being during the treatment. Most of visit and talk to lonely patients. Most patients the time, such teams consist of a coordinator, an really look forward to the weekly meetings with art therapist, a music therapist, and a group of the volunteers. volunteers. In the hospital they can make a “living room” where patients and their family can Rental Service (in Some Hospitals/Organiza come to relax and optionally can partake in a cre- tions) Patients have the possibility to rent items ative activity or a workshop. It consists of four that will make their stay more pleasant. They can different subdivisions: activity therapies, art get laptops, game consoles, e-readers, tablets, therapies, music therapies, and complementary and audio book players. Patients can rent Dvd’s therapies/care. Each division will be specified directy from a webpage. Offering board games, below. puzzles, and handy tools like a book seat (a handy device that makes it possible to put a book or a tablet on the bed without the need of holding it) is 10.10.1 Activity Therapies some of the special offers you can give to the patient. Activity therapies consist of three different pil- lars: creative activities, social activities, and a rental service. 10.10.2 Art Therapies

Creative Activities Patients can choose from a Art therapy focuses on the power of the image, wide range of creative activities. They can do this where color and form play an important role. Art on their own, with a volunteer, or with other therapy can give support when the body, mind, 212 S. J. van der Linden et al. and soul are out of balance because of the physi- ing their own music during the stay in the hospital. cal and mental pressure that comes with being ill. Listening to music alongside the music therapist is With art therapies a guiding question or a specific also a possibility (the therapist has a blue tooth theme forms the basis for the therapy. Some pos- speaker box for these occasions), and the patient sible themes are acceptance, come closer to your can compose and then record his/her own song on inner self, enlightenment, relaxation, and how to CD. This is a great opportunity because the music handle emotions. With art therapies the process is is not only beneficial for the moment but also acts the most important aspect. It does not matter if as a nice memory for a later time. the patient is creative or not; it only matters that The musical instruments the patients can the patient is willing and open for the therapy. choose from are as follows: guitar, keyboard, There are many different creative forms a sound bars, and a lyre (a kind of harp). patient can choose from: drawing, painting, felt- Patients make regular use of the music thera- ing, and molding. A combination of said pies. A lot of patients find the music that the art techniques is also possible. Making a collage or therapist plays very soothing, and they can let writing poetry can also be offered. The materials their emotions run free. Some patients even that can be used are diverse: pastel chalk, request that the music therapist plays music on aquarelle pencil, and aquarelle and acrylic paint. their deathbed or at their funeral. The art therapist decides together with the patient what material and technique to use. Patients make regular use of art therapies. 10.10.4 Complementary Because of their long stay in the hospital, the art Therapies/Care therapist can offer lots of therapeutic sessions to the patients which make it easier to work on a Because of the side effects of the disease or HSCT certain set goal. treatment, some complementary therapies like massage, manicure, and pedicure are limited or not possible for the patient group. The complementary 10.10.3 Music Therapies therapies that can be used by the patients are:

Music therapy focuses on the power of melody, Aromatherapy With the use of aromatherapy, harmony, and rhythm. Music therapy can give the patient can experience a wide range of differ- support when the body, mind, and soul are out of ent aromas. Every aroma has its own use. Some balance because of the physical and mental pres- will sooth or calm, while others will activate the sure that comes with being ill. With music thera- patient. The use of electric scent streamers in the pies a guiding question or a specific theme forms patient room distributes the aromas. the basis for the therapy. Some possible themes are acceptance, come closer to your inner self, Therapeutic Touch Therapeutic touch is a tech- enlightenment, relaxation, and how to handle nique to help people relax, relieve their pain, and emotions. With music therapies the process is the help them heal faster. It is sometimes called a most important aspect. It does not matter if the “laying on of hands” and is based on ancient patient is creative or not; it only matters that the healing practices. Therapeutic touch is thought to patient is willing and open for the therapy. promote healing through balance in the body. There are many different musical forms a patient can choose from, both in an active form and Philips Living Color Lamp The Philips living the recipient. The music therapist can play along- color lamp can change the color of the room to side the bed of the patient; the patient can choose match the mood of the patient. Patients can change to just listen, but he/she can also sing or play along the colors with a remote, so that they can alternate with an instrument. It is possible for the patient to between colors. Just like aromatherapy colors can borrow an instrument, so that they can enjoy play- also influence the well-being of the patients. 10 Supportive Care 213

10.11 Skin Care (see also Chap. 11 tissue and is much different in content than the epi- GvHD about skin care) dermis which consists of a few types of cells. The leather skin is also the most important part of the active defense system of the skin: through which Introduction special white blood cells play an important role, Our skin is important in many ways. Grégoire viruses and bacteria can be recognized and directed (1999) stated that the skin is the first line of harmlessly. The leather skin also ensures the elas- defense against harmful influences of our envi- ticity and tensile strength of the skin. When the ronment. The skin prevents us from overheating, skin ages or is damaged by sunlight, the elasticity undercooling, or drying out. The skin has a sense and resilience decrease. The leather skin is not con- of touch, so we can feel things and also perform stantly renewed, as happens with the epidermis. complex actions, for example, with our hands Damage to the leather skin will therefore always be and face. Our skin is unique to us and who we are visible as a scar. However, if only the epidermis as a person, recognizable to the people around us becomes damaged, it will heal completely. or through identification by fingerprints and The subcutaneous connective tissue is the scars. layer that separates the skin of the muscles and The skin exists of three layers: tendons in our body. There are blood vessels (food and oxygen supply), lymph vessels (drain- • The epidermis age of waste), and nerves (touch sensation, pipe- • The dermis (leather skin) line, temperature sensation). The blood supply is • The subcutaneous connective tissue ingenious and precisely regulates the supply of nutrients and oxygen to the leather skin and the Grégoire (1999) wrote in his book about lower layers of the epidermis. The blood vessels pathology and physiology of the layers of the in the skin also play an important role in the skin. The epidermis is the outer layer. This con- body’s temperature control. By dilating the blood sists for the most part of horn cells. These cells vessels, extra heat can be delivered to the outside, are constantly newly formed in the lower layer of and with vasoconstriction, the release of heat can the epidermis. The cells multiply by division. be reduced so that no energy is lost. The newly formed horn cells always move slightly to the surface of the skin because they are Skin and Chemotherapy pushed upward by the continuous production of When a patient receives chemotherapy, problems new cells. When the cells reach the top of the epi- of the skin are common. The skin contains many dermis, they die. Our skin will form a very strong fast-growing cells which will be affected by the layer (like an armor), which is difficult to pene- chemotherapy. trate for pathogens and, in addition, counteracts Possible complaints are: dehydration of the skin. This dead horn layer is extra thick on some areas of the body, such as on • A dry, flaky skin the soles of the feet and on the palms of our hand. • Rash There are also other cells in the lower layer of • Faster discoloration or skin damage by the sun the epidermis between the horn cells: the mela- • Brown spots and brown discoloration nocytes. The pigment cells make small pigment • White spots without pigment pellets that they pass on to the horn cells to place • Acne the pigment like an umbrella above their core • Redness nucleus. Vulnerable hereditary material in the • Itching nucleus is shielded against the damaging effect of • Hyper-/hypopigmentation ultraviolet radiation in the sunlight. The Grégoire (1999) wrote about the leather Usually, after the end of chemotherapy, the skin (dermis) as a solid construction of connective skin will recover quickly. 214 S. J. van der Linden et al.

The basic advise for chemotherapy patients Skin and Rash (Erasmus MC (Care guide) (2009): If the patient endures itching, scaling, splitting, and burning, you can advise: • The use of perfume or roller deodorant, aftershave, and razor blade is not advised. As a result • Use soothing and protective creams and oint- of treatment, the skin may become more sensi- ments. They keep the skin smooth and prevent tive to these products and may lead to irritation the skin from drying out. Examples of non-dry or damage. When this happens, it increases the skin creams: lanette cream and cetomacrogol risk of infection. The use of shower gel, sham- cream. Examples in very dry skin: Vaseline poo, and body lotion is allowed. lanette cream. • Makeup may be used, as long as the skin and • Do not treat skin rash with anti-acne agents. nail bed can be well observed. For example, eye shadow and noncolored lip balm are allowed, as they cover a very small part of the Skin and Acne skin and are not specific. Rouge, powder, and Chemotherapy can cause acne. This is a side similar products may not be used, as they effect that creates uncertainty in our patients. You cover a larger surface of the skin and possible can advise: skin abnormalities may be masked. • Recommend wearing bath slippers and plenty • Leave the skin alone. of clothes. Clothes need to be changed when • Wash the skin with not too cold or too warm they are visibly dirty. However, in the pres- water and do not use any soap. Or use a pH- ence of fever (perspiration), dry skin (skin neutral shower gel. scales), or cream use, changing the outfit is • Carefully dry the skin with the towel. desirable. Washing can be done in a normal • Do not scratch or squeeze. washing machine, with other people’s clothes. • A dermatologist may be able to recommend However, they must be washed at least 40 °C. specific topical therapy.

Skin Responding at the Treatment Advice on Itching The skin changes depend on the type of chemo- Because of the treatment, the skin can dry out it therapy the patient receives. For example, the skin which can cause itching or a prickling sensation is drier, darker (= pigmentation problem), or look that can be uncomfortable. You can advise: dusky or gray. Also, the nails can change in structure. This is due to the effects of the chemotherapy. • Do not scratch. Tell the patient to cut the nails It is good to advise the patient to adjust the daily very short and keep them clean. care of the skin to the changes that have occurred. • Itching gets worse sometimes by heat or by You can advise the patient (Erasmus MC contact with clothes or bedding. (Care guide) (2009): • Use a cool ointment or menthol powder (on localized areas) to relieve the itching. This • Not to use very hot or very cold water during only applies if the skin is not broken. shower or bathing. • Avoid alcohol-based products. They will dry Skin and Risks of Bleeding and Infections out the skin. Chemotherapy may (temporarily) increase the • Do not use any perfumed soap during shower risk of infection and bleeding. Observe the patient or bathing. A little (almond) oil in the bath for wounds, blisters, or discolorations. In case of water can help to keep the skin smooth. sudden redness of the skin or the occurrence of • Use mild, unperfumed, moisturizing body blisters, contact the attending physician. A little lotion or cream. extra care for the skin is recommended. 10 Supportive Care 215

Skin and the Sun etc.) should be discouraged. Cat’s litter Advise caution with sun exposure and encourage boxes and bird cages can easily transmit the application of high SPF sunscreen (30–50). germs (toxoplasmosis). If nobody can’t take The patient needs to be careful in direct sun and over this task, recommend the patient to also if they are in the shade due to reflected light. clean the animal shelter with (household) During the periods the patients undergo chemo- gloves. therapy, they can take a walk or work in the gar- • The patient can do some gardening but advise den but advise them against sunbathing. They to avoid contact with sand and/or soil with should avoid the sun between 12 and 15 o’clock. their bare hands (toxoplasmosis) and avoid Chemotherapy can cause the loss of hair and moving leaves and debris which may release thinning of the hair on the scalp. The scalp is fungal spores. Ask them to use garden tools more at the risk for sunburn. After chemotherapy, and wear (household) gloves. the sun can cause more discoloration of the skin. • Fresh flowers and plants can stay in the home, Our patients must always protect their skin. but give the patients advice to regularly refresh Wearing a (sun) hat or cap and covering the arms the water of the flowers. are recommended. Using a sunscreen with a protection factor of 30 or more is extremely Social important. • Patient should be advised if they want to take some outdoor trips, such as holidays or camp- 10.12 Discharge from Inpatient ing visits, to discuss this with their treating Care physician. This is especially important if the patient wants to go abroad following When a patient is discharged following HSCT, HSCT. The patient must consider the hygienic this is often an anxious time. They are now leav- conditions or vaccinations that may be needed ing the “safe” environment of doctors and nurses. in the visiting country. Some of the patients feel that they don’t have any • The patient needs to avoid visits of family trust in their own body to let them know when and/or friends from sick (contagious) people they are not well. until they are out of their leukopathic phase It is advisable to inform the patient about the and while they remain immunocompromised. general aspects/living rules so that they can pick up their daily routine at home: housework or Driving social events. School, study, and work • The patient should consult with their attending physician when to resume driving. Some • Patients who are no longer neutropenic and medications or having anemia can affect the when their physical condition allows may ability to concentrate so that driving is not slowly take up their studies or activities. safe.

Domestic work Sports activities

• Patients can pick up and expand household • Give the patient information about building tasks. For most patients, a full-day job is too up their physical strength and condition. heavy. Ask them to start slowly. It can be Some rehabilitation sports programs can be very stimulating for patients to feel “useful” given in the living area of the patient. The again. patient can also seek information from a phys- • If the patient is neutropenic, cleaning the iotherapist in the area to improve their physi- residences from pets (birdcages, dog basket, cal condition. 216 S. J. van der Linden et al.

10.13 Readmissions to Hospital • Pain in the mouth • Difficulty and pain with swallowing Patients are often unsure about the rules of life • Painful and burning sensation during and their physical condition during and after urination HSCT. It is important that patients from the out- • Burning and/or painful eyes patient clinic receive clear information when they • Insufficient drinking or passing urine can resume certain activities in their social and general life. It is important to inform the patient fully about the rules of life so that they can pick 10.14 Pediatric Considerations become independent more quickly after this intensive treatment period. Advances in treatment and improved prognosis In the home situation, side effects or problems increase the number of children and families may occur after HSCT. The patient should con- living through the experience of childhood can- tact the hospital or attending physician. In many cer. Increased survival rates come at the cost of HSCT centers, emergency call procedures are aggressive combinations of chemotherapy, well established. The patient should be aware of radiotherapy, and surgery, each of which may be these. According to the Erasmus MC (2009) associated with adverse effects and psychoso- Zorggids (care guide), the contact moments cial difficulties for families (Kieman et al. should be as follows: 2010). Hematopoietic stem cell transplantation (HSCT) may affect children and their families 10.13.1 Urgent Complaints inducing depression, anxiety, burnout symptoms, and post-traumatic stress symptoms, as well as Following HSCT, they should contact immedi- post-traumatic growth (PTG) which includes ately (inside and outside office hours) with the feelings of inner strength, closer relationships following complaints: with family members and friends, and a greater appreciation for life, factors that might lead to a • Fever (temperature above 38.5 °C) general feeling of growth (Riva et al. 2014). • Cold shivers Furthermore, these treatments can lead to • Blood in stool or urine physical late effects, which may also have • Nosebleed psychosocial consequences to the patient and the • Hematomas or bruising without bumping family long after treatment has ended (Kieman • Difficulty moving the arms and/or legs et al. 2010). • Sudden shortness of breath It is important to understand the general • Persistent and constant vomiting impact of childhood cancer on families, like the • Persistent diarrhea emotional impact, the specific impacts for indi- • Sudden/new skin rash vidual family members and extended family, and the disruption to family life. How the illness impacts on the social lives and networks of the 10.13.2 Complaints family and the social implications for families needs to be taken into consideration (Kieman Following HSCT the patient should contact et al. 2010). (within office hours) at: There are many specific psychological interventions to help children deal with cancer treat- • No stool for longer than 3 days ment. As quoted by Weinstein and Henrich • Symptoms of anemia, such as severe tiredness (2013) in their research, the interventions that are or dizziness mostly used to help children before they undergo 10 Supportive Care 217 a painful or anxiety-inducing procedure are edu- the child and their families (Weinstein and cating children by explaining the procedure, pro- Henrich 2013). Contacts should be offered to viding emotional support to children by listening social services, psychologists, and therapeutic and answering children’s fears and worries or healthcare professionals as well as religious sup- holding their hands, and distracting children port or counseling when requested, taking into through passive forms such as music, television, account the family’s cultural background and and books or through active forms such as play- contact with self-help groups, relevant support ing, telling stories, singing, and using bubbles. groups, and patient or consumer organizations Weinstein and Henrich (2013) explains the least (EACH 2016). commonly reported strategies that nurses used For children it is important to try to make the were breathing exercises to relax the child using life in hospitals as close to normal life as possi- books, tapes, and videos to educate children on ble. School is an important part of it for school- their treatment and hypnosis. All these psycho- aged children. School is also an important part of logical interventions are effective in reducing adolescents’ and young adults’ lives, and being pain and anxiety, along with enhancing accep- diagnosed with cancer in childhood may affect tance of medical treatments (Weinstein and perceptions of school. Cancer and its treatment Henrich 2013). have a negative impact on mental and physical Also Weinstein and Henrich (2013) stated that health and often lead to an increased absence one of the primary benefits of these psychological from school. Furthermore, treatments with radia- interventions is that children shift from a passive tion and chemotherapy, especially among patients and helpless state of pain and anxiety to a state of diagnosed with a central nervous system (CNS) control and empowerment with an active adaptive tumor, may significantly affect neurocognitive attitude toward life. Through these interventions, function and levels of education (Winterling et al. children are considered an active participant 2015). within their own care. By preparing children psy- Results from Winterling et al. (2015) studies chologically for medical procedures and teaching show that survivors appear to achieve education them coping strategies, nurses may help reduce levels comparable to those of control groups the risk of developing maladaptive behaviors and although some studies indicate that survivors psychopathologies. Kieman et al. (2010) indicate more often repeat a school year and receive addi- that physicians and nurses working in pediatric tional academic support. oncology are in a unique position to identify and Furthermore, worry over missing school is a manage psychosocial issues in childhood. great concern for adolescents starting In order to prevent feelings of isolation and chemotherapy. helplessness, the children’s rights in hospital (EACH 2016) stresses that steps should be taken to mitigate physical and emotional stress. The References staff should avoid or reduce situations or actions described by the child as stressful. The staff Agulnik A, Forbes PW, Stenquist N, Rodriguez-Galindo should learn to recognize and act upon the fears C, Kleinman M. Validation of a pediatric early warn- or concerns of the child and families whether or ing score in hospitalized pediatric oncology and hematopoietic stem cell transplant patients. Pediatr Crit not explicitly expressed. To mitigate emotional Care Med. 2016;17(4):e146–53. stress, the child and family should be offered Al-Dasoogi N, Sonis ST, Bowen JM, Bateman E, emotional support. Blijlevens N, Gibson RJ, Logan RM, Nair RG, It is important to work together with a multi- Stringer AM, Yazbeck R, Elad S, Lalla RV. Emerging evidence of the pathology of mucositis. Support Care disciplinary team members like the child life Cancer. 2013;21:3233–41. therapists, psychologists, and social workers who Braamse AMJ. Psychological aspects of hematopoietic all can help to provide psychological support to stem cell transplantation in patients with hemato- 218 S. J. van der Linden et al.

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Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Graft-Versus-Host Disease (GvHD) 11 John Murray, Jacqui Stringer, and Daphna Hutt

Abstract Acute and chronic graft-versus-host disease (GvHD) is a major cause of morbidity and mortality in patients who undergo allogeneic haematopoietic cell transplantation (HCT) and affects approximately 30–40% of recipients. Its diagnosis is complicated, and staging of the disease varies dependent upon the transplant centre involved. Standardisation through the use of National Institute of Health (NIH) guidelines helps clinicians diagnose and treat their patients more effectively. For the majority of patients who go on to develop GvHD, corticosteroids remain the first-line treatment for both acute and chronic GvHD. Recipients that are refractory to systemic steroids have a plethora of second- and third-line options available to them. A ‘standard of care’ approach has not yet become agreed globally due to poor evidence from small and limited randomised control trials. Supportive care is paramount, and the nurse is often at the centre of the patients care and in the best position to guide and advise the patient and family through this often long-term complication.

Keywords Acute graft-versus-host disease • Chronic graft-versus-host disease

11.1 What Is GvHD?

J. Murray (*) • J. Stringer 11.1.1 Definitions The Christie NHS Foundation Trust, Manchester, UK e-mail: [email protected]; Acute GvHD is a reaction of donor immune cells [email protected] against host tissues. The three main tissues that D. Hutt acute GvHD affects are the skin, liver and gastro- Department of Paediatric Haematology-Oncology and BMT, Edmond and Lily Safra Children Hospital, intestinal tract (Jacobsohn and Vogelsang 2007). Sheba Medical Center, Tel-Hashomer, Israel Chronic GvHD is a syndrome of variable clin- e-mail: [email protected] ical features resembling autoimmune and other

© EBMT and the Author(s) 2018 221 M. Kenyon, A. Babic (eds.), The European Blood and Marrow Transplantation Textbook for Nurses, https://doi.org/10.1007/978-3-319-50026-3_11 222 J. Murray et al. immunologic disorders. Manifestations of body. GI and liver GvHD symptoms such as nau- chronic GvHD may be restricted to a single organ sea, vomiting, diarrhoea, abnormal liver enzymes or site or may be widespread, with profound and jaundice are similar in both acute and chronic impact on quality of life (Jagasia et al. 2015). forms of GvHD. According to the 2014 NIH consensus, the broad category of acute GvHD includes classic 11.2 Background to GvHD acute GvHD (maculopapular erythematous rash, gastrointestinal symptoms or cholestatic hepati- The New England Journal of Medicine reported tis), occurring within 100 days after HCT or the infusion of bone marrow into patients by donor leukocyte infusion. The broad category of E.D. Thomas and colleagues in 1957, following acute GvHD also includes persistent, recurrent or radio- or chemotherapy. Preclinical animal stud- late-onset acute GvHD, occurring more than ies revealed that transplantation of splenocytes 100 days after transplantation or donor leukocyte from non-oncogenic donor strains facilitated hae- infusion. The presence of GvHD without diag- matopoietic recovery but led to a severe illness nostic or distinctive chronic GvHD manifesta- characterised by anorexia, reduced weight, diar- tions defines the broad category of acute GvHD rhoea, ruffled fur and eventual death. It was (Vigorito et al. 2009; Jagasia et al. 2015). labelled at the time ‘secondary’ or ‘runt’s disease’ and later became known as graft-versus-host disease (GvHD). It was clear that the effect was not 11.3 Acute GvHD one of the conditioning therapies but was associated with an immune-mediated syndrome (Wolf Overview: acute graft-versus-host disease et al. 2012). (aGvHD) occurs following an allogeneic haema- GvHD remains a leading cause of non-relapse topoietic stem cell transplant and is a reaction of mortality and is associated with a high morbidity donor immune cells against host tissues and that increasingly affects quality of life (Lee et al. remains a major cause of morbidity and mortality 2003; Dignan et al. 2012). (Greinix 2008). High-dose chemotherapy +/− However, the success of allogeneic HSCT radiotherapy inflicts cellular damage, and this depends on simultaneous graft-versus-tumour leads to an inflammatory process; the activated (GvT) effects. Therefore, broad-based immuno- donor T cells interact with the host epithelial suppressive strategies are less attractive as these cells. Approximately 35–50% of haematopoietic may dampen the GvT benefit. Relapse accounts stem cell transplant (HSCT) recipients will for a significant proportion of treatment failures develop aGvHD (Dignan et al. 2012). There are after HSCT; thus strategies for GvHD prevention several factors that can influence the develop- with minimal impact on GvT are the holy grail of ment of aGvHD: the stem cell source, age of the transplantation (Magenau and Reddy 2014). patient, conditioning regimen and GvHD pro- Historically, GvHD is termed ‘acute’ before phylaxis used. All aGvHD can be associated with day 100 and ‘chronic’ any time after day 100. culture negative fever. Commonly the three most However, it has since been recognised that there cited organs are skin (rash/dermatitis), liver (hep- can sometimes be ‘overlap’ between the types, so atitis/jaundice) and GI tract (abdominal pain/ signs and symptoms are used to aid and deter- diarrhoea), and these may occur in isolation or in mine the diagnosis. The skin is the most common combination. Biopsies of skin and GI tissue organ affected followed by the gastrointestinal (more rarely liver) are often obtained, although (GI) tract and then the liver. Typically, the skin the diagnosis of aGvHD is regularly made based develops a rash which often but not always upon clinical signs and symptoms. A biopsy is appears on the palms of hands and soles of the useful to help differentiate from other diagnoses feet first and can rapidly spread to the rest of the which may mimic GvHD, such as viral infection 11 Graft-Versus-Host Disease (GvHD) 223

(hepatitis, colitis) or drug reaction (causing skin teins. These small differences are recognised by rash). The modified Glucksberg-Seattle criteria the body as ‘non-self’, and subsequently these (Przepiorka et al. 1995) are widely used and give cells get questioned and stopped repeatedly by a stage and grade (grade 0–IV) for each organ the body’s policing or immune system. and its degree of involvement. Those with grade This is the basis behind all the components of III/IV aGvHD tend to have a poor overall out- our immune system and why and how we fight come. Upon development of signs and symp- any external invader trying to enter our body. The toms, immunosuppression should be optimised. greater the differences in the tissue types, the Oral or intravenous corticosteroids are frequently greater the chance of the recipient developing initiated, and although steroids remain the gold GvHD. standard of initial therapy, they are effective in In the 1960s, Billingham (1966) proposed only 40% of patients (Weisdorf et al. 1990). three central tenets for the development of Many protocols suggest a steroid treatment fail- GvHD. The essential components are: ure, if there is no improvement in symptoms after 3–7 days of treatment. At this point salvage (sec- (i) The presence of immunocompetent cells ond-line), immunosuppressive therapy for which from the donor there is currently no worldwide consensus is (ii) The inability of the recipient to reject donor implemented. Additional management issues are cells to pay attention to wound infections in skin (iii) The histocompatibility differences between GvHD and fluid/nutrition management in gastro- the donor and recipient intestinal GvHD. About 50% of patients with aGvHD will eventually develop manifestations Donor T cells are now recognised as occupy- of chronic GvHD (Jacobsohn and Vogelsang ing a central role in mediating GvHD following 2007). interactions with activated host and donor antigen-presenting cells (APC). A complex network of cytokines, chemokines, cellular recep- 11.4 Pathophysiology of GvHD tors and immune cell subsets then modulate T-cell/APC interactions that result in the initia- GvHD happens because the donated cells are not tion and maintenance of GvHD (Magenau and identical to the cells of patient (the host). GvHD Reddy 2014). is the body’s response, a manifestation of the The three phase process for aGvHD fight between the T cells of the donor and host’s comprises: immune system. T cells are white blood cells that usually pro- initial tissue damage from the conditioning therapy tect us against foreign bodies, like bacteria, fungi and viruses. The T cells in our bodies are able to recognise the proteins on the cells as either belonging to us or not belonging to us. Those that Activation of host APC belong to us are allowed to live within us in harmony, and our immune systems do not usually (except autoimmune disorders) defend themselves against these cells. Activation and then proliferation of donor T cells The donated haematopoietic stem cells are closely matched (except in a haplo-identical transplant) to those of the recipient, and unless Finally, inflammatory cytokines are released they are from an identical twin, the donor cells such as interleukin-1 and tissue necrosis factor will express slightly different cell surface pro- alpha that produce tissue necrosis. 224 J. Murray et al.

Fig. 11.1 The three (1) Recipient conditioning phases of acute GVHD, as described by Ferrara Tissue Damage and colleagues (From Hill and Ferrara 2000. Reproduced with Host Small permission) tissues intestine IL-6 IL-1 TNF-a LPS

Host APC TNF-a IL-1 Donor Target cell T cell IL-12 apoptosis Perforin CTL FasL TNF- (2) Th IFN-g a (3) Donor 1 Cellular and T cell IL-2 NK inflammatory activation effectors

Acute GvHD is modulated in part by the pres- specifically a multiparous female donor into a ence of cells capable of inhibiting immune male patient. Furthermore, the intensity of the responses, most notably regulatory T cells preparative regimen does appear to correlate with (Magenau and Reddy 2014) (Fig. 11.1). increased incidence of aGvHD. This effect may Both prevention and treatment of aGvHD occur due to greater tissue damage from the pre- attempt to disrupt the three-step pathophysiologi- parative regimen, predisposing these tissues to cal cycle. Most current treatment options of aGvHD more inflammation from the alloreactive cells. affect more than one event in this cycle through Higher doses of radiation also gives rise to more relatively non-specific immunosuppressive and GvHD. Equally, more recent use of non- anti-inflammatory mechanisms (Greinix 2008). myeloablative preparative regimens has led to Reduced intensity conditioning will usually lower incidence of aGvHD in some studies contain drugs that deplete T cells, such as (Jacobsohn and Vogelsang 2007). Campath-1H or ATG. This reduces the initial risk of aGvHD but increases the risk of infective complications such as CMV and also the risk of late- 11.4.2 Signs and Symptoms onset aGvHD and chronic GvHD. of aGvHD Incidence: the incidence of serious (grade III/IV) aGvHD is about 30% with a fully matched (8/8) Acute GvHD mainly affects the skin, gut and unrelated donor but 40% with one or two allelic liver but can affect almost any part of the body. mismatches at class I. This compares to about a 20% incidence for recipients of HLA-identical sib- 11.4.2.1 Skin ling transplants (Al-Kadhimi et al. 2014). Acute GvHD can cause a rash which is usually flat and red and often occurs on the hands, feet and around the ears and upper chest, at first. This can 11.4.1 Risk Factors quickly spread to cover the whole body. It is often, but not always, itchy and sore and can feel like sun- Factors that can increase the likelihood of aGvHD burn. A biopsy may be taken but is not always diag- include older recipient/donor, sex mismatch and nostic. On examination the features may include 11 Graft-Versus-Host Disease (GvHD) 225 apoptosis at the base of epidermal rete pegs, dys- GvHD) or more widely on a number of tissue keratosis, exocytosis of lymphocytes, satellite lym- cells that have antitumour activity, thereby pre- phocytes adjacent to dyskeratotic epidermal venting disease relapse (Baron et al. 2012). keratinocytes and perivascular lymphocytic infiltration in the dermis (Ferrara and Deeg 1991). 11.4.4 Classification of Acute 11.4.2.2 Gastrointestinal GvHD: Grades I–IV Signs and symptoms include weight loss, stomach discomfort and pain, nausea, vomiting and Regardless of the benefits, aGvHD carries a signifi- diarrhoea. The diarrhoea can be profuse with cant transplant-related mortality (TRM) with grades secretions and may also result in bleeding from 0–I (mild) having a TRM of approx. 28% and grade ulceration of the mucosa. The effects of high- II, III and IV (very severe) TRM of 43% 68% and dose therapies and infection need to be excluded. 92%, respectively (Greinix 2008). Classification is Biopsy in this group of patients is more informa- performed using the revised Glucksberg-Seattle cri- tive and may show apoptotic bodies at crypt teria (Przepiorka et al. 1995), which measures how bases, crypt ulceration and flattening of surface severe signs and symptoms are in the skin, gut and epithelium (Dignan et al. 2012). liver (see Appendix 11.A.1). The treatment for aGvHD will depend on the grade, and the grade 11.4.2.3 Liver itself is predictive of overall survival. Jaundice from hyperbilirubinaemia is the hallmark of advanced liver GvHD with a cholestatic pattern of elevated conjugated bilirubin, alkaline 11.4.5 Prevention of GvHD phosphatase and gamma-glutamyl transpeptidase (GGT) and may be associated with pruritis. There Prophylaxis: prevention is always better than is a wide range of differential diagnoses which cure. Contemporary GvHD prophylaxis at most should be considered and excluded such as veno- centres is based on calcineurin inhibitors (CNIs) occlusive disease, drug toxicity and infection. It along with short-course methotrexate (MTX). is often extremely difficult to perform biopsy due This works by interfering with calcium-dependent to the increased risk of bleeding, but, if taken, interleukin-2 (IL-2) gene activation and de novo histology shows endothelialitis, lymphocytic purine metabolism, respectively; CNIs and MTX infiltration of the portal areas, pericholangitis and act synergistically to non-selectively inhibit lym- bile duct destruction (Dignan et al. 2012). phocyte activation and proliferation. The combination of ciclosporin and MTX or tacrolimus and MTX as prophylaxis for aGvHD compared to 11.4.3 The Benefits of aGvHD any single-agent treatment has been shown to be superior (Greinix 2008). With standard prophy- There is a fine line with aGvHD. The symptoms laxis, approximately 40% of patients receiving and side effects can be unpleasant and sometimes HLA-matched HSCT will develop GvHD requir- harmful and, in severe cases, life-threatening. ing high-dose corticosteroids. However, it is well documented that some level of aGvHD is beneficial. It has been found that relapse rates post allograft were lowest in patients 11.4.6 Drugs Used as Part with aGvHD versus those without. As mentioned of Conditioning Therapy earlier, a graft-versus-tumour effect exists that to Prevent GvHD can be exploited. It is suspected that there are reactions to polymorphic minor histocompatibil- Ciclosporin (CsA): is given as an intravenous ity antigens expressed either specifically on hae- infusion commencing usually 1–2 days prior to matopoietic cells (and therefore not causing HSCT infusion to load the blood stream and is 226 J. Murray et al. eventually converted to an oral preparation when Campath 1-H or alemtuzumab: is given in a the patient is able to tolerate tablets again. variety of doses from 30 to 90 mg within the con- Ciclosporin binds to cyclophilin and prevents ditioning regimen dependent upon the cell source generation of nuclear factor of activated T cells and degree of mismatch between donor and (NF-AT), which is a nuclear factor for initiating recipient. It is an unconjugated humanised IgG1 gene transcription for lymphokines including kappa monoclonal antibody that targets the CD52 interleukin-2 and interferon gamma. This action antigen on the T and B lymphocytes as well as on leads to suppression of cytokine production and monocytes, macrophages, eosinophils and den- subsequent inhibition of T-cell activation (Greinix dritic cells. The major disadvantage of this drug 2008). is the increase of infections due to the extended Mycophenolate mofetil (MMF): used mainly period of lymphopenia. CMV reactivations and in reduced intensity transplant conditioning regi- infections are particularly troublesome in this mens is an antimetabolite that results in non- patient cohort necessitating strict surveillance competitive reversible inhibition of inosine (Dignan et al. 2012). monophosphate dehydrogenase. This leads to Antithymocyte globulin (ATG): decreases T selective inhibition of lymphocytes purine syn- cells and also leads to viral infections. Epstein- thesis and proliferation. Patients have less muco- Barr virus (EBV) reactivations can be problem- sitis and faster neutrophil recovery compared to atic and can result in post-transplant methotrexate (Greinix 2008). lymphoproliferative disease (PTLD). Tacrolimus: is an alternative to ciclosporin within the conditioning regimens at some cen- 11.4.6.1 Initial Treatment tres. It binds to FK506 protein 12, a different pro- of Acute GvHD tein to the one that CsA does but their final Despite all of the recent advances in the under- common pathway is identical. They both prevent standing and treatment of GvHD, steroids remain the generation of NF-AT, a nuclear factor for ini- the best and first-line therapy. The mechanism of tiating gene transcription for lymphokines like action of steroids for aGvHD is unclear but most IL-2 and interferon gamma leading to suppres- likely relates to the suppression of cytokines such sion of cytokine production and thus inhibition of as prevention of synthesis of interleukin-1 by T-cell activation (Greinix 2008). antigen-presenting cells and lymphocyte activi- Sirolimus: is used within conditioning regi- ties (Greinix 2008). mens and is a natural macrolide antibiotic that Grade I: should not require systemic treatment. exerts its immunosuppressive effect by inhibiting If CsA levels are optimised, then topical steroids cytokine-driven signalling pathways of the T and in conjunction with an emollient may be intro- B cell via mTOR blockade and specifically inhib- duced along with antihistamine for itchy skin. It is iting the progression of cells from the G1 phase important, however, to ensure the emollient is to the S phase. The advantage is that sirolimus acceptable to the patient and to reinforce the neces- has a completely different toxicity profile to cal- sity of using the creams or lotion regularly. For a cineurin inhibitors and can be used in combina- topical treatment to be effective, it must be applied. tion with them (Dignan et al. 2012). If the preparation (cream or lotion) is not liked by Methotrexate (MTX): is an anti-proliferative the patient, then compliance is poor, and it will not agent given intravenously on days 1, 3, 6 and 11 be effective. Precautions such as avoiding scented after HSCT for those patients receiving a full- soaps and perfumes can minimise the risk of addi- intensity transplant. It prevents the division and tional skin irritation. Reminders to maintain a clonal expansion of T cells. It is important to good fluid intake to avoid dehydration are impor- receive all four doses, but severe mucositis (grade tant as are prompts to wear natural clothing next to IV) often prohibits administration of the 4th and the skin – silk, for example, is relatively non-irri- final dose and is given at the clinician’s discretion. tant and thermoregulating. 11 Graft-Versus-Host Disease (GvHD) 227

Grade II: anything at or above grade II is lowing addition of second-line treatments in com- likely to require systemic treatment. If the parison to steroids alone (Greinix 2008). patient progresses from grade I to grade II following optimisation of CNI and topical therapy, then systemic corticosteroids are indicated. 11.4.7 Second-Line Therapies Patients presenting with grade II signs should for aGvHD commence systemic steroids for their anti- inflammatory properties. The starting dose is Extracorporeal photopheresis: 8-methoxyp open to discussion, and local guidelines should soralen (8-MOP) is a photoactivated drug that be followed. Some patients with GI symptoms covalently binds to DNA pyrimidine bases, cell may benefit from budesonide as a steroid-spar- surface molecules and cytoplasmic components ing treatment as it is regarded as a non-absorb- in the exposed nucleated white cells causing a able therapy. lethal defect. It is added to a patient’s blood fol- Grades III and IV: requires treatment with sys- lowing withdrawal by a cell separator; this is temic steroids. If GI symptoms are the major fea- then exposed to ultraviolet light A (UVA) and ture, then the steroids should be given intravenously returned to the patient. The blood is separated to prevent problems with absorption because of into buffy coat as well as red cells and plasma, vomiting, diarrhoea and abnormal mucosal lining. which are returned to the patient. The buffy coat Steroids were first seen to be an effective treat- is exposed to the UVA in the presence of the ment in the 1980s and remain effective globally in 8-MOP. Once reinfused, the cells undergo apop- approximately 40% of people, with 30% having a tosis over the next 24–48 h (Greinix 2008). long-lasting response and a probability of survival The mechanism of action is not currently fully at 1 year of 53%. The skin being the most respon- understood but may relate to apoptosis of leuco- sive at 40% with a response rate of 15–35% for cytes. When the cells are reintroduced into the those with liver involvement and 45% in GI. The patient, they continue to phagocytose. The rein- lower the grade of aGvHD and the fewer organs fusion of these cells and subsequent phagocytosis affected result in a better response to steroids. by antigen-presenting cells (APCs) may regulate There is currently no standard time for assessing immune homeostasis through modulation of the effectiveness of the steroids with a time gap of cytokine production and tolerance induction of 3–7 days often given as indicative of treatment APCs (Bladon and Taylor 2006). This possible failure and requiring escalation to second-line mechanism of ECP-induced immune tolerance therapies. The GvHD may at this point be labelled includes inhibition of pro-inflammatory cytokine as ‘steroid refractory disease’ which carries a dis- secretion, increased secretion of anti- mal long-term prognosis (Magenau and Reddy inflammatory cytokines, reduced stimulation of 2014) with infection being the leading cause of effector T cells, induction of accelerated death of mortality followed by organ failure in nonre- effector cells and stimulation of regulatory T-cell sponders (Greinix 2008). Below is a list of sec- generation (Greinix 2008). ECP is a safe treat- ond- and third-line treatment options for those ment as it has fairly minimal side effects, hypo- who have had their CNI optimised and have failed tension, fevers, drop in haemoglobin, photophobia to respond to corticosteroids for at least 7 days. and tiredness post procedure. The procedure is The evidence for many of the second- and third- performed in most centres by highly trained line treatments is sparse and comes from small apheresis nursing staff. The patient is assessed patient series with heterogeneous populations. If and accepted onto the ECP service following patients fail a second-line therapy, then a further local policy. Venous access is assessed, and if this second-line therapy should be tried before mov- is inadequate via the antecubital fossa, a central ing on to third-line options (Dignan et al. 2012). venous catheter will be placed. Long-term survival has not been improved fol- Further second- and third-line therapies include: 228 J. Murray et al.

Second-line therapies Antitumour necrosis Infliximab Etanercept Mammalian target or Sirolimus rapamycin inhibitors mTOR Mycophenolate mofetil (MMF) Interleukin-2 receptor Daclizumab Denileukin diftitox Inolimomab Basiliximab antibodies Third-line therapies Mesenchymal stem cells MSC Alemtuzumab Pentostatin Methotrexate Tyrosine kinase inhibitor Imatinib Often at least two second-line therapies will be used before moving on to a third-line treatment

11.4.8 Nursing Care Considerations screen (e.g. SunSense SPF 50+) and localised use for aGvHD of topical antipruritic agents (e.g. Dermacool 0.5–1%) if required. If the skin is still flaky, the In addition to systemic treatments, there are often patient can be advised to apply lipids (e.g. coco- topical management techniques as well as gen- nut oil) in addition to the emollients. Topical eral care that nurses can offer to patients that will immunomodulation (e.g. steroid/tacrolimus lead to relief from frequently troublesome symp- cream) should be prescribed as per local protocol; toms of aGvHD. Below are a few pointers for however, there are a few general rules about the consideration when seeing patients with aGvHD use of topical steroids: think about the potency/ affecting their skin, gastrointestinal system, eyes, duration of the product used in relation to the age mouth or genitals. of the patient and the area of the body it is being applied to. Always apply thinly – once daily is usually enough. Think about whether the skin is 11.4.9 Cutaneous weepy, when a cream/lotion is appropriate or dry/ scaly in which case an ointment may be prefera- Basic skin care: ble. Steroids should be applied at a different time The key issue with patients who have cutane- to emollients (at least a 30 minute gap between) to ous aGvHD is to maintain the integrity of the ensure effective absorption and remember that skin, and the following suggestions are key fac- broken skin is a contraindication to use. tors in doing this: Regular application of preferred Topical management of specific stages of emollients (e.g. QV, Hydromol, Diprobase). cutaneous aGvHD: Advise application of a thin layer (enough to make the skin appear ‘shiny’), in the direction of 1. Maculopapular rash (pruritic/painful). Most hair growth. Try not to ‘rub’ as this will increase common areas: soles of feet, palms of hands, any pain or itch. As guidance for amounts, it cheeks, ears, neck, trunk and upper back. would be suggested that an adult would use on average 500 g/week and a child, 250 g/week. Use Emollients are key to management at this of bath/shower preparations (e.g. Dermol, QV, stage. With sensitive, irritated skin, an emollient Hydromol) rather than soap, use of high SPF sun- which is too thick will just not be used, whereas 11 Graft-Versus-Host Disease (GvHD) 229 one which is too ‘thin’ will be perceived as inef- very soothing (note: do not use aloe vera gel fective. It is worth offering sample packs with a alone as this will dry the skin). variety of products to trial, either made up by the hospital or provided by a specific company (e.g. 3. Bullous/desquamation (stage IV): formation QV products by Crawfords). In situations where of large blisters and separation of the dermis/ pruritis is a major issue, a product with high epidermis from the basal layer causing mas- water content can be useful as they are more sive fluid loss. cooling but will need regular application. Topical steroids, each hospital will have its These patients need treating as a person with own protocol for prescription of topical steroids severe burns. Your hospital may have a protocol and this should be adhered to. specifically for this but an example would be to irri- Menthol cream (0.5–1%, e.g. Dermacool), gate with sterile water, apply an antibacterial cream these products can be useful for management of (e.g. Flamazine) and protect the area from the air to painful and pruritic skin but must be used with minimise pain and risk of infection. The cream can care as they can make the patient feel very cold be applied directly to sterile theatre gauze and with widespread use so are better used only on wrapped around the patient to prevent trauma. focal areas of extreme itch/pain. Medical grade silk clothing (e.g. Dermasilk, Espere Healthcare), it is important to explore the 11.4.10 Oral holistic care of the patient. Many clothing materials can cause irritation – even natural materials Patients with oral aGvHD complain of a sore such as cotton. If there are widespread areas of the mouth that is not dissimilar to the pain suffered torso affected, it is worth suggesting the use of with oral mucositis post chemotherapy/radiother- medical grade silk as this is manufactured to cause apy. Tolerance of spicy food stuff is poor, tooth- minimal irritation and, in some countries, can be paste burns and hot drinks such as tea and coffee prescribed. If this is not available, clothing made are almost impossible to take. It is important to from bamboo can be suggested as an alternative. rule out infection as this will cause pain to be worse. Frequent swabs for virus, bacterial and 2. Erythroderma: intense generalised redness of fungal infection should be taken and acted upon the skin; inflammation that gives rise to ery- promptly. To aid with oral pain management, the thema and scaling all over the body. Classically use of caphosol, Gelclair, lidocaine, paracetamol involves greater than 90% of the body mist and Difflam mouth wash can be used. surface. Advise patients to frequently swill the mouth after eating to remove any debris using plain The topical management of erythroderma is water. This is refreshing and ph7 so comfortable similar to the advice mentioned above, with to do. Encourage the use of products to aid pro- emphasis on the regular application of easily duction of saliva as the mucosa is usually very applied emollients and increasing fluid intake. dry. Artificial saliva or sugar-free gum and in However, because erythroderma is so wide- some centres pilocarpine may be used. spread, the use of menthol creams is limited – Many medications have side effects of dry unless there are specific areas of the body which mouth. Look to see if there are any alternatives are causing particular distress. that could be prescribed for your patient. In addition to the products above, in an attempt Early referral to the dentist is vital as the risk to maintain skin integrity, organic coconut oil or of dental caries and secondary oral cancers is other natural lipids (e.g. olive oil) can be useful higher in patients with oral GvHD. Advice to supplements to the emollients. Equally good perform regular oral exercises to reduce the risk quality creams containing aloe vera gel are often of contractures. 230 J. Murray et al.

11.4.11 Gastrointestinal may offer some symptomatic benefit. With female patients, application of an emollient to Patients who develop diarrhoea will have stool the vulval region and use of dilators with a samples sent to exclude infective components. lubricant such as olive oil or coconut oil will Once ruled out and treatment started, nursing help to minimise the risk of contractures. care may aid in a more rapid recovery and main- Vaginal moisturisers may make women feel tenance of weight. Ensuring an adequate oral more comfortable. Referral through to endocri- input with high-calorie supplements, strict fluid nology for discussions about hormone replace- balance is of primary importance. The options of ment therapy (HRT) with oestrogen can be enteral feeding or intravenous total parental initiated by nursing staff. Men may mention nutrition in the short term to rest the bowel need tightening of the foreskin and gentle frequent to be kept in mind if the above actions are not retraction, and application of emollient is sug- sufficient, with procedures such as a radiologi- gested alongside good hygiene. cally inserted gastrostomy (RIG) used for long- term issues. Those with upper GI disturbance, nausea and vomiting need advice on small and 11.5 Chronic Graft-Versus-Host frequent meals as well as supplements. Patients Disease who develop grade IV GI aGvHD will benefit from use of flexi-seal faecal collection devices. The understanding of the pathophysiology of chronic graft-versus-host disease (cGvHD) is in its infancy, and progress to prevent and treat 11.4.12 Eyes cGvHD remains limited (Greinix 2008). Chronic GvHD remains the major cause of late morbidity Patients with dry and gritty eyes will benefit from and mortality after allogeneic haematopoietic regular and frequent use of lubricating eye drops. cell transplantation and is a serious and common Infection should be excluded and treated if appar- complication occurring in 20–80% of patients ent. Wearing dark glasses will reduce irritants (Lee and Flowers 2008). Chronic GvHD preva- such as wind and block any debris that it may lence and severity has increased over the past blow into the patient’s eyes. There are a variety of 20 years in line with the increasing use of haema- graded dark glasses that may be obtained through topoietic stem cell transplantation for treatment an optician that can block up to 90% of light and of older age patients, the widespread use of reduce photophobia significantly. It is often use- mobilised blood cells instead of marrow for ful to wear glasses inside the house to reduce dis- grafting and improvements in survival during the comfort. Cold compress with ice packs and first several months after allograft. Typically chamomile tea bags are useful in some instances. occurring in the first 12 months, it can be seen as early as 2 months and as late at 7 years at onset, although onset at >1 year from transplant occurs 11.4.13 Genito-urinary System in <10% of cases (Flowers and Martin 2015). The risk of infection due to the delay in immune This is an under-reported area of GvHD from reconstitution and use of immunosuppressive patients; some basic nursing input can help with therapies to treat cGvHD remains, however, the symptoms of pain and discomfort experienced. leading cause for death in this group of patients Asking patients if this is a problem for them is (Couriel et al. 2006b). Supportive care advances the first step as patients are often reticent about have decreased the morbidity, but survival has mentioning genital problems to the medical not changed significantly since the 1980s. team. Once infection has again been ruled out or Patients with cGvHD have a 5-year survival of treated, there are a variety of treatments that 40–70% with only 50% being able to stop immu- 11 Graft-Versus-Host Disease (GvHD) 231 nosuppression at 5 years, with 10% needing 11.6 Acute Vs Chronic GvHD treatment beyond this time point. The other 40% either die or develop a further malignancy before Historically if patients developed signs and symp- cGvHD resolves (Martin et al. 2006). toms of GvHD after day 100, this was labelled as As cGvHD only occurs in allografted patients chronic even if clinically the patient appeared to and can be prevented by T-cell depletion from have acute features. The criteria for the diagnosis the donor graft, donor T cells responding to allo- of cGvHD are based on pathological changes geneic antigens in the patient are of critical occurring in the skin, lung, mucous membranes, importance in the development of cGvHD gastrointestinal tract and musculoskeletal system (Kuzmina et al. 2011). Chronic GvHD was ini- (Greinix 2008). The National Institute of Health tially thought to be as a consequence of persis- (NIH) developed a set of criteria following a content recognition of antigenic tissue differences sensus meeting in 2005 to help address the prob- between donor and host. However, the role of lem of diagnosis and wrote several guidelines on alloreactivity versus autoreactivity in the patho- the diagnosis and classification of chronic genesis of cGvHD remains an area of debate GvHD. They stated that acute and chronic GvHD (Greinix 2008). should be distinguished by clinical features rather Meier et al. (2011) explain that: than time from transplant. There should be the Donor-derived immunocompetent T cells react presence of at least one diagnostic clinical sign of directly or through exaggerated inflammatory pro- cGvHD or presence of at least one distinctive cesses against tissue after allograft. The persis- manifestation confirmed by pertinent biopsy or tence of alloreactive T cells, a Th1-Th2 shift of the other relevant test. All other diagnoses should be cellular immune response (cGvHD seems to be mediated prominently by the Th2 cytokine excluded (Filipovich et al. 2005). response), defective peripheral and central toler- The broad category of cGvHD includes clas- ance mechanisms (i.e. failure of control by regula- sic cGvHD; presenting with manifestations that tory T cells and /or impaired negative selection of can be ascribed only to cGvHD, however, it also T cells in the thymus), replacement of antigen presenting cells (APC) of the host by APC’s of the includes an overlap syndrome, which has diag- donor leading to indirect antigen presentation of nostic or distinctive cGvHD manifestations allo-antigens, an increasing role of B cells produc- together with features typical of aGvHD (Vigorito ing auto and allo-antibodies against the host and et al. 2009). non-specific mechanisms of chronic inflammation leading to fibrosis of involved organs. It is no longer useful to simply describe cGvHD as limited or extensive based on the num- The importance of autoreactivity is suggested ber of organs involved as this was a system by clinical manifestations of cGvHD that fre- devised in 1980 following the study of 20 patients quently mimic those of autoimmune diseases, as in a retrospective review (Shulman et al. 1980). A well as the finding of autoantibodies derived more reliable and reproducible scoring scheme from B cells after Th2-mediated stimulation and was described to evaluate the individual organ cytokine release (Greinix 2008). severity over four grading scores 0–3 by the NIH: The advances in understanding of this process will have an impact on patients overall survival. • None; score 0 Using a multidisciplinary team approach for best • Mild involvement (no significant impairment care, identifying those at risk, monitoring, early of daily living); score 1 recognition with prompt diagnosis and high- • Moderate involvement (significant impair- quality follow-up with an agreed management ment of daily living); score 2 plan to prevent complications of therapy that can • Severe impairment (major disability); score 3 often lead to disabilities are vital to continue to make headway in this immensely challenging The clinical score describes how affected the area (Flowers and Martin 2015). patient is by their inability to perform activities 232 J. Murray et al. of daily living. This evaluation covers the involve- Presentation with signs and symptoms of ment of individual organs and sites. For example, cGvHD nearly always occurs within the first year if they are unable to work due to ocular loss, they post allograft but can occasionally happen sev- would be scored as 3 severe (Carpenter 2011). eral years later. Single organs alone may be The scoring should be undertaken initially at affected and can progress to other organs; how- 3 months post-transplant and at 3 monthly inter- ever, cGvHD nearly always affects multiple sites, vals and more frequently if new signs or symp- having major impact upon a patient’s quality of toms are found or there is a change in treatment. life. The eyes, mouth, skin, GI tract and liver are The NIH in 2014 provided a further update the most frequently affected organs. There is a with the Diagnosis and Staging Working Group wide range in severity and how this relates to Report. Following new evidence, refinements compromise in patients’ QoL, with some mani- were made to address the areas of controversy or festations being more problematic to treat. confusion such as overlap and classic chronic Fasciitis or cutaneous sclerosis, severe ocular GvHD. The subcategories of ‘overlap’ as it was sicca and bronchiolitis obliterans syndrome transient and often depended on the degree of (BOS) often require extensive periods of time immunosuppression and is subject to changes with multiple immunosuppressive agents to treat during the disease course and ‘classic’ cGvHD as (Flowers and Martin 2015). patients may develop acute features when immunosuppression is tapered were removed. A revi- sion was made to the diagnostic criteria for 11.6.1 Diagnosis of cGvHD involvement of the mouth, eyes, genitalia and lungs. Schirmer’s test has been removed from the For a diagnosis of cGvHD to be made, the NIH severity scoring form, and an ophthalmology 2014 working group suggest that at least one review is recommended. Also if an unequivocal diagnostic manifestation of cGvHD or at least explanation can be made for a specific abnormal- one distinctive manifestation, with the latter con- ity that is not GvHD, then that organ should be firmed by pertinent biopsy, laboratory tests, eval- regarded as not affected by GvHD (Jagasia et al. uation by a specialist or radiology in the same or 2015). other organ, be present, unless stated otherwise. Chronic GvHD commonly occurs in patients It is important with any organ considered for a who have previously had aGvHD although it is diagnosis of cGvHD that other causes for the not simply a case of evolution from one to symptoms are excluded such as infection, recur- another. Chronic GvHD usually occurs within rent or new malignancy (Jagasia et al. 2015). The 3 years of allograft and is a disease of deregulated features should also differ from the typical der- immunity with protean manifestations that mimic matitis, enteritis and cholestatic liver manifesta- autoimmune disorders such as Sjogren syndrome, tions of aGvHD (see Appendix 11.A.2 for the full primary biliary cirrhosis, wasting syndrome, tables of assessment). bronchiolitis obliterans, immune cytopenias and chronic immunodeficiency (Jagasia et al. 2015). Due to the ambiguity of diagnosis, the limited 11.6.2 Chronic GvHD of the Skin understanding of pathophysiology and the additional clinical complexities that accompany this In cGvHD the skin is the most frequently affected group of patients, a systematic approach to man- organ if the patient has received HCT and has a agement has been somewhat lacking (Couriel wide variety of manifestations (Pavletic et al. et al. 2006a). There is still no unified consensus 2006). For a clinical diagnosis of skin cGvHD on the diagnostic features, although recent work features of poikiloderma, lichen planus-like erup- from the NIH (2014) has in some ways addressed tion, deep sclerotic features, morphea-like super- this with an attempt to bring a standardised ficial sclerotic features or as lichen sclerosus-like assessment to clinical practice. lesions are needed (Jagasia et al. 2015). 11 Graft-Versus-Host Disease (GvHD) 233

Assessments of skin are performed to look at the apy, and the loss is often patchy and happens four anatomic levels of involvement, and the across the whole body. Patients may suffer with score is based on the percentage of area involved premature greying, thinning or brittleness of their and the differentiation between non-sclerotic and hair (Jagasia et al. 2015). sclerotic features:

1. Erythematous rash (epidermal involvement) 11.6.3 Chronic GvHD 2. Movable sclerosis (dermal involvement) of the Oral Cavity 3. Non-movable sclerosis, hidebound skin or involvement of subcutaneous tissue and facia For patients who have received stem cells derived (subcutaneous involvement) from the bone marrow (BM), oral cGvHD is the 4. Ulceration (full-thickness loss of epidermal most common site of involvement, and the oral tissue) cavity is the second most common site with PBSC (Meier et al. 2011). There are three com- Points 1–3 are assessed using the ‘rule of 9s’ ponents to mouth and oral mucosa assessment: body surface area score. Local skin involvement below 20% body surface and the absence of scle- 1. Mucosal involvement rotic features is classified as ‘mild’. Skin involve- 2. Salivary gland involvement ment between 20% and 50% is ‘moderate’ with 3. Sclerotic involvement of mouth and surround- more than 50% becoming ‘severe’ (Greinix ing tissues (Couriel et al. 2006b) 2008). This scoring system is effective in adults but less so in children; however, it is still used in Within the oral cavity clinical diagnostic fea- children over the age of 1 year. Ulceration is tures include lichen planus-like changes. These recorded by measuring the diameter of the largest are described as white lines and lacy-appearing ulcer (Pavletic et al. 2006). The skin is often very lesions or plaque like changes. This can occur on fragile and becomes damaged easily with poor any oral surface including the tongue and lips. healing of any wound. Distinctive features of The mouth will be dry (xerostomia) and have cGvHD that are not seen in aGvHD are depig- mucoceles, mucosal atrophy, ulcers and pseudo- mentation although this occurs gradually and membranes. Common features of both acute and may only be perceptible over long time periods chronic GvHD are gingivitis, mucositis, ery- and papulosquamous lesions, although this alone thema and pain (Jagasia et al. 2015). If new is not enough for a diagnosis. It must be made in lesions occur >3 years post-transplant, secondary combination with other signs or confirmed with malignancy should be excluded with biopsy. The biopsy. Common features of both acute and lesion often starts as leukoplakia and can be con- chronic GvHD are erythema, maculopapular rash fused with cGvHD but may be a squamous cell and pruritis (Jagasia et al. 2015). Itching is com- carcinoma (SCC) (Couriel et al. 2006b). mon and, therefore, should be recorded using a Chronic GvHD of the mouth is scored on scale of 1–10 for severity with the patient asked three areas using the standard 0–3 scale with a what was the highest score this week (Pavletic percentage of area involved: et al. 2006). Distinctive signs of nail cGvHD are longitudi- 1. Erythema nal ridging, splitting or brittleness, onycholysis 2. Lichenoid and loss of nails that is usually symmetric and 3. Ulcers affects most nails (Jagasia et al. 2015). Loss of hair can be a devastating effect of Oral sensitivity is measured on a self-score cGvHD for patients, and in this context it is con- system from 1 to 10, with worst it has been for sidered a distinctive feature alone. Hair has often the past week (Pavletic et al. 2006). The conse- returned following chemotherapy or radiother- quences of oral cGvHD in cases of hypo- 234 J. Murray et al. salivation and xerostomia are in relation to the that 3–15% of women have vulvar or vaginal function of saliva and lack thereof. Poor protec- cGvHD (Couriel et al. 2006b). The diagnosis tion against oral infections and mechanical and relies heavily on sign and symptom reporting. chemical epithelial injuries can occur. Symptoms in women may include dryness, burn- Remineralisation is impaired that can lead to ing, pruritis, pain to touch, dysuria and dyspareu- dental caries, speech may be altered and eating nia. Signs include patchy or generalised erythema, becomes problematic (Meier et al. 2011; Treister mucosal erosions or fissures, labial resorption, et al. 2013). circumferential fibrous vaginal banding, vaginal shortening and complete vaginal stenosis. Female genital tract involvement is scored as ‘mild’ if 11.6.4 Chronic GvHD of the Eyes any erythema on vulvar mucosal surfaces, vulvar lichen planus or vulvar lichen sclerosis exists. New onset of dry, gritty or painful eye with cica- Those with any erosive inflammatory changes of tricial conjunctivitis, keratoconjunctivitis sicca the vulvar mucosa or fissures in the vulvar folds and confluent areas of punctate keratopathy are are scored as ‘moderate’. Severe scores are when distinctive features and may occur in isolation there is labial fusion, clitoral hood agglutination, with no other active cGvHD (Couriel et al. fibrinous vaginal adhesions, circumferential 2006b). Lacrimal dysfunction or destruction is fibrosis vaginal banding, vaginal shortening, syn- responsible for dry eye symptoms (Pavletic et al. echia, dense sclerotic changes and complete vag- 2006). Patients may describe photophobia, burn- inal stenosis (Couriel et al. 2006b). ing, irritation; pain, a foreign body sensation, In the absence of diagnostic manifestations of blurred vision and paradoxically excessive tear- cGvHD in other organs, histological evidence is ing. Scoring of eyes is based on frequency of use strongly recommended and ruling out of oestro- of eye drops and the occurrence of keratocon- gen deficiency or infection with yeast, HPV or junctivitis sicca. Asymptomatic keratoconjuncti- bacteria (Couriel et al. 2006b). A referral path- vitis sicca or need for eye drops less than three way to the gynaecologist and if possible one with times per day is classed as ‘mild’, whilst symp- an interest in assessing these patients should be tomatic and the need for more than three times implemented. daily eye drops +/− punctual plugs is ‘moderate’. Men may have painful intercourse and a burn- Those with ‘severe’ ocular cGvHD are unable to ing sensation on micturition. Signs include non- work because of ocular symptoms or require spe- infectious balanoposthitis, lichen sclerosis-like cial eyewear to relieve pain or have loss of vision or lichen planus-like features, phimosis or ure- due to keratoconjunctivitis sicca (Greinix 2008). thra or meatus scarring or stenosis (Jagasia et al. 2015). Signs of lichen planus-like features are classed as ‘mild’, lichen sclerosis-like features or 11.6.5 Chronic GvHD of the Genitalia moderate erythema is ‘moderate’, and ‘severe’ signs are phimosis or urethral or meatal scarring. Patients who suffer from oral cGvHD are also very likely to have some degree of genital cGvHD. This affects both men and women and is 11.6.6 Chronic GvHD significantly under-reported. In women vaginal of the Gastrointestinal scarring and clitoral/labial agglutination occur, (GI) Tract and in men phimosis and urethral/meatus scarring are features. In both sexes, lichen planus-like Gastrointestinal tract symptoms occur frequently, and lichen sclerosis features are diagnostic. It is and oesophageal web, stricture or concentric essential due to the under-reporting of symptoms rings demonstrated on endoscopy or imaging are that patients are examined for early signs espe- diagnostic features for GI cGvHD. Patients may cially if oral features are present. Studies suggest have dysphagia, odynophagia, heartburn, 11 Graft-Versus-Host Disease (GvHD) 235 anorexia, nausea, vomiting, abdominal pain, phosphatase and GGT followed by jaundice cramping, diarrhoea, weight loss and malnutri- (Jagasia et al. 2015). Any elevation of liver tion, and these are all common features present in enzymes greater than twice normal may be both acute and chronic GvHD as well as other regarded as ‘mild’, 2.5 times upper limit of nor- aetiologies. It is important to make a firm diagno- mal as ‘moderate’ and ‘severe’ if five times. sis before commencing treatment. Diarrhoea should be investigated with stool culture and virology examination to exclude C. diff and CMV 11.6.8 Chronic GvHD Pulmonary in particular (Couriel et al. 2006b). Patients may System also suffer from pancreatic atrophy and exocrine insufficiency that causes malabsorption and can Historically for a firm diagnosis of pulmonary respond to pancreatic enzyme supplementation cGvHD, a biopsy was essential to prove bronchi- (Jagasia et al. 2015). For upper GI, early satiety, olitis obliterans (BO); however, as there was a anorexia or nausea and vomiting are scored on high risk of bleeding, it is now accepted that a occasional symptoms with little reduction in oral diagnosis of bronchiolitis obliterans syndrome intake during the past week being ‘mild’; a ‘mod- (BOS) can be made following pulmonary func- erate’ score of cGvHD as intermittent symptoms tion testing (PFT). Pre-transplant screening is with some reduction in oral intake during the past essential to obtain a baseline PFT with post- week; and ‘severe’ if the patient has persistent transplant PFT at 3 months and 1 year or more symptoms throughout the day with a marked frequently if the patient develops signs as patients reduction in oral intake on almost every day of remain asymptomatic with an insidious onset of the past week. Lower GI disturbance with diar- symptoms (Flowers and Martin 2015). A new rhoea will score ‘mild’ if the patient has occa- onset of an obstructive lung defect is indicative of sional loose or liquid stool on some days BOS. Clinically the patient may be short of throughout the week. If the patient is having breath on exertion and have a cough or wheeze, intermittent loose or liquid stool throughout the but these may be later effects. There are strict cri- day, on almost every day of the last week without teria for BOS and all need to be met for a requiring intervention to prevent or correct vol- diagnosis: ume depletion scores as ‘moderate’. Those with ‘severe’ disease have voluminous diarrhoea on 1. FEV1/VC < 0.7 or the 5th percentile of almost every day of the past week requiring inter- predicted. vention to prevent or correct volume depletion. (a) FEV1 = forced expiratory volume in 1 s. (b) VC = vital capacity (forced vital capacity (FVC) or slow vital capacity (SVC), 11.6.7 Chronic GvHD of the Liver whichever is greater). (c) The 5th percentile of predicted is equiva- The liver has no firm diagnostic features of lent to the lower value of predicted confi- cGvHD, and all other causes need to be excluded, dence interval. e.g. viral infections, biliary obstruction and drug (d) For paediatric patients or elderly popula- toxicity. A biopsy if possible can help but carries tions, use < predicted confidence interval a high risk of bleeding and is therefore not fre- using NHANESIII calculations. quently performed; imaging may be useful to exclude liver abscess, infiltration or gall bladder disease (Couriel et al. 2006b). Patients may pres- 2. %FEV1 <75% of predicted with >10% decline ent in two ways, with a liver function test show- over less than 2 years. %FEV1 should not ing a steep rise in serum ALT, with or without correct to >75% with salbutamol, and the rate jaundice or transaminitis, or as a progressive cho- of decline for the corrected values should still lestatic picture with elevation of serum alkaline remain at >10% decline over 2 years. 236 J. Murray et al.

3. Absence of infection in the respiratory tract, Table 11.1 NIH global severity of chronic GvHD documented with investigations directed by Mild chronic GvHD clinical symptoms, such as radiologic studies 1 or 2 organs involved (not lung) plus (radiographs or computed tomographic scans) Score in involved organs 1 plus or microbiologic cultures (sinus aspiration, Lung score 0 upper respiratory tract viral screen, sputum Moderate chronic GvHD culture, bronchoalveolar lavage). 3 or more organs involved plus 4. Either one distinctive manifestation of chronic Score of 1 in each organ GVHD or another supporting feature of BOS. OR Atleast 1 organ (not lung) with a score of 2 OR Air trapping by expiratory chest high- Lung score 1 resolution CT or small airway thickening or Severe chronic GvHD bronchiectasis or trapping on PFT where there is 1 organ with a score of 3 a residual volume of >120% or residual volume/ OR total lung capacity >120% predicted is support- Lung score of 2 or 3 ing evidence for BOS (Jagasia et al. 2015). Key points 1. In skin: Higher of the two scores to be used for calculating global severity. 11.6.9 Chronic GvHD 2. In lung: FEV1 is used instead of clinical score for of the Musculoskeletal System calculating global severity. 3. If a non-GvHD documented cause unequivocally explains the entire organ abnormality, then the organ Diagnostic features of the musculoskeletal system is not scored for global severity. If the abnormality is include fascial involvement usually of the fore- thought to be multifactorial, it is scored without arms or legs, but frequently affecting the abdo- attribution from non-GvHD causes. men and chest wall with sclerosis of the overlying Jagasia et al. (2015) with permission skin and subcutaneous tissue and joint stiffness or contractures that can develop and severely impact patient’s functional status and organ impairment on quality of life (Jagasia et al. 2015). The degree and is defined by Jagasia et al. 2015 as (Table 11.1): of functional impairment is scored as ‘mild’ if there is mild tightness of arms or legs, normal or mild decreased range of movement (ROM) and 11.8 Assessment of Response does not affect activities of daily living (ADL). Where there is tightness of arms or legs or joint Pavletic et al. (2006) proposed a set of measures contractures, erythema thought due to fasciitis, a for assessing the response to treatment of cGvHD moderate decrease of ROM and mild to moderate patients. These should be performed at 3 monthly limitation of ADL scores as ‘moderate’. For intervals or whenever a major change occurs. ‘severe’ then the patient will have contractures Organ-specific measures should be recorded with significant decrease of ROM and significant from clinical signs and symptoms, and a global limitation of ADL, e.g. unable to tie shoe laces, rating of mild/moderate/severe made. button a shirt or dress self. Assessment with non-specific ancillary measures such as grip strength, 2-min walk test (or Activity Scale for Kids (ASK)) and Karnofsky 11.7 Scoring of Chronic GvHD score with a quality of life score (QoL) are recommended. Quality of life assessment tools such The global scoring system of NIH 2014 was devel- as SF-36 or FACT-BMT in adults or CHRIs oped to be suitable for clinical trial assessments (Child Health Ratings Inventories) in children and reflects the clinical impact of cGvHD on the can be used. 11 Graft-Versus-Host Disease (GvHD) 237

11.9 Treatment of Chronic GvHD trials. The choice for further therapies is in most part governed by the features of cGvHD and the The long-term aim of cGvHD therapy is for the toxicities that may be inflicted as well as the patient to develop immune tolerance and reduce availability of the drug locally. The lack of con- the morbidity. This is recognised by the ability to sistently effective treatment in this setting withdraw immunosuppression without a flare of underscores the need for high-quality clinical symptoms. Most therapeutic options focus on the trials. Please refer to local policies and guidance development of immunosuppressive agents and with respect to second-line and subsequent the ex vivo removal of the unfractionated donor therapies. T-cell population from the stem cell graft (Greinix Extracorporeal photopheresis (ECP) is widely 2008). The mainstay of treatment has for more used in mucocutaneous cGvHD as a second-line than 30 years been the use of systemic steroids, therapy in steroid refractory patients and has usually with a starting dose of 1 mg/kg per day been shown to be effective in up to 80% of with or without calcineurin inhibitor (CNI). patients (Couriel et al. 2006b). A UK consensus Steroids have a multitude of side effects such as paper supported the findings and recommended toxicities, diabetes, weight gain, bone loss, ECP use in this group, with paired sessions every myopathy, hypertension, mood swings, cataracts, 2 weeks with reassessment at 3 months avascular necrosis and an increase in infections (Scarisbrick et al. 2008). (Flowers and Martin 2015). Imatinib, a tyrosine kinase inhibitor licenced Treatment for cGvHD is far from satisfactory for use in chronic myeloid leukaemia (CML), has with only approximately 50% of patients gained in popularity over the past few years. responding to systemic steroids with or without Experiments have shown reduction in fibrosis calcineurin inhibitors and less than 20% of possibly from a dual inhibition process of trans- patients alive without disability at 4 years. forming growth factor beta and platelet-derived Combinations of steroids with azathioprine, tha- growth factor pathways (Dignan et al. 2012). lidomide, mycophenolate mofetil or hydroxy- Sirolimus mTOR inhibitors such as sirolimus chloroquine in randomised trials have not yielded may be used in combination with other agents but any benefit over steroids alone for survival or with caution in CNI due to increased risk of throm- duration of therapy (Flowers and Martin 2015). botic microangiopathy and hyperlipidaemia. Despite this, steroids still offer the best first-line Rituximab is commonly used in haematology treatment choice for those with cGvHD and for B-cell malignancy and is a potent anti-CD20 should be started as soon as a diagnosis is made. monoclonal antibody, and there is some limited There are a number of second-, third- and evidence of its use in cGvHD for musculoskeletal fourth-line therapies available, and approxi- and cutaneous manifestations (Dignan et al. mately 50% of patients will require alternatives 2012). within 2 years of initial therapy due to progres- Mesenchymal stem cells (MSC) (Ringden and sion of cGvHD (Flowers and Martin 2015). Keating 2011) have generated considerable interest in treatment of aGvHD following initial studies from the group at the Karolinska Institute. There 11.9.1 Second-Line, Third-Line was some evidence from early experiments that and Other Therapies MSC worked in autoimmune disorders, and given for Chronic GvHD the fact that cGvHD may resemble this in some ways, MSC have been used for cGvHD treatment Below is a brief list of second- and third-line but remain mainly within clinical trials. therapies for cGvHD; it is not exhaustive by any Infliximab, an antitumour necrosis factor (TNF) means, and many treatments are used following antibody, is a chimeric human anti-TNFa-IgG1(j) limited evidence from small non-randomised monoclonal antibody that inhibits the binding of 238 J. Murray et al.

TNF to its cellular receptors and has been used in whilst maintaining oral function and restoring some cases of GI GvHD (Dignan et al. 2012). mucosal integrity (Meier et al. 2011). It may Thalidomide inhibits angiogenesis, expression appear obvious, but the single most important of adhesion molecules, TNFa, interleukin-6, action for patients is to maintain good oral interleukin-12 and nuclear factor kappa B hygiene (daily care and regular dental visits). activity. A randomised clinical trial of thalido- Children’s toothpaste causes less irritation and mide, ciclosporin and prednisolone compared to should be used with a soft toothbrush, with the ciclosporin and prednisolone did not show any addition of lip salve if appropriate. Suggest also additional benefit in the primary treatment of avoidance of potential triggers for flares of cGvHD. Thalidomide has significant side effects cGvHD such as spicy or hot food or sharp food- including constipation, neuropathy, neutropenia, stuffs that can cause damage. Sip water and chew thrombocytopenia, tiredness and thrombosis sugar-free gum to improve xerostomia. (Dignan et al. 2012). Often patients require systemic therapy as multiple sites are involved. However, the oral cavity can be refractory to systemic therapy; thus 11.9.2 Topical Treatments complementary topical treatment is needed. for cGvHD of the Eyes There are a variety of topical steroid mouthwashes that are the first line of therapy, including The aim of treatment is to give symptomatic relief prednisolone, budesonide or betamethasone. of dry eye and care should be co-ordinated with an Tacrolimus 0.1% mouthwash is well tolerated experienced ophthalmologist. Focus is placed and has shown to be an effective option and may upon increasing ocular surface moisture via lubri- be used alongside steroid mouthwashes as cation and decreasing tear evaporation and tear second-line therapy. It is important to describe drainage from the eye and decreasing ocular sur- adequately how to use these preparations as in face inflammation. Preservative-free drops coat many cases this is not their usual route of admin- the eye surface minimising dry spots on the cor- istration. Several centres in Europe have access nea, decreasing ocular symptoms and improving to phototherapy with ultraviolet A and B light. vision. It may take several different trials of drops This stems from work in cutaneous cGvHD. A to find one that works as patients may be more sen- glass fibre extension of an UVA source is used for sitive to one solution. Temporary (with punctual manual intraoral application three to four times a plugs) or permanent (with cauterisation) occlusion week (Meier et al. 2011). of the tear duct may offer a solution to those with To relieve oral pain, topical application of severe dry eye. Where there is inflammation of the local anaesthetics such as lidocaine can be ocular surface, direct application of steroid eye applied, either as a gel, mouthwash or spray. drops may be beneficial especially if the patient is These should be used with caution as the gag on a taper of systemic immunosuppression and the reflex may be compromised and lead to choking eye symptoms flare (Couriel et al. 2006b). and aspiration. Ciclosporin eye drops appear to offer a solution, but they cause irritation in most patients, and thus compliance is poor. If available, autolo- 11.9.4 Ancillary and Supportive Care gous serum eye drops may decrease surface for cGvHD of the Skin inflammation. Chronic GvHD of the skin remains the most affected organ and is often debilitating when in 11.9.3 Topical Treatments extremis. Topical treatments are a vital therapy in for Oral cGvHD addressing the manifestations of itch, rash, pain and dyspigmentation, whilst the use of physical Management of oral cGvHD aims to alleviate therapy helps patients with limited range of symptoms of dry mouth, sensitivity and pain movement maintain some degree of functional- 11 Graft-Versus-Host Disease (GvHD) 239 ity. Other healthcare providers such as tissue Once the skin barrier has become breached, viability and infection control teams can offer bacterial, viral and fungal tests should be taken help, guidance and support when skin becomes and, if infection confirmed, treated rapidly. If friable and breaks down leaving ulcers, erosions swabs do not support an infective cause, it is and superadded infections. The patient with cuta- important to rule out other pathologies; the ulcer neous cGvHD is at an increased risk of skin can- may be as a consequence of vasculitis, malig- cer, and regular monitoring and assessment are nancy, drug reaction or dermatitis and will need advised. Any suspicion should be followed up appropriate management (Couriel et al. 2006b). with biopsy. Advice with respect to UV exposure One of the major challenges for topical man- should be given regularly: avoiding direct sun agement of chronic skin GvHD is the often severe exposure and using sun blocks and sunscreens sclerotic features – characterised by thickened, and loose fitting clothing with hat and glasses. tight and fragile skin. This is often associated Emollients are the backbone of skin care to with poor wound healing, inadequate lymphatic maintain the integrity of unbroken dry skin and drainage and skin ulcers from minor trauma or can be applied frequently throughout the day. It is idiopathic origin. There is basic advice which therefore important to work with the patient to should be given and regularly reinforced to all ensure the prescribed product is one they are patients: happy with and addresses their issues; otherwise they are unlikely to use it regularly enough for it • Take care to minimise risk of bumps/knocks. to be effective (see section on aGvHD). It is • Pat skin dry – no rubbing. worth noting they may need more than one prod- • Wear loose clothing to minimise risk of fric- uct; areas of extreme scaling or with plaques, for tion/irritation. example, will require an ointment (commonly on • Avoid the sun as much as possible. the lower limbs), whereas areas with delicate • Maintain a good oral intake (water). skin will require a lighter product (e.g. the face). • Minimise/avoid the use of perfumes directly Whilst emollients tend to be petroleum based, onto the skin (advise to spray onto clothes using a product which incorporates lipids (e.g. instead); make-up, if used, suggest minimal coconut oil in QV cream) will help ‘nourish’ the skin applications, researching into good qual- skin in addition to providing a barrier. ity products and protect the skin by initial Topical steroids are initiated in a stepwise application of a moisturiser. fashion, attempting to deliver the least potent ste- • Provide clear, consistent and repeated rein- roid to achieve the result desired. Lower strength forcement regarding the importance of regular steroid hydrocortisone can be applied to the face use of emollients. as can Eumovate under strict supervision, whilst the more potent Dermovate and Betnovate should be applied to the body only. 11.9.5 Wound Care Pruritis is common and can be a distressing symptom. Itch usually responds to systemic ther- As previously stated, patients with cutaneous apy, i.e. antihistamines; however, topical antipru- cGvHD are at high risk of skin breakdown. Any ritic with menthol such as Dermacool (0.5–1%) breaks must be taken seriously as they will may be applied if still problematic (Couriel et al. quickly turn into chronic wounds if not managed 2006b). It is important to note however that such effectively. products must be used with care. Widespread use If a lesion is superficial, it may be possible to can lead to alteration in thermoregulation, and contain it by the use of a hydrocolloid dressing the patient will feel very cold. It is therefore (e.g. DuoDerm extra thin). These are dressings important to use a maximum of twice daily and which form a waterproof, protective layer over on targeted areas only. Night time is often the the lesion, are typically self-adhering and main- worst, and as such, one application at bedtime tain a moist environment to encourage healing. may be sufficient. They generally only require changing every 240 J. Murray et al.

3–4 days, so although they do absorb exudate, face; there are several methods which can be they would not be appropriate for a highly exud- used: ing wound. Equally, it is advisable to clean the wound with a topical antimicrobial solution (e.g. • Autolytic debridement (breakdown of bacte- Octenilin) to minimise risk of high bacterial load rial cells), the use of moist dressing such as in the wound bed. Because of the fragility of skin hydrogels or hydrocolloids may facilitate this. affected by cGvHD, to minimise risk of macera- • Surgical debridement, with scissors or scalpel, tion and to facilitate adherence of the dressing, it however this should be undertaken with cau- is advisable to apply a barrier film (e.g. Cavilon tion and by experienced tissue viability nurses/ or Sorbaderm) to the surrounding epithelium trained medical personnel. prior to application of the dressing. • Mechanical debridement, pulse lavage, gentle In the case of cavity lesions, extra precautions washing, there are pulse lavage systems avail- are required. Wound healing in this patient cohort able; they have the benefit that they stimulate will commonly be slower (see below), and as such blood flow to the area, which can speed up lesions are at risk of bacterial colonisation/infec- granulation. Standing under the shower (espe- tion thus further delaying the healing process. cially a ‘power shower’) prior to dressing can Healing results from the interaction of plate- have a similar effect, if the lesion is in an lets, with cells such as neutrophils, macrophages, appropriate place. fibroblasts and keratinocytes combined with • Biological debridement, with larvae of Lucilia extracellular matrix (ECM) components, such as sericata (green bottle fly). Use of larvae can fibronectin, tenascin and collagens. Interface be considered; however, it should only be used with ECM components is regulated by mediators with the supervision of an experienced tissue such as cytokines and growth factors (e.g. inter- viability nurse. Larvae of the green bottle fly, leukins, interferons and TNF-α) (Olczyk et al. introduced into a wound (usually in a sterile 2014). The inflammatory response is triggered, bag), can remove necrotic, sloughy and/or and components such as growth factors facilitate infected tissue; they can also be used to main- proliferation, differentiation and metabolism of tain a clean wound after debridement. Larvae cells involved in the healing process. Others help should only be considered when other avenues regulate inflammatory processes and play a che- have been exhausted. They do not digest motactic role (encouraging cell movement) for healthy tissue; however in some cases of neutrophils, macrophages, fibroblasts and epithe- cGvHD, the tissue in the wound bed has such lial cells (keratinocytes) to stimulate angiogene- a poor blood supply that it will not be differen- sis and the formation of ECM (Olczyk et al. tiated by the larvae as healthy and they may 2014). start to digest it if not carefully supervised. Because this cohort of patients will commonly be experiencing disruption to levels of the com- To pre-empt the risk of infection, there should ponents required to facilitate healing due to sys- be a very low threshold for using antimicrobial temic management of GvHD, wound healing wound irrigation solution to cleanse wounds and becomes ever more complex and challenging. surrounding skin. An additional precaution is to In addition to the issue summarised above, if a pack the wound with a hydrofibre (e.g. Aquacel), wound becomes infected, this can initiate a ‘flare’ which turns into a gel on contact with exudate and of acute GvHD requiring more intensive manage- contains any bacteria within the gel. These dress- ment and potentially compounding the situation. ings can be obtained with ionic silver (Aquacel Bioburden can be compounded if there is a Ag) to facilitate extra protection. If the wound is significant amount of slough on the wound sur- ‘dry’, dampen the hydrofibre prior to packing to face or in cases where the patient presents with a prevent adherence to the wound bed. Although thick layer of eschar over the wound surface. hydrofibres minimise the risk of maceration, it is Debridement can contribute to a significant still preferable to protect the surrounding skin decrease in the bacterial load on the wound sur- with a barrier film; this will also facilitate adher- 11 Graft-Versus-Host Disease (GvHD) 241 ence of the secondary dressing to the classically tions may be required to release strictures and flaky skin of someone with cGvHD. adhesion formation. In all cases, particularly if the If the wound is not responding, collagen dress- woman is not sexually active, dilators lubricated ings can be used to try and facilitate effective with, for example, a lipid, such as coconut oil, healing (e.g. Promogran Prisma). Collagen is a should be thought about as a way of maintaining key component of a healing wound. Due to issues vaginal patency and capacity. such as bioburden, repeated trauma and ongoing Crucially, it is important that these matters are immunosuppression, wounds in the patient with addressed in a sensitive manner as there is often a cGvHD can halt at the inflammatory phase, thus psychological impact and it may be affecting any compounding the chronicity of the wound and partnership the patient is in. For this reason, any- impeding the formation of the ‘scaffold’ needed one working with these women needs to be for cell migration. This will ultimately limit any skilled in offering them the opportunity to dis- formation of extracellular matrix (ECM) and close any emotional concerns and, if necessary, granulation tissue (Brett 2008). Collagen-based refer them for expert counselling. wound dressings are uniquely suited to address Body image and sexual dysfunction are sig- this issue by acting as a substitute substrate, plus nificant problems for both men and women post- collagen breakdown products are chemotactic for transplant and are especially problematic upon cells required for the formation of granulation development of cGvHD. Counselling and early tissue (Brett 2008). In addition, collagen-based involvement with psych-oncology services are dressings have the ability to absorb wound exu- important to aid in maintaining normality in an date and maintain a moist wound environment abnormal situation. and do not require removal at subsequent dressing changes. However, it is important to note that they remain inactive when dry, so where there is 11.11 Chronic Lung GvHD minimal exudate in the wound, it is important to dampen them before application. Chronic lung GvHD may be treated with bron- chodilators, inhaled corticosteroids, systemic steroids, montelukast and referral to a physical 11.10 Vulvovaginal GvHD rehabilitation programme (Couriel et al. 2006b). Lung GvHD has a somewhat dismal outcome as As with cGvHD in other parts of the body, symp- it is not very responsive to any modality. Nurses toms associated with vulvovaginal GvHD and physiotherapists can help patients manage (vv GvHD) may be attributable to other patholo- the distress and possible panic situations the gies; Candida infection, for example, can cause patient may feel due to increasing breathlessness, discharge or itch, whilst hormone reduction/ by teaching complementary self-management menopause may be responsible for vaginal dry- skills such as breathing techniques, focused ness/soreness. Such co-morbidities require diag- relaxation and stress management. nosis and appropriate treatment. In women with chronic vvGvHD, mechanical and chemical irritants should be avoided. Washing 11.12 Connective Tissue with warm water, using products from such ranges Involvement in cGvHD as Oilatum or Dermol if required (rather than soap), cleaning in a front-to-back direction and Patients with cGvHD affecting skin, joints and then air-dried is to be advised. Bacteriostatic gels connective tissue will benefit from inclusion in such as Replens may be used in the vagina for an exercise rehabilitation programme along with comfort as this adheres to the vaginal wall and has occupational therapy. Functional losses associ- a long-lasting effect. Vulval and vaginal topical ated with muscle loss, weakness, contractures management can include steroid/immunosuppres- and limb swelling lead to fatigue and a decreased sant cream. In extreme cases, surgical interven- ability to perform activities of daily living and 242 J. Murray et al. often preclude patients from being able to return 11.14 The Future to work. Rehabilitation should aim to improve strength and mobility of joints and muscles and Considering the increased utilisation of HSCT, ideally should occur before permanent and last- the morbidity and mortality associated with ing damage has set in (Couriel et al. 2006b). Such GvHD and the limitations inherent to contem- programmes should include family members porary therapies, novel approaches are urgently where possible, as exercises need to be carried needed. Rationally designed treatments that out on a regular basis to be effective, with the inhibit deregulated pathways in malignant cells patient often needing support to do this. It can are typically the focus of ‘targeted’ therapy. In also be psychologically helpful to any family/ GvHD, the ‘target’ is elusive, as the goal is to carers involved as it allows them to feel confident carefully contain an overzealous but biologi- to be part of the care of their loved one. cally normal immunologic response (Magenau In addition to exercise, regular massage can and Reddy 2014). Success in prophylaxis and help maintain flexibility and function of affected treatment of GvHD will depend on whether limbs. If there is fascial involvement, any massage GvHD can be prevented without losing the provided will need to access these tissue layers to antitumour effect. Improvements in the under- be effective. It is therefore important that the thera- standing of the pathophysiology will move cli- pist providing this treatment has been trained in nicians towards this goal. Risk stratification using such techniques. Again, it is possible to teach and the emergence of a bedside GvHD test family members appropriate massage skills, which based on proteomics may be on the horizon will improve the efficacy of therapy provided. and will ultimately then improve the outlook for this difficult-to-treat group of patients (Greinix 2008). 11.13 Quality of Life

QoL is severely compromised in cGvHD, with 11.15 GvHD in Children reports of fatigue, pain and GI upset. FACT-BMT QoL questionnaire studies have revealed that Data and research on GvHD in the paediatric physical, sexual and social functioning is also population are limited with only a few studies lower with higher rates of depression and anxiety specifically focused on children. Most studies are and adverse effects on social and family interac- small, and children are often grouped into larger tions. Depressive symptoms are more severe and adult series (Baird et al. 2010). In this short last longer and often manifest when patients com- review, we will emphasise on the specific aspects plain of loss of memory or poor concentration. of paediatric GvHD primarily focusing on Fatigue may be considered as a separate entity but cGvHD. is often mixed in with QoL, anxiety and depres- Most of the literature on cGvHD has focused sion. It may be described as a persistent and sub- on adults. Although the clinical manifestation jective state of tiredness that interferes with usual of cGvHD in children is similar to that in adults, functioning and can continue for several years the consequences of treatment and nonre- after transplant (Couriel et al. 2006b). Using sponses are remarkably different in a growing questionnaires to assess these issues with individ- organism (Lawitschka et al. 2012). Children ual patients is something which nurses can insti- with cGvHD are of particular interest, given gate to identify the impact of psychological their longer life expectancy and developmental morbidity in specific cases. These can be used as issues following the complications of cGvHD a framework to enable patients to express their and its therapy (Jacobsohn 2010; Jacobsohn concerns and structure a support programme to et al. 2011). Compared with childhood cancer help manage specific issues – including onward survivors who did not undergo transplantation, referrals to appropriate professionals. HSCT survivors have a substantially increased 11 Graft-Versus-Host Disease (GvHD) 243 burden of serious chronic conditions and pharmacologic strategies for both prevention and impairments involving every organ. A history treatment of aGvHD were used in these patients. of GvHD or presence of cGvHD contributes to The condition of mixed donor chimerism is associ- increase rate of long-term complications in the ated with reduced susceptibility to GvHD. Some of paediatric transplant survivors (Chow et al. the children with non-malignant disorders (those 2016). Chronic GvHD has negative effects on with aplastic anaemia or with congenital immuno- an individual’s physical and mental health and deficiencies) are given less intensive preparative can lead to the development of functional regimens, and it has been hypothesised that the impairments and activity limitations over their cytokine storm, which is dependent on the intensity lifetime (Baird et al. 2010) as well as reduced of the conditioning regimen, triggers development quality of life (Inagaki et al. 2015). However, of GvHD. Malignant diseases and the use of mye- paediatric cGvHD remains an understudied loablative protocol as well as TBI as part of the area of research (Jacobsohn et al. 2011); there- preparative regimen have an increased risk of clas- fore, large paediatric multicentre studies are sic aGvHD (Faraci et al. 2012). Older recipient and needed (Watkins et al. 2016). donor ages are another risk factor for cGvHD (Watkins et al. 2016).

11.15.1 Incidence and Risk Factors 11.15.2 Treatment Overall the rates of cGvHD are lower in children than adults (Champlin et al. 2000; Rocha et al. The major emphasis in GvHD has been on pre- 2000). However, the incidence of cGvHD in the vention, as results with treatment have been dis- paediatric population is still substantial and has appointing. Currently most centres use a increased recently in association with the combination of a calcineurin inhibitor (ciclospo- expanded use of peripheral blood stem cells and rin or tacrolimus) with short-course methotrexate unrelated donors (Baird et al. 2010). Zecca et al. (Jacobsohn 2008). (2002) in a large paediatric study reported a The treatment of cGvHD in paediatrics is cumulative probability of cGvHD of 27%; this highly variable and mostly extrapolated from the probability is nearly half of the estimated prob- experience in adults. Although there is no proven ability of 40–50% described in adults. Flowers standard therapy, prednisolone and ciclosporin et al. (2011) published a large single-centre are commonly used as frontline therapy. As ste- study of risk factors for aGvHD and cGvHD. The roids remain the basis of cGvHD therapy, the sample included both adult and paediatric consequences of long-term steroid use in children patients; cGvHD was defined according to the are well described, and long-term harmful effects NIH cGvHD criteria (Filipovich et al. 2005). on growth and bone density persist even after dis- The incidence of moderate to severe cGvHD in continuation of therapy. the paediatric patient was 28% (Watkins et al. Other potential treatment strategies include 2016). extracorporeal photopheresis (as discussed ear- The risk factors for cGvHD in childhood are lier in this chapter) and the infusion of allogeneic still poorly defined. Zecca et al. (2002) reported the human mesenchymal stem cells (MSC) for the risk factors associated with cGvHD in children: treatment of aGvHD and cGvHD. Multiple MSC male patients transplanted from a female donor infusions are safe and effective for children with experience more cGvHD. Children with non- steroid-refractory aGvHD, especially when malignant disorders had a reduced risk of develop- employed early in the disease course. Early treating cGvHD. This might be due to the fact that ment may be associated with reduced treatment- children with these diseases do not benefit from related mortality and better overall survival (Ball GvHD since they do not need any graft-versus- et al. 2013). MSC offer new potential modalities malignancy effect, and therefore the most effective of treatments for paediatric cGvHD refractory to 244 J. Murray et al. standard treatments (Lawitschka et al. 2012). The adolescent developmental need. Patients and treatment in paediatric patients must take into families, who initially felt great relief to be cured consideration the potential effect on growth, from their primary disease, now face the chal- nutrition, organ function, bone metabolism, hor- lenge of a chronic devastating illness for which monal balance, psychosocial aspects and immune preventative and treatment strategies are subopti- reconstitution (Baird et al. 2010; Lawitschka mal (Baird et al. 2010). The treatment and sup- et al. 2012). port of the children and their families require a The nursing management and care of children multidisciplinary team care that will be able to with GvHD are complex and require expert skills provide a comprehensive response to all their and knowledge as well as adjustment to the child/ needs.

Appendix Appendix 1: Classification of Patients with Acute GVHD

Skin/maculopapular rash Liver bilirubin Stage BSA (mg/dl) Gut (ml diarrhoea/day) 0 No rash <34 umol/L <500 ml/day 1 <25% of body surface area 34–50 umol/L >500–999 ml/day or persistent nausea with histological evidence stomach/duodenum 2 25–50% of body surface area 51–102 umol/L 1000–1500 ml/day 3 >50% of body surface area 103–255 umol/L >1500 ml/day 4 Generalised erythroderma with >255 umol/L Severe abdominal pain with or bullous formation and without ileus desquamation

Acute GvHD clinical grading modified Glucksberg/ keystone criteria Grade Skin Liver Gut 0 None None None I Stages 1–2 None None II Stage 3 Stage 1 Stage 1 III – Stages 2–3 Stages 2–4 IV Stage 4 Stage 4 –

Glucksberg et al. (1974) modified criteria taken from the EBMT 2008 revised edition of handbook with permission 11 Graft-Versus-Host Disease (GvHD) 245

Appendix 2: Scoring of Chronic GvHD

SCORE 0 SCORE 1 SCORE 2 SCORE 3 PERFORMANCE Asymptomatic and Symptomatic, Symptomatic, Symptomatic, SCORE: fully active (ECOG fully ambulatory, ambulatory, capable limited self-care, 0; KPS or LPS restricted only in of self-care, >50% >50% of walking physically of waking hours KPS ECOG LPS 100%) hours in bed (ECOG strenuous activity of bed (ECOG 2, 3-4, KPS or LPS (ECOG 1, KPS KPS or LPS 60- <60%) or LPS 80-90%) 70%)

SKIN †

SCORE % BSA GVHD features to be scored No BSA 1-18% BSA 19-50% BSA >50% BSA by BSA: involved Check all that apply: Maculopapular rash/erythema Lichen planus-like features Sclerotic features Papulosquamous lesions or ichthyosis Keratosis pilaris-like GVHD SKIN FEATURES Check all that apply: SCORE: No sclerotic Superficial Deep sclerotic features sclerotic features features “not hidebound” “Hidebound” (able to pinch) (unable to pinch) Impaired mobility Ulceration Other skin GVHD features (NOT scored by BSA) Check all that apply: Hyperpigmentation Hypopigmentation Poikiloderma Severe or generalized pruritus Hair involvement Nail involvement Abnormality present but explained entirely by non-GVHD documented cause (specify):______

MOUTH No symptoms Mild symptoms Moderate Severe symptoms with Lichen planus-like with disease signs symptoms with disease signs on features present: but not limiting disease signs with examination with major Yes oral intake partial limitation limitation of oral intake No significantly of oral intake Abnormality present but explained entirely by non-GVHD documented cause (specify):______

246 J. Murray et al.

SCORE 0 SCORE 1SCORE 2SCORE 3 EYES No symptoms Mild dry eye Moderate dry eye Severe dry eye symptoms not symptoms partially symptoms significantly Keratoconjunctivitis affecting ADL affecting ADL affecting ADL (special sicca (KCS) confirmed (requirement of (requirement lubricant eyeware to relieve pain) by ophthalmologist: lubricant eye eye drops > 3 × per OR unable to work Yes drops ≤ 3 × per day or punctal because of ocular No day) plugs), symptoms OR loss of Not examined WITHOUT new vision due to KCS vision impairment due to KCS

Abnormality present but explained entirely by non-GVHD documented cause (specify):______

GI Tract No symptoms Symptoms Symptoms Symptoms associated Check all that apply: without associated with with significant weight Esophageal web/ significant weight mild to moderate loss* >15%, requires proximal stricture loss*(<5%) weight loss* nutritional supplement for or ring (5-15%) OR most calorie needs OR Dysphagia moderate diarrhea esophageal dilation OR Anorexia without severe diarrhea with Nausea significant significant interference Vomiting interference with with daily living Diarrhea daily living Weight loss ³ 5%* Failure to thrive Abnormality present but explained entirely by non-GVHD documented cause (specify):______

LIVER Normal total Normal total Elevated total Elevated total bilirubin and bilirubin and ALT bilirubin but bilirubin > 3 mg/dL ALT or AP ≥3 to 5 x ULN or ≤3 mg/dL or <3 x ULN AP ≥ 3 x ULN ALT > 5 ULN Abnormality present but explained entirely by non-GVHD documented cause (specify):______LUNGS** Symptom score: No symptoms Mild symptoms Moderate Severe symptoms (shortness of symptoms (shortness of breath at breath after (shortness of breath rest; requiring 02) climbing one flight after walking on of steps) flat ground) Lung score: FEV1≥80% FEV1 60-79% FEV1 40-59% FEV1 ≤39% % FEV1

Pulmonary function tests Not performed Abnormality present but explained entirely by non-GVHD documented cause (specify):______

11 Graft-Versus-Host Disease (GvHD) 247

SCORE 0 SCORE 1 SCORE 2 SCORE 3

JOINTS AND FASCIA No Mild tightness of Tightness of arms or Contractures WITH symptoms arms or legs, legs OR joint significant decrease of P-ROM score normal or mild contractures, ROM AND significant (see below) decreased range of erythema thought limitation of ADL Shoulder (1-7):___ motion (ROM) due to fasciitis, (unable to tie shoes, Elbow (1-7):___ AND not affecting moderate decrease button shirts, dress self ADL ROM AND mild to etc.) Wrist/finger (1-7):___ moderate limitation Ankle (1-4):___ of ADL Abnormality present but explained entirely by non-GVHD documented cause (specify):______GENITAL TRACT No signs Mild signs‡ and Moderate signs‡ and Severe signs‡ with ‡ (see Supplemental figure ) females with or may have or without Not examined without discomfort symptoms with symptoms Currently sexually active on exam discomfort on exam Yes No Abnormality present but explained entirely by non-GVHD documented cause (specify):______

Other indicators, clinical features or complications related to chronic GVHD (Check all that apply and assign a score to severity (0-3) based on functional impact where applicable non–0, mild-1, moderate-2, severe–3) Ascites (serositis)___ Myasthenia Gravis___ Pericardial Effusion___ Peripheral Neuropathy___ Eosinophilia > 500/µl___ Pleural Effusion(s)___ Polymyositis___ Platelets <100,000/µl___ Nephrotic syndrome___ Weight loss>5%* without GI symptoms___ Others (specify) :______

Overall GVHD Severity (Opinion of the evaluator) No GVHD Mild Moderate Severe Photographic Range of Motion (P-ROM) 1(worst) 2 3 456 7(Normal)

Shoulder

1(worst) 2 3 456 7(Normal)

Elbow

1(worst) 2 3 456 7(Normal)

Wrist/finger

1(worst) 2 3 4(Normal) Ankle

† Skin scoring should use both percentage of BSA involved by disease signs and the cutaneous features scales. When a Discrepancy exists between the percentage of total body surface (BSA) score and the skin feature score, OR if superficial sclerotic features are present (Score 2), but there is impaired mobility or ulceration (Score 3), the higher level should be used for the final skin scoring. * Weight loss within 3 months. ** Lung scoring should be performed using both the symptoms and FEV1 scores whenever possible. FEV1 should be used in the final lung scoring where there is discrepancy between symptoms and FEV1 scores. Abbreviations: ECOG (Eastern Cooperative Oncology Group), KPS(Karnofsky Performance Status), LPS(Lansky Performance Status); BSA(body surface area); ADL(activities of daily living); LFTs(liver function tests); AP (alkaline phosphatase); ALT (alanine aminotransferase); ULN(normal upper limit). ‡ To be completed by specialist or trained medical providers (see Supplemental Figure). 248 J. Murray et al.

Name:______Date of birth:______Assessment date:______

SCORE 0 SCORE 1 SCORE 2 SCORE 3 GENITAL TRACT No signs Mild signs and Moderate signs Severe signs with or (male or female) females may have and may have without symptoms* symptoms* symptoms* WITH discomfort with on exam discomfort on exam Currently sexually active: Yes No Check all signs that applies: Lichen planus-like features Lichen sclerosis-like features Vaginal scarring (female) Clitoral/labial agglutination (female) Labial resorption (female) Erosions Fissures Ulcers Phimosis (male) Urethral meatus scarring/ stenosis (male) Abnormality present but NOT thought to represent GVHD (specify cause):______Abnormality thought to represent GVHD PLUS other causes (specify cause):______*Genital symptoms are not specific to cGVHD and can represent premature gonadal failure or genital tract infection. If a gynecologist is unavailable, external examination may be performed to determine “discomfort on exam” as follows: a) Spread the labia majora to inspect the vulva for the above signs. Touch the vestibular gland openings (Skene’s and Bartholin’s), labia minora and majora gently with a qtip. Vulvar pain elicited by the gentle touch of a qtip is classified as discomfort on examination. Palpate the vaginal walls with a single digit to detect bands, shortening, narrowing or other signs of vaginal scarring. b) If the woman is sexually active, determine whether qtip palpation or gentle palpation of scarred ridges elicits pain similar to that which the woman experiences during intercourse. Female genitalia: Severity of signs: 1) Mild (any of the following); erythema on vulvar mucosal surfaces, vulvar lichen-planus or vulvar lichen-sclerosis 2) Moderate (any of the following); erosive inflammatory changes of the vulvar mucosa, fissures in vulvar folds 3) Severe (any of the following); labial fusion, clitoral hood agglutination, fibrinous vaginal adhesions, circumferential fibrous vaginal banding, vaginal shortening, synechia, dense sclerotic changes, and complete vaginal stenosis

Male genitalia: Diagnostic features include lichen planus-like or lichen sclerosis-like features and phymosis or urethral scarring or stenosis. Severity of signs: Mild – lichen planus-like feature; Moderate – lichen sclerosis-like feature or moderate erythema; Severe – phimosis or urethral/meatal scarring

Biopsy obtained: Yes No Site biopsied:______GVHD confirmed by histology:Yes No

Change from previous evaluation: No prior or current GVHD Improved Stable Worse N/A (baseline)

geneic transplantation patients. Biol Blood Marrow Jagasia et al. (2015) with permission Transplant. 2014;20:979–85. Baird K, Cooke K, Schultz KR. Chronic graft-versus- host disease (GvHD) in children. Pediatr Clin N Am. 2010;57:297–322. References Ball LM, et al. Multiple infusions of mesenchymal stromal cells induce sustained remission in children with Al-Kadhimi ZG, Chen W, Smith D, Abid M, Deol A, steroid-refractory, grade III–IV acute graft-versus- Ayash L, Lum L, Waller EK, Ratanatharathorn V, host disease. Br J Haematol. 2013;163:501–9. Uberti J. High incidence of severe acute graft-versus- Baron F, Labopin M, Niederwieser D, Vigouroux S, host disease with tacrolimus and mycophenolate Cornelissen JJ, Malm C, Vindelov LL, Blaise D, mofetil in a large cohort of related and unrelated allo- Janssen JJWM, Petersen E, Socie´ G, Nagler A, 11 Graft-Versus-Host Disease (GvHD) 249

Rocha V, Mohty M. Impact of graft-versus-host dis- Flowers MED, Inamoto Y, Carpenter PA, Lee SJ, et al. ease after reduced-intensity conditioning allogeneic Comparative analysis of risk factors for acute graft- stem cell transplantation for acute myeloid leukemia: versus-host disease and for chronic graft-versus-host a report from the Acute Leukemia Working Party of disease according to National Institutes of Health con- the European group for blood and marrow transplan- sensus criteria. Blood. 2011;117:3214–9. tation. Leukemia. 2012;26:2462–8. Flowers MED, Martin PJ. How we treat chronic graft ver- Bladon J, Taylor P. The down regulation of IL1 and IL6, sus host disease. Blood. 2015;125(4):606–15. in monocytes exposed to ECP treated lymphocytes, Filipovich AH, Weisdorf D, Pavletic S, et al. National is not dependent on lymphocyte phosphatidylserine Institutes of Health consensus development project externalisation. 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Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Graft Versus Tumour Effect 12 Mairéad NíChonghaile

Abstract The treatment of relapsed disease remains challenging, and it is well accepted that concept of allogeneic HSCT relies upon both the conditioning or preparative regimen used for the recipient and the graft versus malignancy (GvM) or leukaemia (GvL) effect provided by the donor T cells and NK cells. Strategies which involve harnessing this effect are crucial to success and need to be exploited and refined to improve outcome. Further research is required to identify new strategies and therapies to improve the outlook for patients who relapse post-HSCT. The nursing challenges following relapse are immense; the psychological support required is complex and largely falls to the nurse to coordinate and deliver regardless of the selected treatment approach.

Keywords Graft versus malignancy (GvM) or leukaemia (GvL) • Donor lymphocyte infusions (DLI) • Relapse • Chimerism

12.1 Introduction mune attack on the malignancy helps to eradicate the disease in the recipient with the aid of the con- It is well accepted that concept of allogeneic hae- dition regimen. The susceptibility of a malignant matopoetic stem cell transplant (HSCT) relies condition being eradicated by GVM of GvL effect upon both the conditioning or preparative regimen varies with the most sensitive conditions being used for the recipient and the graft versus malig- chronic myeloid leukaemia, chronic lymphocytic nancy (GvM) or leukaemia (GvL) effect provided leukaemia, low-grade B-lymphoproliferative dis- by the donor T cells and NK cells. The autoim- orders, mantle cell lymphoma and EBV lymphoproliferative conditions. Most other conditions have an intermediate sensitivity to the GvM or GvL M. NíChonghaile effect with conditions that have a special prolifera- HOPE Directorate, St James’s Hospital, Dublin, Ireland tion or that are advanced or chemo-refractory hav- e-mail: [email protected] ing the least response.

12.2 Mechanism of GvM/GvL Table 12.1 Common targets for MRD screening in dif- Effect ferent malignancies Disease MRD target Both T lymphocytes and NK cells participate in Myelodysplastic syndromes Del(5q); monosomy 7, the GvL effect, and it is believed that cytotoxic T trisomy 8 cells recognise several classes of antigens on leu- Chronic myeloid leukaemia t(9;22) Acute myeloid leukaemia t(8;21); inv (16) kaemic cells. The NK cells target MMag self- Acute lymphoblastic t(9;22) proteins (present on the tissues of the recipient) leukaemia t(4;11); t(8;14) which are overexpressed by the leukaemia, e.g. Follicular lymphoma t(14;18) proteinase 3 and elastase tumour-specific anti- Mantle cell lymphoma t(11;14) gens, e.g. Wilms tumour 1, and fused proteins, Chronic lymphocytic del(13q), del(11q); e.g. BCR-ABL, by using the perforin-granzyme leukaemia del(17p) pathway to kill their targets. However they are Multiple myeloma del(13q), del(11q) only activated when inhibitory signals from self (recipient) MHC class 1 molecules on the target Table 12.2 Examples of Molecular targets in different are missing or overcome by activating signals malignacies through the NKG2D receptor. The suppressor of Disease Molecular target the recipient’s immune system allows the donor B-ALL TEL-AML1 cells to provoke this effect. BCR-ABL1 Ig/TCR gene rearrangements T-ALL Ig/TCR gene rearrangements 12.3 Minimal Residual Disease Tald1 (MRD) APML PML-RARA AML AML1-ETO CBFb-MYH11 The purpose of monitoring MRD in the post- WT-1 transplant setting is to track disease response or NPM1 mutated remission or low-level disease recurrence when FlT3 the quantity of a particular marker starts to increase. This enables a therapeutic intervention cells and offers the possibility to identify to be implemented very early and may optimise impending graft rejection and can also be an the chance of success. indicator of disease relapse or recurrence. MRD can be monitored using molecular Chimerism can also be used as a basis for treat- methods – this is where the underlying condition ment intervention to prevent graft rejection and has a specific market or protein that can be moni- maintain engraftment and is used as a mecha- tored by using flow cytometry. Table 12.1 shows nism to administer pre-emptive immunotherapy the cytogenetic abnormalities that can be targeted to provoke the GvM or GvL effect particularly in in some diseases (page 410 Treleaven and Barrett high-risk patients. 2009), and Table 12.2 shows some of the molecu- Chimerism allows the monitoring of the ratio lar targets (Apperly et al. 2012) if they were pres- of donor- and recipient-derived cells in non- ent at diagnosis. genetically identical donor and recipient pairs. This allows for timely intervention in the care of the recipient. The term “chimerism” comes from 12.4 Chimerism Greek mythology where the chimera was a fire- spitting monster with the head of a lion, body of Chimerism analysis is another important tool in a goat and the tail of a serpent and is used to the post-HSCT follow-up of the recipient. It describe the fact of two entities – DNA from two demonstrates the degree of engraftment of donor people – existing in the one person. 12 Graft Versus Tumour Effect 255

Initially it was felt that in order for all HSCT 12.5 Management of Relapsed to be considered successful, an individual would Disease have to be 100% donor chimerism, and this is certainly the case with malignant conditions. When a recipient has evidence of MRD or a However, in non-malignant conditions (e.g. decrease in chimerism, there are a number of strate- aplastic anaemia or haemoglobinopathies), a gies that can be followed. In the case of mixed chi- mixed chimerism may be enough to restore nor- merism, the schema in Fig. 12.1 can be followed. mal haematopoiesis. Relapse usually occurs in the BM but may also While the total (unfractionated) chimerism be at extramedullary sites, thought to be due to result is important, more information can be immune escape from patrolling lymphocytes. It is elicited if lineage-specific chimerism is per- also thought that leukaemia can escape from the formed allowing separate tracking of lymphoid immune control provided by the donor’s T cells by and myeloid engraftment and in itself can pro- mutating or becoming a more resistant clone of the vide very useful information about possible dis- original disease. The cause of the relapse may also ease relapse. This should be used in conjunction be different in different haematological malignan- with other means of MRD analysis and cies. While relapses can occur many years after diagnosis. HSCT suggesting that perhaps the underlying dis- Schedule and protocols for chimerism analy- ease was never eradicated and was held in control sis are centre, disease and treatment specific, and by the donor immune system, it is more common reference should be made to your institution’s with CML, and in this disease, the administration policy. of DLI can often restore remission.

Increasing mixed chimerism after allo-SCT

On Not on cyclosporine (CSA) cyclosporine (CSA)

Cessation of CSA

Response: No response: Start of donor lymphocyte decrease of MC further increase of MC infusion (DLI)

Wait and see: Response: No response: weekly analysis of MC decrease of MC further increase of MC

Wait and see: Repeat DLI weekly analysis of MC

Fig. 12.1 Patients with increasing MC post transplant is based on the number and potential severity of HLA mis- (5% or more autologous cells) compared to the previous matches between the donor and recipient, and starting sample are offered further therapy. Immunotherapy for doses range from 2.5 × 104 to 1 × 106/kg BW. After DLI, patients receiving CSA consists of immediate discontinu- chimerism status is assayed weekly until CC status is ation of the immunosuppressive agent. Chimerism is then restored. Patients who show a further increase in MC are assayed weekly until CC status is restored. If MC contin- given an additional DLI after at least 3 weeks have ues to increase after cessation of CSA, a DLI is given. elapsed. If no GVHD occurs, the dose of DLI is doubled Immunotherapy for patients not receiving CSA consisted (Bader et al. 2005) of DLI as frontline treatment. The cell dose administered 256 M. NíChonghaile

However the outlook for the recipient who 12.6 Treatment Options for Post- relapses post-HSCT is poor and requires frank allogeneic HSCT Relapse discussion with the recipient and their family to define the likely outcomes and success. Care for Immunotherapy the relapsed patient revolves around five potential strategies: Palliative care Chemotherapy • Immunotherapy • Chemotherapy • Molecular targeting • Supportive care Molecular • Palliative care Suppotive care Targeting

The timing of relapse is extremely important. Early relapses are difficult to treat, and any intervention may be challenging for the patient or 12.7 Management of Relapsed precluded due to the proximity to the HSCT and Disease complications experienced by the recipients. Patients who relapse after HSCT may find it Immunotherapy This is an important tool in extremely difficult to adapt to and accept the fact the management of the relapsed patient and can that further treatment may not be possible or range from withdrawal of immunosuppression (if may be ineffective particularly if they have the patient is still on it) to the administration of already received intensive treatment prior to donor lymphocyte infusions (DLI) infusions in HSCT. incremental doses. However, it is important to provide ongoing support so that patients do not feel abandoned at this stage, and this helps patients to maintain real- 12.8 Withdrawal istic levels of hope and optimism. Palliative and of Immunosuppression supportive care measures are valid and realistic options to help maintain a good quality of life and The GvL or GvM effect of HSCT can be enhanced should not be ignored. The help and support of the by reducing and stopping the IS (immunosup- medical team, recipient’s local doctor, referring pressive) agent that the patient may be taking. hospital and often primary care services, e.g. GP Nursing care and education is essential in this and hospice, are essential in the management and circumstance as along with GvL the patient needs treatment of the relapsed patient. Referral to psy- to be monitored for the development of GVHD chology, counselling or psychiatric teams may which is extensively discussed in another also benefit the patient and their family. chapter. 12 Graft Versus Tumour Effect 257

12.9 Responsiveness to DLI (Adapted from Treleaven and Barrett 2009)

Chronic Myeloid Leukaemia

High

Chronic Lymphocytic Leukaemia

Mantle Cell Lymphoma

Follicular Lymphoma Intermediate Hodgkin’s Disease

Multiple Myeloma

Myelodysplastic Syndrome

Acute Myeloid Leukaemia

Acute Lymphoid Leukaemia Low High Grade Non-Hodgkins Lympohma

12.9.1 DLI 12.9.2 Chemotherapy

DLI alone can induce permanent remission of the This may be used to palliate the patient, to underlying disease particularly in the case of CML attempt to reduce the disease burden to facili- where relapses occur at a molecular level. In other dis- tate DLI or targeted therapy or to achieve a eases, the response can be varied from effective to remission. Patients relapsing within 6 months ineffective (Fig. 4). Most centres adopt an approach of HSCT often require reduced or modified with the administration of graduated doses between 1 dosing due to the toxicity of previous treatment × 106 CD3 cells per kg and 1 × 108 per kg recipient or having reached the dosing limits of particu- body weight depending on time from transplant, lar chemotherapeutic agents. Regimens for patient performance status and type of donor. relapsed patients tend to be patient specific, and DLI may also be administered as an adjuvant there are currently very few standardised therapy to chemotherapy or targeted therapies to approaches. The nursing care of these patients augment the effect of that treatment or sustain a has been well documented in previous remission if achieved. chapters. 258 M. NíChonghaile

12.10 Molecular or Targeted improve the outcome for this group of Therapies patients. The nursing challenges are immense, and Consideration needs to be given to the administra- the psychological support required is complex tion of molecular or targeted therapies to patients and largely falls to the nurse to coordinate and who relapse post-HSCT if they are available. deliver regardless of the subseque nt treatment Disease-specific monoclonal antibodies, e.g. approach. The nursing team will continue to brentuximab, in some lymphomas; anti-CD33 support patients and their families and help agents, e.g. gemtuzumab, in myeloid malignan- them to adjust to the changes ahead. The cies; and TKIs in BCR-ABL-positive malignan- demands on the team can mean that it is diffi- cies can have an important role in this setting. cult to take the time to reflect and deal with the changing care and focus for the patients. The adjustments and difficulties experienced in 12.11 Second HSCT caring for the relapse patient need to be matched by a team that continues to support If a patient experiences a relapse later post- each other. HSCT, consideration may be given to a second HSCT using stem cells either from the original donor or an alternative donor. In malignant disease, usually a second procedure is only feasible References when remission has been achieved following successful administration of chemotherapy, a molec- Apperly J, Carreras E, Gluckman E, Masszi T. Haematopoietic stem cell transplantation. 6th revised ular or targeted therapy. The morbidity and ed. Genoa: Forum Service; 2012 mortality associated with a second HSCT is often Bader P, Niethammer D, Willasch A, Kreyenberg H, significant, and the patient and family should be Klingebiel T. How and when should we monitor carefully counselled before such an undertaking. chimerism after allogeneic stem cell transplantation. Bone Marrow Transpl. 2005;35:107–19. Treleaven J & Barrett AJ 2009 Haematopoietic stem Conclusion cell transplantation in clinical practice. Churchill The treatment of relapsed disease remains Livingstone Elsevier; Edinburgh challenging, and further research is required to identify new strategies and therapies to

Daphna Hutt

Abstract Engraftment following HSCT is an essential goal for sustained long-term and effective hematopoiesis. It’s the most important criteria for a better overall survival. However, stem cell engraftment may be accompanied with a clinical condition known as engraftment syndrome (ES) that could have a devastating outcome. Nurses caring for HSCT recipients must be aware of ES symptoms in order to intervene quickly and appropriately. On the other hand, graft failure (GF) is a major complication and is associated with a dismal prognosis. It is classically divided into primary or secondary graft failure. The risk factors associated with GF may be related to characteristics of the graft, the patient, the donor, or the transplant procedure. The conditions that are associated with an increased occurrence of GF and the available treatment options will be thoroughly discussed in the chapter along with the nursing considerations.

Keywords Engraftment • Engraftment syndrome • Graft failure • Graft rejection Pediatrics • Nursing

13.1 Engraftment

Engraftment is the process by which hematopoietic stem cells (HSC) make their way (homing) to free bone marrow (BM) niches where they can find optimal conditions to survive and proliferate. Once they have reached the BM microenviron- D. Hutt ment, HSC have to proliferate to generate all Department of Paediatric Hematology-Oncology and BMT, Edmond and lily Safra Children Hospital, hematopoietic cell subsets (Servais et al. 2013). Sheba Medical Center, Ramat Gan, Israel A fundamental goal for successful engraftment is e-mail: [email protected] that the transplanted HSC are capable of

sustaining long-term effective hematopoiesis; myeloablative conditioning regimen. The median production of red blood cells, white blood cells, time to neutrophil engraftment was 25 days (range and platelets; and their release to peripheral blood 11–108) for children and 23 days (range 11–116) (Locatelli et al. 2014). Engraftment is the most for adult recipients (P = 0.6) (Ruggeri et al. 2014). important variable for a better overall survival Furthermore, when comparing intensity of condi- after stem cell transplant (Cluzeau et al. 2016). tioning regimens, Slavin et al. (1998) described for the first time that allogeneic non-myeloablative HSCT was better tolerated than any standard mye- 13.2 Engraftment Definition loablative conditioning, with a shorter period of neutropenia and a shorter period of platelet Various definitions of engraftment exist in the lit- dependence. erature. Engraftment is most commonly defined as Methods of determining donor engraftment the first of three consecutive days of achieving a rely on the assessment of donor and recipient cell sustained peripheral blood neutrophil count of components in the recipient BM or PB, termed as >500 × 106/L (Wolff 2002). Platelet engraftment is chimerism analysis (see Chap. 12). usually defined as independence from platelet transfusion for at least 7 days with a platelet count of more than >20 × 109/L (Teltschik et al. 2016). 13.3 Engraftment Syndrome The two major factors affecting engraftment are the graft source and the hematopoietic stem cell Engraftment syndrome (ES) is a clinical condi- transplant (HSCT) conditioning regimen. tion that is characterized by fever, rash, pulmo- Generally, there are three common sources of nary edema, weight gain, liver and renal HSCT grafts: bone marrow (BM), harvested from dysfunction, and/or encephalopathy. It occurs at the iliac crest; peripheral blood stem cells (PBSC), the time of neutrophil recovery after stem cell following G-CSF mobilization of HSC to the transplantation (SCT) (Chang et al. 2014). Most peripheral circulation with later collection of these data suggest that ES results from a pro- cells by leukapheresis; and cord blood (CB). inflammatory state caused by the release of Champlin et al. (2000) published a large retrospec- diverse cytokines and other mediators of inflam- tive multivariate analysis which compared results mation. Clinical features of ES are similar in of 288 HLA-identical sibling PBSC transplanta- children and adults. Criteria for the diagnosis of tions with results of 536 HLA-identical sibling ES typically include fever (thought to be not from BM transplantations. Patients who received PBSC infection) and features of systemic vascular leak, had significantly faster recovery of neutrophils and as ES was previously referred to as capillary leak platelets compared to BM transplants. Neutrophils syndrome. ES can resemble acute or hyperacute exceed the threshold of 500 × 106/L between 2 and GvHD giving rise to the question of whether ES 6 days earlier with PBSC than after BM. In an is an early manifestation of GvHD. EBMT study, the time interval for engraftment was 12 days for PBSC and 15 days for BM. Platelet recovery is also faster by approximately 6 days, 13.4 Management of ES i.e., platelet recovery of 20 × 109/L was reached at day +15 for PBSC patients and day +20 for ES may be self-limited and require no therapy. patients receiving BM (Schmitz et al. 2002). CB Indications for treatment include a temperature of transplant is associated with delayed engraftment. >39 °C without an identifiable infectious etiology A large study of 1268 patients (73% children) with and clinically significant manifestations of vascu- acute leukemia (64% acute lymphoblastic leuke- lar leak, especially pulmonary edema. ES is corti- mia (ALL), 36% acute myeloid leukemia) in costeroid responsive, and treatment is given only remission analyzed engraftment kinetics and out- as long as symptoms persist, usually for 1 week comes after a single-unit CB transplantation with (Spitzer 2015). 13 Engraftment, Graft Failure, and Rejection 261

13.5 Nursing Considerations Primary graft failure is defined as no evidence of engraftment or hematological recovery of Due to the potentially devastating outcomes asso- donor cells, within the first month after trans- ciated with ES, nurses caring for SCT recipients plant, without evidence of disease relapse. must be aware of ES and its symptoms in order to Secondary graft failure refers to the loss of a intervene quickly and appropriately (Thoele previously functioning graft, resulting in cytope- 2014). Nursing assessment, in order to identify nia involving at least two blood cell lineages. changes, should include the assessment of the Primary graft failure is usually associated with clinical manifestation of ES, with anticipated a more significant risk of morbidity and mortality presentation 9–13 days posttransplantation: in comparison with secondary graft failure (Olsson et al. 2013; Kato et al. 2013). • Frequent temperature monitoring. • Routine skin assessment for rashes or abnormalities. 13.7 Graft Rejection • Respiratory rate, oxygen saturation, and breath sounds (for signs of pulmonary edema). The term graft rejection refers to immune- • Weight changes. mediated rejection of the donor cells by residual • Appropriate investigations are undertaken to host cells because of genetic disparity between rule out infection such as blood cultures, com- the recipient and the donor. Therefore, this term plete blood count (CBC), and chest X-ray. is only relevant to allogeneic transplants (Lowsky and Messner 2016). Immunological rejection of Nursing care should include symptom relief the hematopoietic stem cell graft is a major cause by administration of antipyretics; oxygen for of graft failure (Olsson et al. 2013). Marrow graft hypoxia; diuretics for weight/fluid gain, edema, rejection is usually defined by the absence of ascites, and effusions; and a renal dose of dopa- donor cells in a patient with pancytopenia and mine if needed. Nurses should educate patients reduced marrow cellularity (Martin 2016). and caregivers about the signs and symptoms of Chimerism studies performed by methods of ES as well as the treatment and management. FISH (in sex-mismatched transplant) or by mic- rosatellites enable early diagnosis of GF, and it could be crucial of optimizing the chance of res- 13.6 Graft Failure cuing patients with graft failure (Locatelli et al. 2014). They should be carried out routinely espe- Although incidence is relatively low, graft failure cially in patients who have inadequate marrow (GF), when it does occur, is a major complication function and might be candidates for donor lym- associated with a dismal prognosis, particularly phocyte infusion (DLI) or a second transplant in recipients of alternative donor HSCT (Ayas (Martin 2016). et al. 2015). It remains an important contributor The incidence of GF varies between different to morbidity and mortality after allogeneic transplant modalities, studies, and reports. In SCT. Recent studies indicate that patients experi- autologous transplants, a reasonable estimate of encing GF have a lower probability of survival in GF is between 1 and 3%. The incidence of GF is comparison to those with sustained engraftment higher in allogeneic transplant recipients espe- of donor cells (Olsson et al. 2013; Locatelli et al. cially if the patient receives an HLA-mismatched 2014). or T-cell-depleted graft or a single-unit CB GF is defined as the lack of hematopoietic cell transplant (Lowsky and Messner 2016). Olsson engraftment following autologous or allogeneic et al. (2013) reported a large retrospective study SCT (Lowsky and Messner 2016). It is classi- of 967 transplants performed between 1995 and cally divided into primary or secondary graft 2010 and an overall GF rate of 5.6%, with a failure. higher incidence of GF in recipients of SCT for 262 D. Hutt nonmalignant disorders. Analysis of 23,272 in a study of 709 participants with hemato- patients from the CIBMTR database produced a logical malignancies who received unrelated similar incidence of primary GF (5.5%) in donor reduced-intensity conditioning (RIC) patients with hematological malignancies after transplants that the risk of GF was comparable myeloablative conditioning (Olsson et al. 2015). between the HLA-matched and HLA- Recently, a retrospective study of a large cohort mismatched donors. However, immunological of 4684 unrelated donor HSCT in the period T-cell-mediated responses toward HLA con- (2006–2012) confirmed a low rate of graft failure tribute to primary GF as seen by the higher (3.8%) (Cluzeau et al. 2016). risk of primary GF in mismatched compared to both well-matched and partially matched unrelated grafts (Olsson et al. 2015). 13.8 Risk Factors Associated 2. ABO mismatching in the donor/recipient with Graft Failure pair – ABO incompatibility between the donor and the recipient occurs in approximately Several risk factors that are associated with GF 25% of HLA-matched transplants. Usually, it have been identified over the years (Fig. 13.1). has no influence on the neutrophil engraft- They may be related to characteristics of the ment, but certain donor/recipient mismatches graft, the patient, the donor, or the transplant pro- have been associated with posttransplant pure cedure (Olsson et al. 2015). The conditions that red cell aplasia (Lowsky and Messner 2016). are associated with an increased occurrence of Olsson et al. (2013) observed that using ABO- graft failure include: incompatible grafts is no longer a risk factor for GF. They assume that removing the red 1. HLA disparity – Earlier studies reported that cells from the graft decreases the number of an increase in the degree of HLA mismatch SC by about 30% of the original dose and this was associated with a higher risk for GF for might be the reason for GF and not the ABO siblings and unrelated grafts (Anasetti et al. incompatibility itself, although more recently, 1989). In particular, HLA class I mismatches in the largest analysis of primary GF (n = are important determinants for graft failure 23,272), Olsson et al. (2015) concluded that (Petersdorf et al. 2001). Donor selection crite- major ABO incompatibility does in fact still ria regarding HLA matching have changed remain a risk factor for primary GF. over the years, and it is difficult to compare 3. Reduced-intensity conditioning (RIC) – RIC the results of previous to current studies. HLA regimens have lower doses of chemoradiation disparity is not a consistent finding in more therapy; the host immune system may persist, recent studies. Passweg et al. (2011) reported resulting with an increased rate of GF (Mattsson et al. 2008; Olsson et al. 2013; Locatelli et al. 2014). Those regimens may •HLA disparity result in an intermediate phase, termed mixed • ABO-mismatching in chimerism, in which hematopoietic cells are the donor/recipient pair derived from both donor and recipient cells, •Reduced-intensity and thus do not fulfill the traditional definition conditioning of GF (Lowsky and Messner 2016). • Primary diagnosis 4. Diagnosis – The primary disease may affect • Graft source the probability of GF indirectly due to •Cell dose differences in the intensity of pretransplant • Graft manipulation chemotherapeutic protocols (Olsson et al. •Others 2015). Patients with severe aplastic anemia (SAA) Fig. 13.1 Risk factors for graft failure include have higher incidence of GF due to sensitiza- 13 Engraftment, Graft Failure, and Rejection 263

tion to components of red blood cell caused risk for GF (Lowsky and Messner 2016). by multiple transfusions; therefore, in SAA Various approaches to TCD are used by trans- transfusions should be minimized prior to plant centers, and they vary in the rates of GF transplant. (Kekre and Antin 2014), although Reisner Hemoglobinopathies (thalassemia, sickle- et al. (2011) emphasize in a review of the cell disease) – The incidence of GF or rejec- developments in the last 15 years that haploi- tion remains high probably due to an intact dentical transplants demonstrate how obsta- immune system. GF is particularly high in cles to successful transplantation can be patients who have heavy iron overload and overcome making full haplotype-mismatched organ damage due to excessive transfusion transplantation a clinical reality that provides and inadequate chelation treatment (Gaziev similar outcomes to transplantation from et al. 2008). matched unrelated donors (MUD). Myeloid disorders (myelodysplastic syn- Encouragingly, in recent years, the graft fail- drome (MDS) and myelofibrosis (MF)) – ure rate for haploidentical transplantation has These patients, most probably, do not receive decreased to levels comparable to those of prior intensive chemotherapy and might resist matched unrelated donors (MUD), matched donor cell engraftment, due to the presence of related donors (MRD), and mismatched unre- residual host cells (Lowsky and Messner lated donors (MMURD) (Reisner et al. 2011; 2016). In addition, patients with absence of Kekre and Antin 2014). complete remission (CR) prior to transplant 8. Other risk factors that have been identified to have more GF compared to patients in CR cause an increased risk of graft failure are (P < 0.0001) (Cluzeau et al. 2016). infections especially of viral origin, such as 5. Graft source – Graft type is the strongest risk cytomegalovirus (CMV), human herpesvirus factor in the multivariate model for primary 6 (HHV-6), and parvovirus, and the use of GF, with three times higher risk in BM com- drugs that may induce myelosuppression, pared to PB grafts (Olsson et al. 2015). such as ganciclovir (Locatelli et al. 2014). Passweg et al. (2011) described that the only characteristic that was associated with GF in Identifying and assessing the risk factors for that study was the use of BM compared with GF, prior to transplant, allow clinicians to make PB (P = .002). Unrelated CB transplants are more informed choices for their patients with associated with the highest engraftment fail- respect to BM versus PB, donor selection, immu- ure rate (Kekre and Antin 2014). nosuppressive regimens, and when to plan for a 6. Cell dose – The higher number of CD3 cells in rescue transplant (Olsson et al. 2015). PB is likely to facilitate engraftment and contributes to the lower incidence of primary GF. BM grafts with low cell dose (TNC doses 13.9 Treatment Options ≤2.4 × 108/kg) result in a 40% increase in pri- for GF mary GF. PB products per se are associated with cell doses above the threshold that would Whatever the etiology of graft failure or rejection affect primary GF, or other cell subtypes such is, it should be identified as early as possible and as T cells may be equally or more important recognized as a serious and life-threatening issue for engraftment. Nevertheless, while other requiring immediate intervention (Wolff 2002). factors seem more important for primary GF, Routine monitoring of donor cell engraftment is CD34 cell dose is probably important for sub- recommended since the evaluation of chimerism sequent secondary graft failure (Olsson et al. status can be crucial for optimizing the chance of 2015). rescuing patients from graft failure (Locatelli 7. Graft manipulation – T-cell depletion (TCD) et al. 2014). No single drug or strategy has incon- of the graft may cause a potential increased trovertibly proven to be superior to others for 264 D. Hutt reversing graft failure; current approaches to patients in that study to convert to complete limit the detrimental impact of this complication donor type. The majority of the patients required are primarily based on its prevention (Locatelli multiple administrations of DLI’s. Therefore, et al. 2014). No standard approach to the man- DLI may convert mixed donor-host chimerism to agement of graft failure exists (Hege et al. 2016), full donor chimerism as a surrogate measure to and the rescue strategies are limited (Servais prevent relapse in patients with hematological et al. 2013). The common approaches are listed malignancies (Hale and Petrovic 2014). Frugnoli below. et al. (2010) reported that escalating doses of DLI is a treatment option for emerging rejection in patients with mixed chimerism following SCT 13.9.1 Changes to Immune for β-thalassemia. The origin of lymphocytes for Suppression DLI could be either frozen aliquots collected from the donor at the time of the original harvest Early detection of decrease in donor chimerism or collected peripherally by leukapheresis or enables to modify the immunosuppressive treat- phlebotomy from the donor before DLI (Haines ment (Dubovsky et al. 1999). Withdrawal of the et al. 2015). Side effects of DLI include increased immunosuppressive drugs is usually the first risk of GvHD (Lowsky and Messner 2016) and, measure, which by itself can control leukemia in in few cases, can lead to marrow aplasia (Mattsson a limited number of patients (Yoshimi et al. et al. 2008). 2005). In case of persistent mixed chimerism after allogeneic transplant, it remains unclear if withdrawal of immunosuppressive drugs will 13.9.3 CD34+ Boost accelerate or prevent GF. The limitation of this method includes an increased risk of graft- Poor graft function is defined by cytopenia of at versus-host disease. least two lineages beyond day +28 in patients with complete or near-complete chimerism (Lowsky and Messner 2016). As manifested by 13.9.2 Donor Lymphocyte Infusion the development of a neutrophil count of <1 × 109/l (grade 4) and/or platelet count of <50 × 109/l Donor lymphocyte infusion (DLI) has a potent (grade 3, 25–50 × 109/l; grade 4, <25 × 109/l) immunological effect and has been increasingly (Frugnoli et al. 2010). Cytopenias may be due to used to treat relapse, especially molecular viral infection, medication side effect, or GvHD relapse, but may also be used to overcome rejec- (Lowsky and Messner 2016). In patients with tion in cases of decreasing donor cell chimerism continued poor graft function in the absence of (Mattsson et al. 2008). Persistent mixed chime- graft rejection, a boost of donor stem cells without rism or declining level of donor cell chimerism is additional preparative chemotherapy may improve associated with increased risk for GF both in overall function of the graft. Because this boost adult and pediatric transplant recipients. A large may induce GvHD, T-cell depletion of the stem (n = 163) prospective multicenter trial of children cells can prevent this and improve survival in with acute lymphoblastic leukemia (ALL) after some patients (Mattsson et al. 2008). CD34+- allogeneic SCT demonstrated that children who selected cell boosts without a conditioning regi- developed increased mixed chimerism were at men prior to infusion can be a valid option in higher risk of developing relapse and can be res- order to improve poor graft function, and fully cued by preemptive DLI (Bader et al. 2004). reverse graft failure, especially in patients with Administration of preemptive DLI after day +100 complete donor chimerism or predominance of to patients that were withdrawn from immuno- donor hematopoiesis (Locatelli et al. 2014; suppressive medications enabled 50% of the Servais et al. 2013). 13 Engraftment, Graft Failure, and Rejection 265

13.9.4 Autologous Backup graft. The use of the same donor was more frequent in the sibling group compared with the Infusion of autologous hematopoietic stem cells unrelated group, in a report of second transplant (HSC) that were collected and stored prior to in SAA patients. This might be due to the avail- transplant can restore hematopoiesis in case of ability of the donor for transplant (Cesaro et al. GF. The collection of autologous backup prior to 2015). However, in patients with an immune- allogeneic transplant is according to center pol- mediated graft rejection, the use of an alternative icy. In patients with hematological malignancies donor, whenever possible, is recommended or with marrow failure syndromes, the collection (Locatelli et al. 2014). PB might be the best stem of autologous backup is controversial (Lowsky cell source for salvage transplantation (Servais and Messner 2016). et al. 2013) in order to improve engraftment and thus achieve faster hematopoietic recovery (Cesaro et al. 2015). 13.9.5 Growth Factors There are no uniform criteria about the best conditioning approach for a second SCT in Administration of growth factors, after autolo- patients who have developed GF although it gous transplant, significantly shortens the time should differ from that used at the first transplant for neutrophil recovery. In case of poor graft (Mattsson et al. 2008; Cesaro et al. 2015). Many function or GF, it is a reasonable approach until a transplant teams favor using an immunosuppres- more definitive intervention is decided. Following sive non-myeloablative, reduced-intensity condi- allogeneic transplants, the role of growth factors tioning (RIC) regimen in order to avoid for patients with poor graft function or GF is unacceptable cumulative toxicities of two con- unclear. It is a reasonable approach for the man- secutive high-dose conditionings given in a short agement of low blood counts, and depending on interval of time (Remberger et al. 2011; Servais the cause, it may or may not be effective (Lowsky et al. 2013; Ferrà et al. 2015; Cesaro et al. 2015; and Messner 2016). Certainly, hematopoietic Cluzeau et al. 2016). The optimal reconditioning growth factors should be considered in the man- regimen after graft failure still needs to be agement of graft dysfunction, especially with defined, and standardized protocols are lacking partial donor chimerism (Wolff 2002). (Teltschik et al. 2016). In general, a second unrelated HSCT is considered a risky procedure with a lower probabil- 13.9.6 Regrafting ity of long-term survival on account of a high incidence of GF, noninfectious organ toxicity, A second allogeneic transplant is the only poten- and infectious complications. This negative out- tial long-term curative option for patients with come is also influenced by the type of underlying GF and rejection (Remberger et al. 2011; Servais disease. However, second transplant using related et al. 2013; Locatelli et al. 2014; Cesaro et al. and unrelated donors in SAA patients is feasible 2015). There are no conclusive data for support- with a good chance of long-term overall survival ing the choice of using either the same donor of in more than 60% of cases (Cesaro et al. 2015). the first allograft or an alternative donor Second transplant should be considered espe- (Mattsson et al. 2008; Locatelli et al. 2014). cially for patients with nonmalignant diseases Different studies recommend a variety of options (Remberger et al. 2011). depending on the availability of a donor, the In conclusion, GF is a rare complication after patient’s clinical condition, and the underlying allogeneic transplant but is associated with poor disease. Gaziev et al. (2008) recommend using outcome. Early identification of the patients at the initial donor for second transplant for patients risk and aggressive intervention could rescue or with thalassemia recurrence following the first prevent some patients from developing GF. 266 D. Hutt

13.10 Pediatric Considerations graft failure or rejection. Satwani et al. (2013) reported a large study of reduced-toxicity condi- The aim of allogeneic transplant in nonmalig- tioning allo-SCT, using both related and unre- nant disease is to achieve sustained engraftment lated allogeneic stem cell sources in pediatric in order to improve the hematopoietic function, recipients, with both malignant and nonmalig- to correct the immunocompetence, and/or to nant diseases. Primary GF occurred in 16 increase or normalize the respective enzyme patients (16%) all in unrelated CBT recipients shortage (Bader et al. 2005). Children who may and none in MUD/MSD graft recipients. have more than 60- to 70-year life expectancy Chemotherapy naivety was the only significant after undergoing allogeneic transplant may ben- risk factor for primary GF. In a single-center efit from the approach of reduced-intensity con- study by Balashov et al. (2015), the incidence of ditioning (RIC) or reduced-toxicity conditioning primary and secondary GF in primary immuno- regimens prior to transplant versus myeloabla- deficient patients undergoing MUD and haploi- tive conditioning. This is especially true in those dentical transplants was 27% (10 out of 37 with nonmalignant diseases and those with patients). This accrued in patients that were ini- malignant diseases that may have a profound tially in high risk for graft failure, such as graft-versus-tumor effect (Satwani et al. 2013). chronic granulomatous disease (CGD) and con- In the last several years, the use of RIC has genital neutropenia. expanded from adults with high indices of However, as with the adult patients, evidence comorbidity to candidates without comorbidi- on the optimal management of GF in children is ties (Satwani et al. 2013) as well as to the pedi- limited; therefore, analysis of pediatric GF is atric population. In pediatric nonmalignant important in order to establish a standard treat- diseases, RIC is an attractive alternative with ment strategy against this rare event (Kato et al. the potential for decreased regimen-related tox- 2013). The case report (Fig. 13.2) demonstrates icities, lower incidence of long-term complica- the process of graft rejection, its consequences, tions, as well as preserving fertility. Graft and treatment options. rejection rates are low, especially when stable mixed chimerism is curative if ensured in the lineage that corrects function (Madden et al. 13.11 Nursing Considerations 2016). Graft rejection, in children with inborn errors of metabolism undergoing RIC trans- When a patient fails to engraft, he or she faces a plants, still remains an obstacle to the success of life-threatening situation. Patients experiencing the transplant since they are immunocompetent disappointment and fear from the failure of the (Kato et al. 2016). The incidence of GF in chil- transplant might express feelings of anger, dren varies in the different studies. In a large betrayal, grief, depression, and hopelessness. report of 240 classical SCID patients who Similarly, healthcare personnel involved in the received allogeneic transplant between 2000 patient’s care may also feel a sense of failure and and 2009 by Pai et al. (2014), 18% of the patients grief (Wilson and Sylvanus 2005). General nurs- received a boost, an additional transplant from ing care of patients experiencing GF does not dif- the same donor without conditioning (23 chil- fer from the treatment during the neutropenic dren), or a second transplant from a different period of the transplant, as described in Chap. 7, donor (with or without conditioning) or from although nurses should routinely monitor the the same donor with conditioning (34 children), patient engraftment by daily CBC during the and 11 children received both a boost and a sec- engraftment phase, as it enables to assess for ond transplant at 5 years. A retrospective study signs of GF as well as delayed engraftment. by Mitchell et al. (2013) of 135 children with Chimerism analysis should be evaluated fre- primary immunodeficiency reported that 18 quently as per local policy especially in patients patients (13%) required a second SCT due to that are at risk for GF (Fig. 13.3). 13 Engraftment, Graft Failure, and Rejection 267

A 13 month old baby was transferred from another hospital to a specialist unit due to recurrent infections since he was one month old. He initially presented with a necrotic infected wound after a supra pubic aspiration and an extremely swollen belly. Family history: parents are cousins, have 6 children, one died of infection when he was a few months old.

The baby was diagnosed with Leukocyte adhesion deficiency-1 (LAD1), CD11 & CD18 deficiency and he underwent a BM transplant on 13.7.14 from his MRD sister. Conditioning regimen included Fludarabine, Treosulfan and ATG. Stem cell engraftment was on day +17. On day + 24 due to decreased donor chimerism, from 63% to 20%, Cyclosporine was stopped. Three days later on day + 27 he developed skin rash and was diagnosed with acute GvHD. He went on to develop severe acute GvHD (grade III-IV) involving skin, liver and GI tract. GvHD was treated with Solumedrol, CSA, ATG and one dose of mesenchimal stem cells (on day +56). GvHD improved and at discharge, two months post-transplant he had mixed chimerism of 43% donor cells according to XX FISH analysis. Subsequently donor chimerism continued to decrease and at one year post transplant was 3.5% donor cells by XX FISH analysis. CD 11 & CD 18 was measured only on lymphocytes and not on neutrophils (split chimerism). During that year he suffered again from recurrent infections. He underwent a second allogeneic BM transplant on 11.10.15 from another MRD sister. Conditioning therapy included Busulfan & Fludarabine. Engraftment was on day +14 and chimerism was 60% donor cells (XX). Except for CVC sepsis and removal of the central line the transplant went very well and he was discharged home on day +24 in a very good overall condition.

Currently, 11 months post second allogeneic transplant he is in a good general condition. He has stable mixed chimerism of 87% of donor cells (XX). During that period he was at home with no infections, no GvHD and no other complications post-transplant.

This case demonstrates two important points: discontinuation of cyclosporine does not always reverse the situation of increased mixed chimerism and carries the risk of developing severe GvHD. Second allogeneic transplant is feasible with good outcome.

Fig. 13.2 Case report

Routine monitoring of Equally important to the physical care is the patient engraftment by emotional support for the patient and family daily complete blood experiencing this devastating, disappointing, and count life-threatening situation. Nurses can help to Serial Chimerism testing reduce patients’ fears by providing accurate, Emotional support for timely information about procedures, symptoms, patient experiencing graft and feelings that the transplant recipient may failure experience or is experiencing. Nurses should pro- Fig. 13.3 Be aware of: vide support and education on the diagnosis of 268 D. Hutt

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Michelle Kenyon, John Murray, Barry Quinn, Diana Greenfield, and Eugenia Trigoso

Abstract Allogeneic stem cell transplantation was successfully performed in 1968, and its use has grown significantly over the past five decades with the total number now exceeding 1 million patients. HSCT is a curative treatment for many haematological cancers and other disorders. Almost 40,000 HSCT procedures are performed Europe-wide per annum (Passweg et al., Bone Marrow Transplant, 2016), and with a 5-year survival around 50% (Friedrichs, Lancet Oncol 11(4):331–338, 2010), the number of transplant recipients achieving ‘long-term survival’ and with late effects directly related to their treatment (Majhail et al., Hematol oncol Stem Cell Ther 5(1):1–30, 2012) is increasing. This growth in survivors is the result of improvements in transplant knowledge and expertise, refinements to conditioning regimes, developments in supportive care and increased numbers of procedures due to broadening transplant indications. The most common cause of death after transplant is relapsed disease. Yet, even without disease relapse, long-term survival is complex for many as other causes of mortality such as graft versus host disease (GvHD), infection, second malignancy, respiratory disease and cardiovascular disease (CVD) (Savani et al., 2011) prove difficult to address.

M. Kenyon (*) D. Greenfield Department of Haematological Medicine, Department of Oncology and Metabolism, King’s College Hospital NHS Foundation Trust, Sheffield Teaching Hospital NHS Foundation Trust, London, UK University of Sheffield, Sheffield, UK e-mail: [email protected] E. Trigoso J. Murray Paeidatric Transplant Unit, Hospital Universitario Haematology and Transplant Unit, The Christie NHS y Politécnico LA FE, Valencia, Spain Foundation Trust, Manchester, UK B. Quinn Palliative Care Department, Woking and Sam Beare Hospices, The Goldsworth Park Centre, Woking, Surrey, UK

Recovery post-HSCT is challenging, lasting several months to years. These individuals are susceptible to the development of post-treatment physical and psychological sequelae years to decades after completion of treatment leading to a reduced life expectancy with greater morbidity when compared to an age-adjusted population (Socié et al., N Engl J Med 341:14–21, 1999). Survivors with late effects experience significantly poorer physical and mental health, report more unmet needs for care and have significantly greater use of health services compared with survivors without late effects (Treanor et al., Psychooncology 22(11):2428–2435, 2013). Furthermore, as the number of survivors continues to grow, their long- term health problems and subsequent needs demand increasing attention. The unpredictable, complex and multifactorial nature of these long- term and late effects in HSCT survivors means that patients require regular life-long assessment guided by rigorous protocols. However, it is important to remember that even using standardised protocols, these should be different for adults and children and the resulting care must be tailored to the needs of the individual survivor. And finally, further consideration is needed for the growing number of young people and adult survivors in long-term follow-up who have been treated in childhood and transitioned into adult long-term follow-up care.

Keywords Late effects • Survivorship • Survivors • Follow-up

14.1 Principles of Care priate services that will better meet the needs of future survivors. Protocol-led assessment and treatment is *Late effect: A health problem that occurs included in the current FACT-JACIE standards months or years after a disease is diagnosed or (version 6), which has evolved the standard of after treatment has been administered. Late care recommending the assessment of recipi- effects may be caused by the primary disease or ents for evidence of acute and chronic GVHD, its treatment and may include physical, mental or need for vaccinations and post-transplant late social problems and/or secondary cancers. effects. There should be policies and procedures in place for monitoring by appropriate specialists of recipi- 14.2 Survivorship and Quality ents for post-transplant late effects, including at a of Life minimum endocrine and reproductive function, osteoporosis, cardiovascular risk factors, respiratory function, chronic renal impairment, secondary While there are many definitions of survivorship, cancers, and the growth and development of pedi- it is widely accepted that a survivor is anyone liv- atric patients. (Standard B7.6.8) ing after a diagnosis of cancer or ‘living with and beyond cancer’. A further benefit of life-long survivorship care Survivorship includes ‘those who are undergo- is the acquisition of knowledge and understanding primary treatment, those who are in remission ing through data collection and analysis which in following treatment, those who are cured and those turn facilitates the design and delivery of appro- with active or advanced disease’ (DoH 2010). 14 Late Effects and Long-Term Follow-Up 273

By developing and implementing strategies to survivors through the routine use of patient- improve the care and support for HSCT survi- reported outcome measures (PROMs) in follow- vors, we will also improve their quality of life up services. Quality of life (QoL) is an important and experience of care. outcome measure following HSCT. Treatment- There are a broad range of issues experienced specific QoL tools exist and have been validated by HSCT survivors which are detrimental to in patients receiving haematopoietic stem cell overall quality of life (QoL) and have been transplant. reported in the literature. Instruments for assessing QoL can be general Unmet physical or psychological needs are or specific to a certain disease or treatment. A reported in 60% of cancer survivors. Beyond number of cancer-specific tools (QLQ – LEU, the first post-HSCT year, a fifth report psycho- EORTC SF 36, FACT-G/ FACT-BMT) exist and social difficulties including fatigue, social can be seen in publications of large-scale studies. reintegration, finance and employment. A third They are often holistic, assessing different dimen- worry about the future and their health (Baker sions of well-being, such as physical, emotional, et al. 1999; Andrykowski et al. 2005; Gielissen social/family and functional. Many of the com- et al. 2006). monly used scales such as EORTC and FACT are Finance, employment and education are self-complete and produce a numeric score from leading survivor concerns. The economic cost which an inference on the relative QoL can be of cancer is a substantial personal and societal drawn. problem; 92% of sufferers lose income, These holistic assessments can be used to col- impacting adversely on QoL for 40% (Bieri lect information on individuals at set time points et al. 2008). These are among the major chal- during treatment and recovery and also can lenges that significantly hinder the cancer increase our knowledge of our patients as a group patient survivorship transition from treatment or groups. QoL data can help us to understand the phase to reintegration phase and limit the post- differences between groups, e.g. comparing QoL HSCT potential for personal growth and in male versus female recipients or haplo- fulfillment. identical versus cord recipients. Work and education are immensely important Standardised assessment tools can reveal to cancer survivors (Snyder 2002) and have information in certain groups or individuals that health benefits, and interventions addressing may not have been previously identified through return to work are cost-effective (Waddell and conventional outpatient consultation alone. This Burton 2006). Reintegrated survivors are more can lead to increases in referrals to other services likely to self-manage (Richards 2013), make a such as counselling, assisted conception, sexual positive contribution to self and society, depend dysfunction, social work, etc. less on the state financially and potentially reduce At a local level, this increase in referrals can healthcare costs. have resource implications, but it can also lead to: A range of psychological and psychosocial interventions including education, exercise, • Formalising referral pathways counselling, cognitive behavioural therapy (CBT) • Cultivating interest and expertise in certain and psychotherapy have been investigated, aim- areas ing to address survivor concerns and improve • Developing services that meet the unmet overall quality of life. holistic needs of the patients

Furthermore, this information can be used to: 14.2.1 Quality of Life Assessment • Identify how quality of life can be improved There is a new emphasis on understanding and for individuals and to help plan holistic care monitoring the concerns and outcomes for cancer for individual patients 274 M. Kenyon et al.

• Assess quality of care in individual services 14.2.2.2 Psychological Distress • Measure progress on survivorship care across It is known that 5–19% of HSCT survivors networks or countries exhibit symptoms that are consistent with post- traumatic stress disorder (PTSD). In those with- This holistic approach to assessment identifies out PTSD, four out of ten report clinically individual information needs. These needs can be significant psychological distress at an average of met through a discussion with a healthcare pro- 3.4 years post-transplant. The same study found fessional, which is supported by written or multi- that there was no difference by age, gender, trans- media materials and offers signposting for plant type or time following transplant (Rusiewicz individuals to high-quality information and sup- et al. 2008). port (Table 14.1). The table below illustrates the most common issues expressed through assess- 14.2.2.3 Return to Work ment. They are multidimensional in nature repre- HSCT survivors return to work despite ongoing senting psychological, physical and functional physical and psychological symptoms. Younger concerns. age and higher levels of education have been linked to a higher probability of post-transplant employment. Those who are unsuccessful in 14.2.2 Common Post-HSCT Concerns returning to work have poorer physical, cognitive and social functioning and report more pain, 14.2.2.1 Physical Well-Being sleep disorders and distress (Mosher et al. 2009). Most studies found that survivors report resump- While return to work or education is important tion of routine physical activities but describe a to survivors, in guiding our patients, it is essential greater number of medical problems (Mosher to consider the following: et al. 2009). Fatigue is one of the most commonly reported concerns, and many HSCT patients are • Type of work dissatisfied with their energy levels many years –– Physical demand after treatment. Providing information materials –– Environment and education on fatigue management is a key –– Routine area where nurses can positively influence this –– Hours troubling issue (Anderson et al. 2007; Andorsky • Support of employer et al. 2006). –– Phased return is usually the optimal way of enabling people to return to work progressively Table 14.1 Top 10 common concerns (www.eHNA/ • Financial pressure Macmillan.org.uk analysis 2015) –– Many people need to return to work due to 1. Worry, fear or anxiety mounting financial difficulties 2. Tiredness, exhaustion or fatigue • Self-esteem 3. Sleep problems/ nightmares –– Some people feel ‘lost’ without their work 4. Pain identity and feel a sense of urgency to 5. Eating or appetite return 6. Anger or frustration 7. Getting around (walking) 8. Memory or concentration 14.2.2.4 Sexuality 9. Hot flushes/ sweating Evidence suggests that sexual function is one of 10. Sore or dry mouth the most prevalent and persistent long-term con- Accessed Aug 2016 cerns after HSCT. 14 Late Effects and Long-Term Follow-Up 275

Fig. 14.1 Range of concerns in relation to Function sexual response cycle Desire • Atrophic vaginitis (Adapted from • Relationship problems Greenfield 2012 • Erectile dysfunction www.ebmt.org accessed • Body image • Vaginismus Sept 2016) • Self esteem •Dyspareunia • Fatigue Orgasm • Hypoactive sexual desire disorder • Anorgasmia • Low libido •Changes in orgasm Difficulties with arousal/ excitement • Premature ejaculation • Hormonal changes General • Infertility • Chronic GvHD • Fatigue and weakness • Infections

Despite its prevalence and the range of con- ners, most people will have sexual needs and cerns that can be experienced across the entire desires throughout their life (Osho 2002; sexual response cycle (Fig. 14.1), sexual func- Williams 2003; Quinn 2010). There is a danger tion issues are under-reported. However, a that in seeing sexuality as merely a physical range of sexual concerns have been described expression that the haematology and transplant with a tendency for women to report more care team may fail to see that sexuality is about problems than men and women continue to the whole person including how they relate to describe more sexual concerns a number of others in an intimate way. Whether the patient is years post-transplant (Mosher et al. 2009). or is not sexually active during the prolonged Sexual function is typically multifactorial in treatment period before, during and after trans- origin with endocrine, mechanical and psycho- plant, patients will need support and advice from logical factors. People may benefit from relax- the team caring for them, on sexual changes, ation, massage therapy, aromatherapy or other choices and concerns. complementary procedures. Those that resume Sex and sexuality are largely seen as a very pri- sexual relations in the first post-transplant year vate matter, and a patient and/or partner may be tend to experience fewer long-term issues (Jean reluctant to talk about their concerns or unexpected and Syrjala 2009). changes to a member of the transplant team who appear busy dealing with other aspects of the treatment process (Schover 1997; Twigg 2000; Mulhall 14.3 Addressing Sexuality 2008). It is important that the team make it clear that they are there to help with sexual changes and Sexuality is a part of each person’s life and iden- worries and to know what help is available. tity and is much more than the physical act of There may be a misconception from some mem- sexual intercourse or sexual expression. It is also bers of the transplant team that a person undergoing about less obvious components including how a stem cell transplant will not have an interest in sex. people perceive themselves as sexual beings and In reality, whether a person is in a relationship or the need to be recognised, connected with, loved not, human beings are born as sexual human beings and cared for by others. Whether the person is in and will die as sexual human beings (Quinn 2010). a relationship (gay, lesbian, heterosexual), is What that means for each person and how they will single or enjoys sex with one or multiple part- express that need throughout periods of their life 276 M. Kenyon et al. will change. For some, people being sexually inti- and where to access practical and expert help, if mate with their partner during the treatment and required (Schover 1997; Quinn 2010). transplant process may bring comfort, reassurance While some of the changes to the person’s and hope amidst ongoing uncertainty and change, sexuality may appear obvious, many of the more while others will have no interest in being sexually profound changes that a person may face and the active. However, feeling loved, accepted and cared impact they have on an individual are often hid- for as one faces the uncertainty of transplantation den and not so obvious to others (Murphy 1990). may bring great comfort to the person and their Many of the treatments and changes required in partner (Schover 1997). the transplant process can affect a person’s sexu- In a busy haematology or transplant setting, ality including how they relate to their own body the team can help to facilitate times of privacy and to others (Schover 1997). when the individual can be alone or with their It is worth considering the impact of other co- partner if this is what they wish. The transplant morbidities the person may have and the treat- team who recognise the importance of these inti- ments required for these conditions and how mate moments can often organise treatments and these too may affect their sexuality and their abil- interventions, at less acute points in the trans- ity to have sex. In addressing sexual concerns, the plant process, in order to provide these moments transplant team can be proactive in supporting or times of privacy. the person with body changes and psychological The diagnosis of cancer or indeed any illness concerns that may be interfering with their sexual and the treatments and changes required may identity and sexual expression. have a profound impact on the person and part- Members of the transplant team who are aware ner, affecting them physically, emotionally, of the possible impact that treatments, the trans- socially and spiritually (Murphy 1990; plant protocol and supportive medications may Brandeburg et al. 2010). For example, facing the have on a person’s sexuality will be better able to reality of temporary or permanent infertility and speak to the person sensitively, honestly and the multiple body and life changes secondary to clearly before the commencement of treatment. disease and treatments can affect a person’s sex- These issues should be an important part of the ual identity. The physical and psychological preparation for treatment and transplantation demands of dealing with a serious illness, the (Quinn 2010). Support may take the form of transplant demands and setting can interfere with practical advice, including adjusting to an altered the human sexual response cycle (desire/interest, sex life during treatment, adequate pain/symp- arousal, readiness (penetration), orgasm and res- tom control, comfortable positioning during sex, olution, satisfaction). Any of these points on the contraception, providing private moments, advice response cycle may be affected but can be sensi- on sexual aids and medical treatments or simply tively addressed (Schover 1997). The team can an opportunity to talk about concerns and fears sensitively support the person and the partner (Table 14.2). Practical support and guidance can through the transplantation process and treat- help the person returning to sexual activity after ments mindful of the impact on the person’s sex- transplantation or simply regaining confidence in ual being. This includes providing accurate being sexually expressive again. information on potential sexual changes that may Many of the treatment agents (chemotherapy, occur, practical advice on the choice of treatment targeted therapies and radiation) used in the field of and interventions and a listening ear. Many sex- haematology and transplantation are known to ual concerns arising in the haematology and cause specific problems which can lead to lower sex transplant setting can be resolved or certainly drive, vaginal dryness (which may cause pain dur- reduced by a member of the team simply listening intercourse), erection concerns, ejaculation and ing to the person’s concerns and knowing how orgasm difficulties (which may lead to loss of con- 14 Late Effects and Long-Term Follow-Up 277

Table 14.2 Providing support (Quinn 2010) dental dams) (Quinn 2010). This is to protect the Sensitively listening and addressing fears patient’s partner from the minimal risk of irrita- Creating time and privacy for couples to be alone tion caused by a small amount of chemotherapy Providing adequate symptom relief agents remaining in bodily fluids such as semen, Support with body changes urine and rectal and vaginal secretions. These Encouraging couples/sexual partners to talk to one barrier methods may also reduce the risk of infec- another tion especially if the patient is at risk of neutrope- Advice on creative foreplay (hugging, stroking, having a shared bath, kissing, mutual masturbation) nia and prolonged immunosuppression. While Advice on alternative positioning individuals are advised to take steps to prevent Alternatives to sexual penetration infection, rarely should this prevent the person Guidance on sexual aids (dilators, vacuum pumps, from enjoying sex with a partner. Occasionally dildo, toys) the team may learn of partners no longer sleeping Guidance on medical treatments (oral, injection, in the same bed for fear of contamination to their pellets) partner; the team can reassure the couple that this Counselling is not necessary and they can continue with their usual sleeping arrangements. The team can also be sensitive to the demands made and the confidence and lack of sexual enjoyment) (Brandenburg cerns that arise on the person or couple due to the et al. 2010). Some drugs including the vinca alka- transplant process. loids and some targeted therapies may cause nerve Other sexual difficulties may arise due to body damage giving rise to erectile dysfunction and to changes and other symptoms including weight ejaculation and orgasm difficulties. Following total gain or loss, skin changes, graft versus host dis- body irradiation, a small number of patients may ease, constipation, diarrhoea, nausea, fatigue, oral experience damage to the nerve, vascular and mus- complications, depression and anxiety. The per- cle tissue giving rise to possible erectile difficulties, son’s confidence in being sexual active may be including the inability to get or maintain an erection affected by the unwanted body changes that occur. suitable for sexual penetration or vaginal changes Poorly controlled symptoms, such as nausea, including stenosis and/or dryness which may cause vomiting, constipation, diarrhoea, loss of appetite pain during sexual intercourse. and extreme tiredness caused by the treatments Women may benefit from the team explaining and the underlying disease, may affect the person the use of vaginal lubricants and dilation to pre- physically and psychologically. Carefully assess- vent vaginal stenosis. Men may require support ing and managing these symptoms may enable in exploring treatment options for erectile con- the person to enjoy the comfort of sexual intimacy cerns. These complications may require interven- with their partner (Schover 1997). tions including advice on oral medications Some of the supportive treatments used in the (sildenafil, tadalafil, vardenafil), pellet (intraure- transplant setting while bringing relief to these thral alprostadil) (MUSE), injection (intracaver- unpleasant symptoms can also give rise to sexual nosal alprostadil) and appliances (vacuum difficulties. Pain relief including opiates may give device) to address erectile dysfunction. Hormone rise to uncomfortable constipation, tiredness, nau- replacement therapy unless contraindicated may sea and mucosal dryness leading to painful vagina/ have a place, an opportunity to talk through fears anal intercourse and erectile dysfunction. Some and concerns and/or psychosexual therapy sup- anti-sickness medication while providing neces- port (Brandenburg et al. 2010). sary relief from nausea can effect erectile func- If patients are sexually active during treat- tioning. While antianxiety and anti-depressant ment, the team should advise them to use some mediations help with stress and anxiety, these form of barrier method (condoms, femidoms, medications can lead to a lower sex drive, erectile 278 M. Kenyon et al. dysfunction, ejaculatory and orgasm difficulties both in the hospital and community, ensuring the and vaginal dryness (Quinn 2010). person has support that they can access. Individuals Many of the chemotherapy agents used in the and couples may need support and advice over their haematology and transplant setting can affect the concerns of having passed or passing on genes to person’s fertility including alkylating agents their children predisposing them to a higher risk of which are known to cause most damage, result- cancer (Quinn 2010). ing in either temporary or permanent infertility. Some patients will be at risk of bleeding due For many young patients, this may be the first to thrombocytopenia and should be advised to time that they have had to consider the possibility continue a sex life if they so wish but to be of planning children, and this will require support aware of reducing trauma during sex, including from the team, family and friends. Facing the vaginal, oral and anal intercourse. Localised possibility of being infertile can have a profound trauma may be reduced by using a more gentle effect on how the person feels about themselves thrusting movement during penetration or and their place in the world. masturbation. Patients will be advised not to plan children Many of the drugs used in the transplant set- during the treatment as the drugs and the demand- ting may bring on the early onset of menopause ing treatment requirements will affect the devel- and the associated symptoms which can cause opment of the embryo leading to foetal defects great distress. Medically induced menopause and miscarriage. For some people/couples, it brings unwanted symptoms including vaginal may be very painful having to put their plans for dryness, mood changes, hot flushes, low confi- a family on hold during the treatment and trans- dence and sometimes a lack of interest in sex. plant period. Occasionally a woman may dis- Women may find it more difficult to achieve a cover a cancer diagnosis during her pregnancy satisfactory orgasm (Brandenburg et al. 2010). It and may be advised to undergo a medical termi- is important that women and their partners are nation because the pregnancy will not be viable forewarned about these symptoms but also to and/or in order to proceed with necessary treat- ensure these issues are revisited sensitively dur- ment. This can be a very difficult time for the ing and after treatment. woman and her partner; sometimes the full Men and women may need support and advice impact of this loss becomes more apparent fol- on finding alternative ways to express themselves lowing the completion of treatment. sexually both during and after transplant. Although The team can be there to talk about the impact of men and women may have a reduced interest in treatment and to support and advice on the possible sex for a period of time, their interest in returning options available to support fertility (Schover 1997). to a sexually active relationship may return in For men this may include sperm banking and the weeks and months following the transplant. possibility of cryopreservation of testicular tissue, Practical measures including the careful generally used for younger patients. For women, this positioning of medical devices may enable a may include cryopreservation of embryos or eggs person to be held and hugged during prolonged and ovarian preservation. In some cases, the urgency hospitalisation. These measures also include of treatment may mean that fertility-saving options reducing clutter around the persons’ bed so are not possible. During the transplant process, the that their partner can be closer to them and focus for everyone including the patient may be on critically reviewing and removing any unnec- treating the disease, and the reality of being infertile essary infection control measures that may act becomes more important in the months and years as a barrier to intimacy. Practical advice on following transplantation. This can be extremely dif- how to deal with medical devices including ficult for patients who are beginning new relation- urinary catheters and emptying bowels and/or ships and have to disclose this to their new partner. bladder before having sex can provide greater This reality can be addressed at follow-up clinics comfort. While the person may lack the energy 14 Late Effects and Long-Term Follow-Up 279 to participate in sexual intercourse, they may Important components for successful deliv- wish to try alternatives including cuddling, ery of LE service include: hugging, lying in bed together, increased time • Assessment tools incorporating clinical and for foreplay, sharing a bath or shower together psychosocial late effects and sharing quiet and private moments together • Availability of a range of medical and allied (Schover 1997). health specialists Although the sexual needs of patients in the • Access to psychological services highly technically setting of transplantation can • Implementation of second malignancy screen- sometimes be overlooked, the ability to be inti- ing, e.g. mammography and PAP smear mate with a partner might be a welcome relief from some of the demands made on the person by the transplant process. 14.4.3 Opportunities for Nurses

14.4 Summary Nurses have a significant role in delivering and/or coordinating post-HSCT care for patients. 14.4.1 Wider Impact Nurses have an opportunity to: of Survivorship Care • Identify useful resources for patients Carers of those with cancer report high levels of • Develop post-HSCT services for patients emotional distress. The psychological difficul- • Ensure that care meets the needs and concerns ties that carers report can be prolonged. This is of patients exacerbated by their own lifestyle and role dis- • Develop innovative roles as individual practi- ruption; carers report financial difficulties and tioner and as part of a wider multidisciplinary are often unable to work for periods themselves team or have to give up work altogether due to their • Develop the evidence base by leading/partici- ‘carer role’ commitment. It is important to rec- pating in survivorship research ognise these issues and offer carers support and • Develop creative ways of working and provid- information. ing suitable clinical and supportive care

14.4.2 Models of Long-Term 14.5 Post-transplant Follow-Up Complications and Surveillance It is widely recognised that HSCT recipients require structured long-term follow-up and screening to Standardisation of follow-up protocols is impor- reduce the morbidity and mortality demonstrated in tant to prevent important tests being overlooked those considered as long-term survivors. or being duplicated unnecessarily. There are clear guidelines around screening requirements (Majhail et al. 2012) but little direction on how these might best be implemented in a 14.5.1 Second Malignancies late effects (LE) service. A survey of UK transplant centres identified that all had a LE service There is an increased risk of developing a second and most had a standard operating procedure out- solid cancer post-transplant in the range of 2–6% lining its process but identified wide variability in at 10 years. Data suggests that second solid can- almost every aspect of the late effects services cers occur twice as frequently in the transplant (Hamblin et al. 2017). population than in the general public with this 280 M. Kenyon et al. increasing to threefold at 15 years. There are sev- consumption and taking care of their skin in the eral risk factors that may contribute to the devel- sun will all have beneficial effects. opment of a second solid cancer (Curtis et al. 1997): 14.5.2 Systematic Post-transplant • Total body irradiation Screening and Investigations • Primary disease • Male sex A specific screening plan for transplant patients has • Pre-transplant conditioning been published by Majhail et al. (2012) on behalf • Genetic predisposition contributing to initial of the Center for International Blood and Marrow cancer and subsequent malignancy Transplant Research (DeFilipp et al. 2016), American Society for Blood and Marrow Clinicians have long been aware that radiation Transplantation (ASBMT), European Group for leads to second solid cancers with a latent period Blood and Marrow Transplantation (EBMT), Asia- of approximately 3–5 years before developing a Pacific Blood and Marrow Transplantation Group malignancy (Rizzo et al. 2009). The risk for non- (APBMT), Bone Marrow Transplant Society of squamous cell cancer is higher in younger Australia and New Zealand (BMTSANZ), East patients (especially those under 30 years) at ten Mediterranean Blood and Marrow Transplantation times that of nonirradiated patients. Other can- Group (EMBMT) and Sociedade Brasileira de cers such as breast, thyroid, brain, central ner- Transplante de Medula Ossea (SBTMO). vous system, bone and connective tissue and These comprehensive guidelines written by an melanoma are all related to radiation exposure. expert group in 2006 and updated in 2011 pro- Screening for some of these cancers is available vide a consensus for screening and preventative and aids in early diagnosis (Savani et al., 2011). measures for autologous and allogeneic stem cell All patients should be enrolled into national transplant patients who have survived for at least cancer screening programmes for breast, cervi- 6 months following transplant. There are also cal, colon and skin cancer. Particular attention patient versions of the guidelines that can be should be paid to women who receive radiation found at www.BeTheMatch.org/Patient (Majhail to their chest >800cGy to ensure they follow et al. 2012). guidelines laid down for paediatric survivors. The recommendations take each system and These state that annual mammogram screening describe the late complication and the general should begin at 25 years of age or 8 years after risk factors for developing them. It goes on to exposure whichever occurs later. Women should suggest the monitoring tests and preventative have PAP smears annually to three yearly, and measures that should be undertaken supported by those with GvHD should be screened annually. associated evidence from randomised trials and if Patients should have at least six monthly dental none is available from retrospective studies or reviews and an annual thyroid assessment, and if from expert opinion when no evidence exists at any thyroid nodule is identified, imaging and all (Majhail et al. 2012). potential biopsy should be undertaken (Savani Infection and revaccination are described else- et al. 2011). where in this textbook, but regardless of time At the initial consent for transplant consulta- since transplant, all presentations of infection tion, patients should be counselled about the should be thoroughly and rigorously investigated future potential risks of second malignancy. This and treated aggressively. Revaccination should is an ideal time to engage with the patient and be initiated as per the widely accepted Tomblyn help them make changes to their lifestyle that et al., (2009) guidelines. will have an impact on their lives moving for- Majhail et al. (2012) elegantly describe the ward. Smoking cessation, a healthy balanced general follow-up that a transplant patient should diet, taking regular exercise, reducing alcohol receive in a systematic order and this can be 14 Late Effects and Long-Term Follow-Up 281 applied fairly easily in the clinic environment. Table 14.3 Recommended screening and prevention Below is a concise form of the guidance. Please (Majhail et al. 2012) printed with permission from Elsevier Inc refer to Table 14.3 for the recommended screening guidelines and the full publication for further Recommended screening/ 6 1 prevention months year Annually details. Immunity Encapsulated organism 2 2 2 prophylaxis 14.5.3 Ocular Screening PCP prophylaxis 1 2 2 CMV testing 2 2 2 Ocular screening should commence at 6 months Immunisations 1 1 1 and continue on an annual basis for assessment of Ocular keratoconjunctivitis sicca syndrome, cataracts Ocular clinical symptom 1 1 1 and ischaemic microvascular retinopathy. Sicca evaluation syndrome (vaginitis, dry skin and xerostomia) Ocular fundus exam + 1 + Oral complications occur in 10–40% of patients. Clinical assessment 1 1 1 Dental assessment + 1 1 Respiratory 14.5.4 Oral Examination Clinical pulmonary 1 1 1 assessment The oral cavity can be affected with chronic graft Smoking tobacco 1 1 1 versus host disease (cGvHD) and, even in the avoidance absence of cGvHD, requires repeated assessment Pulmonary function testing + + + from 6 months especially if there is a sign of Chest radiography + + + xerostomia (dry mouth) as this increases the risk Cardiovascular of dental caries. Good oral hygiene and treatment Cardiovascular risk-factor + 1 1 assessment of oral infections should be initiated promptly on Liver recognition. There is an increased risk of second- Liver function testing 1 1 + ary oral squamous cell carcinoma in those with Serum ferritin testing 1 + oral cGvHD, and patients should be aware to Kidney raise concerns. Blood pressure screening 1 1 1 Urine protein screening 1 1 1 BUN/creatinine testing 1 1 1 14.5.5 Pulmonary Screening Muscle and connective tissue Evaluation for muscle 2 2 2 Respiratory problems include bronchiolitis oblit- weakness erans syndrome (BOS), idiopathic pneumonia Physical activity 1 1 1 counselling syndrome (also known as interstitial pneumoni- Skeletal tis), cryptogenic organising pneumonia (COP) Bone density testing (adult 1 + and sinopulmonary infections. Clinical review at women, all allogeneic 6 months and annually with physical examina- transplantation recipients tion and history should be performed. Counselling and patients at high risk with regard to smoking cessation is extremely for bone loss) Nervous system important. If the patient has GvHD, then it may Neurologic clinical + 1 1 be appropriate to undertake pulmonary function evaluation testing, and if there is evidence of lung involve- Evaluate for cognitive 1 1 ment, then imaging such as inspiratory and expi- development ratory CT for air trapping to exclude BOS is Endocrine indicated. (continued) 282 M. Kenyon et al.

Table 14.3 (continued) and ECHO and referral to cardiology may be Recommended screening/ 6 1 needed. prevention months year Annually Thyroid function testing 1 1 Growth velocity in 1 1 14.5.7 Hepatic Complications children Gonadal function 1 1 1 assessment (pre-pubertal Liver function tests are taken at most clinical men and women) reviews and aid assessing for the onset of Gonadal function 1 + GvHD. Patients with pre-existing liver conditions assessment (post-pubertal such as hepatitis B or C should have monitoring women) of their viral load by polymerase chain reaction Gonadal function + + (PCR) and referral to a hepatologist or virologist assessment (post-pubertal men) for advice on ongoing antiviral therapy. Serum Mucocutaneous ferritin levels should be measured at 1 year, and Skin self-exam and sun 1 1 1 those with elevated levels should be followed exposure counselling more closely and considered for chelation. Gynaecologic exam in + 1 1 women Second cancers 14.5.8 Renal Surveillance Second cancer vigilance 1 1 counselling Screening for second 1 1 Renal injury is common post-transplant as many cancers drugs are nephrotoxic such as ciclosporin, amino- Psychosocial glycosides, acyclovir, etc., and renal function Psychosocial/QOL clinical 1 1 1 should be checked at 6 months and annually there- assessment after. In those with chronic kidney disease (CKD), Sexual function assessment 1 1 1 referral to nephrology and assessment with renal Majhail et al. (2012) ultrasound and/or biopsy should be considered. 1 recommended for all transplantation recipients, 2 recommended for any patient with ongoing cGvHD or immunosuppression, + reassessment recommended for abnormal testing in a previous time period or for new 14.5.9 Musculoskeletal Assessment signs/symptoms Patients with GvHD and especially those receiving 14.5.6 Cardiovascular Tests systemic steroids may encounter problems with muscle strength, general weakness and loss of Cardiovascular disease is rare in the transplant function. All patients should be given advice about setting. Clinical review at 6 months and annually regular daily exercise. Those who have developed with physical examination, blood pressure moni- GvHD should be assessed for range of joint move- toring and history should be performed. ment to detect sclerotic changes and referred on to Counselling with regard to a healthy lifestyle, physiotherapy for active intervention. taking regular exercise, maintaining a healthy Osteoporosis is common with reports of inci- weight, eating well and not smoking should be dence of 25–50% at 18 months (Majhail et al. reinforced in clinic and be in line with the rec- 2012). Those with ongoing GvHD requiring ommendations for the general public. Risk fac- long-term use of corticosteroids are at particular tors such as diabetes, hypertension and risk. DEXA scanning is indicated and advice dyslipidaemia can be addressed with non-medi- regarding diet and exercise given to optimise cation interventions, but some may require treat- bone mineral density and falls prevention. ment if this approach is unsuccessful. If any Supplementation with vitamin D and calcium concerns are raised, investigations with ECG may be required. 14 Late Effects and Long-Term Follow-Up 283

14.5.10 Neurological Assessment for women who receive total body irradiation at age 25 or 8 years following exposure whichever All patients should be assessed annually for signs is later but no later than 40 years. Cervical PAP and symptoms of neurologic deficit such as leu- smears should be performed every 1–3 years koencephalopathy, cognitive impairment or neu- (yearly if presence of GvHD) in women aged 21 rotoxicity as a consequence of long-term use of and over or within 3 years of initial sexual activ- calcineurin inhibitors. Also any signs or symp- ity whichever is earliest. Advice regarding sun toms of peripheral neuropathy should be exam- exposure, wearing sun screen, loose fitting cloth- ined for. If any deficit is found during routine ing and a hat and glasses when outside should be assessment, the patient should be referred for given to all patients. nerve conduction studies or MRI as indicated by the clinical findings. A referral to a neurologist may be appropriate. 14.5.13 Psychological Screening

Psychological problems may manifest in various 14.5.11 Endocrine Surveillance ways in the post-transplant setting, and clinicians need to be vigilant for subtle signs and make Endocrine dysfunction is common following appropriate referrals for interventions. Depression, stem cell transplant. Thyroid function and anxiety, fatigue and psychosexual dysfunction are gonadal testing are recommended at 1 year and frequently observed. This often increases in the then annually with replacement if needed. Up transition from early transplant recovery to lon- to 25% of patients who receive total body irra- ger-term follow-up as the patient adjusts to the diation will have some thyroid dysfunction change in life style, employment and financial (Majhail et al. 2012). Significant gonadal fail- independence. Relationships with family and ure requiring hormone replacement is more friends may change leading to distressing out- common in women than men as the ovaries are comes. A low level of suspicion should be main- more sensitive to the effects of chemoradiother- tained by the clinician for early signs of apy than the testes. Sexual dysfunction and psychological distress throughout follow-up. assessment of sexual function are described more fully in this chapter. Sexual dysfunction is common although typically under-reported and 14.5.14 Fertility Concerns results in impaired quality of life (QoL) and relationship problems. Fertility is often lost due to high-dose treatments although not in all. Patients should be counselled thoroughly regarding safe sex in those of child- 14.5.12 Second Malignancy bearing age. Those who are contemplating preg- Screening nancy should be referred on to specialist services for advice and monitoring. All patients should be counselled regarding the increased risk of secondary cancers and advised to monitor themselves frequently (breast and tes- 14.5.15 Summary ticular examination) and report symptoms promptly. The median time to development is There is no standard instrument guiding post- 5–6 years post-therapy although this risk contin- transplant care that will apply to all patients who ues to rise with no plateau. Cancers of all organs have undergone stem cell transplant. Each patient are well described but the skin, oral cavity, CNS, is an individual, and, as such, an individualised bone, thyroid and connective tissue are more plan needs to be generated. Large institutions prevalent. Breast screening should be carried out have published guidelines, such as Fred 284 M. Kenyon et al.

Hutchinson Cancer Research Center’s LTFU A series of recommendations (Table 14.4) guidelines, the National Marrow Donor Program have been developed (DeFilipp et al. 2016) to Be The Match long-term survival guidelines, the help clinicians provide screening and preventive Livestrong Care Plan and the Passport for Cure, care for MetS and cardiovascular disease among to name but a few. HSCT recipients. Furthermore, all HSCT survi- The key message is that early screening leads vors should be advised of the risks of MetS and to early detection and treatment, although it is not encouraged to undergo the recommended screen- fully proven that this leads to better outcomes. It ing based on their predisposition and ongoing is the role of all healthcare providers to raise risk factors. awareness for the potential for secondary effects of high-dose therapies and to ensure adequate and appropriate survivorship care. Empowering patients to be involved in their own long-term 14.7 Compliance and Adherence care is paramount. Having ‘buy-in’ from the in the Long-Term Follow-Up patient will help to ensure that they are vigilant Setting for subtle changes and attend screening appointments. They have self-interest at heart and are Compliance and adherence issues are common in unlikely to forget that they require certain follow- HSCT survivors. Reasons given in the literature up tests if they are educated in the late effects for refusal, noncompliance or abandonment of clinic. As they enter a passive watchful and wait- treatment include the patient’s physical discom- ing period, this is the time when things can be fort, misunderstanding and uncertainty about the forgotten, so vigilance from the patient and fam- merits of medication, poor communication ily will help the clinical team avoid errors and regarding the diagnosis and treatment regime and omissions. inadequate information on illness in general and Having a written care plan or treatment sum- secondary effects of the disease and its treatment mary detailing the chemotherapies, radiation and in particular. side effects suffered with future dates for screen- Five factors of adherence (WHO 2003): ing is ideal and can be based on any of the published material listed above. Educate the patient 1. Health system and family on the new normal, what can be 2. Socio-economic expected and when, enable them to become an 3. Health or condition active participant in their own post-transplant 4. Treatment care and help our patients navigate the potentially 5. Patient stormy waters ahead.

1. Health System 14.6 Metabolic Syndrome A relationship based on a partnership between the patient, relatives and the treating In addition to the more familiar post-HSCT physician improves adherence (Russmann sequelae, metabolic syndrome (MetS) is of par- et al. 2010). Insufficient and inadequate doc- ticular note due to its collection of cardiovascular tor/patient/family dialogue, relationship, trust risk factors that increase the risk of cardiovascu- and mutual information are quoted as one of lar disease, diabetes mellitus and all-cause mor- the most important causes of noncompliance. tality. Long-term survivors of HSCT have a Poor attention to patient education with considerable risk of developing MetS and subse- regard to medication benefits and risks, side quently cardiovascular disease. The estimated effects and correct dosing can result in prevalence of MetS is 31–49% among HSCT decreased quality of life, more frequent con- recipients. sultations and possible hospital readmissions. 14 Late Effects and Long-Term Follow-Up 285 15 Blood pressure assessment at each visit and at least annually Fasting glucose Fasting 5 at least every years; if abnormal, screen annually Pediatric Pediatric long-term HCT survivors height Weight, and BMI assessment yearly Lipid profile at 5 least every years; if abnormal, screen annually Pulsipher et al . Blood pressure assessment yearly after the age of 3 years, interpreted for age/sex/height Fasting glucose every 2 years glucose every Fasting after the age of 10 years in children with other overweight risk factors General pediatric population General height and BMI Weight, assessment after 2 years of age (no specified screening interval) Lipid panel between 9–11 years of age or earlier if family history ) ( http://www.nhlbi.nih.gov and family history and family 2 14 Blood pressure assessment at least every Blood pressure assessment at least every 2 years of heart disease before age 50 for male or before age 60 for female relatives relatives). Screening for type 2 DM every 3 years in Screening for type 2 DM every adults aged ≥ 45 years or in those with sustained higher blood pressure (>135/80 mm Hg) Adult long-term HCT survivors No specific recommendations Lipid profile assessment every 5 years in every Lipid profile assessment males aged ≥ 35 years and females ≥ 45 years. Majhail et al . Screening should start at age 20 for DM, at increased risk (smokers, anyone HTN, BMI ≥ 30 kg/m Blood pressure assessment every 3-5 years in adults aged 18-39 Blood pressure assessment every years with normal blood pressure (<130/85 mm Hg) who do not other risk factors have Blood pressure assessment annually in adults aged ge1;40 years and for those who are at increased risk high blood pressure (blood or pressure 130 to 139/85 89 mm Hg, those who are overweight obese, and African-Americans) plasma Screening for abnormal blood glucose (HbA1C, fasting 3 years in adults aged glucose or oral tolerance test) every or obese. 40-70 years who are overweight General adult population General height and BMI assessment in all adults (no specific Weight recommendation for screening interval) For persons with increased risk for coronary heart disease, For at age 20. assessments should begin / ) ( http://www.uspreventiveservicestaskforce.org The interval for screening should be shorter for people who have for screening should be shorter people who have The interval and longer intervals therapy, close to those warranting lipid levels had repeatedly normal lipid for those not at increased risk who have levels. Screening guidelines for metabolic syndrome (DeFilipp et al. 2016 ) Blood pressure Hyperglycemia Table 2 Screening guidelines for metabolic syndrome and cardiovascular risk factors for adult and pediatric patients among the general population HCT survivors risk factors 2 Screening guidelines for metabolic syndrome and cardiovascular Table height Weight, and BMI Dyslipidemia Table 14.4 2016 22(8), 1493-1503; doi: 10.1016/j.bbmt.2016.05.007, copyright Transplantation, Biology of Blood and Marrow Reprinted with permission from Elsevier: 2016 52 (2), 173-182; doi: 10.1038/bmt.2016.203, copyright Transplantation, Reprinted with permission from Nature Publishing Group: Bone Marrow DM diabetes mellitus, HbA1C hemoglobin A1C, HCT hematopoietic cell transplantation, HTN hypertension BMI body mass index, Abbreviations: 286 M. Kenyon et al.

A whole team approach to education and sup- edge, health beliefs and expectations are cen- port facilitates the development of joint strate- tral to the degree to which they will be able to gies that increase likelihood of adherence. follow treatment. 2. Socio-economic Psychological distress or other psychologi- Reasons for noncompliance may revolve cal factors may also be a cause of poor com- around a lack of resources, both in the patient’s pliance, often requiring professional finances and in the level of clinical expertise intervention and support. and medical facilities available. For many patients, a simple lack of under- The economic cost of cancer plays a sig- standing of the importance of regular treat- nificant role in therapy adherence. Many ment or assessment is the driver for poor patients need to travel considerable distances adherence or attendance. Others are afraid that to access treatment at substantial personal annual check-ups may reveal sinister pathol- cost. Furthermore, the majority of patients and ogy that they would prefer to ignore. many of their carers are unable to work during and for many months following treatment leading to a loss of income and a lack of finan- 14.8 Immunisations Following cial stability. Stem Cell Transplantation Availability of social support services is yet another potent factor, especially in patients Stem cell transplant recipients have a reduction overwhelmed by multiple pressing needs. in their antibody levels or titres to vaccine- 3. Health or Condition preventable diseases. This ranges from 50% to Extensive symptoms such as nausea, vom- 75% loss of cover for tetanus, diphtheria, polio, iting, pain, constipation and fatigue play an S. pneumoniae and H. influenzae at 1 year, rising important role in a person’s ability to manage to 100% loss of protection at 2 years in the non- medication and follow a treatment course with revaccinated patient Ljungman et al., (2009). a degree of reliability. This may occur in both autologous and alloge- Disease progression and declining health neic stem cell transplant patients having periph- can interfere with the physical ability to eral blood, umbilical cord blood or bone marrow manage treatment and also the willingness to transplantation. Therefore, all stem cell trans- continue with treatment. plant recipients should be routinely revaccinated 4. Treatment (Tables 14.5 and 14.6). As limited data exists in Therapy-related factors refer to the treat- alternative donor settings of cord and haplo-iden- ment regime and the process of taking medi- tical transplant, the guidelines suggest that for cation according to the regime. To optimise simplicity the same revaccination schedule compliance requires precision and concentra- should be followed for all stem cell transplant tion and the ability to follow specific instruc- patients until further evidence is generated tions around timing of dosing. Often careful (Ljungman et al. 2009). planning around the daily programme of treat- There may be some immune function derived ment will increase the patient’s ability to fol- from the donated stem cells, but this is unreliable low the treatment plan accurately. and as such post-transplant vaccine should be Drug frequency, odour, side effects and used (Johnston and Conly, 2002). prior experience of therapy can all impact For those patients who develop chronic graft upon and hinder compliance (Lee et al. 1992). versus host disease (cGvHD), it is likely that all 5. Patient immune function and protection are lost and The patient’s attitude towards their illness Ljungman et al. (2009) recommend the same and treatment are important factors. Their revaccination schedule but advocate measuring support network, resources, disease knowl- antibody levels pre- and post-vaccine to deter- 14 Late Effects and Long-Term Follow-Up 287

Table 14.5 Vaccination of haematopoietic cell transplant recipients Improved by donor Time post-HCT vaccination Recommended for use after to initiate (practicable only in Vaccine HCT vaccine No. of dosesa related-donor setting) Pneumococcal conjugate Yes (BI) 3–6 months 3–4b Yes; may be (PCV) considered when the recipient is at high risk for chronic GVHD Tetanus, diphtheria, Yes 6–12 months 3d Tetanus: likely acellular pertussisc Tetanus–diphtheria (BII) Diphtheria: likely Pertussis (CIII) Pertussis: unknown Haemophilus influenzae Yes (BII) 6–12 months 3 Yes conjugate Meningococcal conjugate Follow country 6–12 months 1 Unknown recommendations for general population (BII) Inactivated polio Yes (BII) 6–12 months 3 Unknown Recombinant hepatitis B Follow country 6–12 months 3 Likelye recommendations for general population (BII) Inactivated influenza Yearly (AII) 4–6 months 1–2f Unknown Measles–Mumps–Rubellag Measles: All children and 24 months 1–2h Unknown (live) seronegative adults Measles: BII Mumps: CIII Rubella: BIII EIII (<24 months post-HCT, active GVHD, on immune suppression) Ljungman et al., (2009) Reprinted with permission from Macmillan Publishers Ltd: Bone Marrow Transplantation, 44, 521–526; doi:10.1038/ bmt.2009.263, copyright 2009 Vaccinations recommended for both autologous and allogeneic HCT recipients Abbreviations: DtaP diphtheria tetanus pertussis vaccine, HCT haematopoietic cell transplant, PCV pneumococcal conjugate vaccine, Tdap tetanus toxoid-reduced diphtheria toxoid-reduced acellular pertussis vaccine aA uniform-specific interval between doses cannot be recommended, as various intervals have been used in studies. As a general guideline, a minimum of 1 month between doses may be reasonable bFollowing the primary series of three PCV doses, a dose of the 23-valent polysaccharide pneumococcal vaccine (PPSV23) to broaden the immune response might be given (BII). For patients with chronic GVHD who are likely to respond poorly to PPSV23, a fourth dose of the PCV should be considered instead of PPSV23 (CIII) cDTaP is preferred; however, if only Tdap is available (e.g. because DTaP is not licensed for adults), administer Tdap. Acellular pertussis vaccine is preferred, but the whole-cell pertussis vaccine should be used if it is the only pertussis vaccine available (see text for more information) dSee text for consideration of an additional dose(s) of Tdap for older children and adults eSignificant improvement of recipient response to hepatitis B vaccine post-transplant can be expected only if the donor receives more than one hepatitis vaccine dose before donation fFor children <9 years of age, two doses are recommended yearly between transplant and 9 years of age306 gMeasles, mumps and rubella vaccines are usually given together as a combination vaccine. In females with pregnancy potential, vaccination with rubella vaccine either as a single or a combination vaccine is indicated hIn children, two doses are favoured 288 M. Kenyon et al.

Table 14.6 Vaccination of haematopoietic cell transplant recipients Vaccine Recommendations for use Rating Optional Hepatitis A Follow recommendations for general CIII population in each country Ig should be administered to hepatitis A-susceptible HCT recipients who anticipate hepatitis A exposure (for example, during travel to endemic areas) and for post-exposure prophylaxis Varicella (Varivax, live) Limited data regarding safety and EIII (<24 months post-HCT, active efficacy GVHD or on immunosuppression) CIII (>24 months, without active GVHD or on immunosuppression) Human papillomavirus Follow recommendations for general CIII population in each country No data exist regarding the time after HCT when vaccination can be expected to induce an immune response Yellow fever (live) Limited data regarding safety and EIII (<24 months, active GVHD or on efficacy immunosuppression) The risk–benefit balance may favour CIII (>24 months, without active GVHD the use of the vaccine in patients or on immunosuppression) residing in or travelling to endemic areas Rabies Appropriate for use in HCT CIII recipients with potential occupational exposures to rabies Pre-exposure rabies vaccination should probably be delayed until 12–24 months after HCT Postexposure administration of rabies vaccine with human rabies Ig can be administered any time after HCT, as indicateda Tick-borne encephalitis (TBE) According to local policy in endemic CIII areas No data exist regarding the time after HCT when vaccination can be expected to induce an immune response Japanese B encephalitis According to local policy when CIII residing in or travelling to endemic areas No data exist regarding the time after HCT when vaccination can be expected to induce an immune response Not recommended Bacillus Calmette–Guérin (live) Contraindicated for HCT recipients EII Oral poliovirus vaccine (live) Should not be given to HCT EIII recipients, as an effective, inactivated alternative exist 14 Late Effects and Long-Term Follow-Up 289

Table 14.6 (continued) Intranasal influenza No data regarding safety and EIII vaccine (live) immunogenicity Should not be given to HCT recipients, as an effective, inactivated alternative exist Cholera No data were found regarding safety DIII and immunogenicity among HCT recipients Typhoid, oral (live) No data were found regarding safety EIII and immunogenicity among HCT recipients Typhoid (i.m.) No data were found regarding safety, DIII immunogenicity or efficacy among HCT recipients Rotavirus Must be given before 12 weeks of EIII age to be safe Zoster vaccine (Zostavax, live) No data regarding safety among HCT EIII recipients Ljungman et al., (2009) Reprinted withby permission from Macmillan Publishers Ltd: Bone Marrow Transplantation, 44, 521-526; doi:10.1038/ bmt.2009.263, copyright 2009 Vaccinations considered optional or not recommended for both autologous and allogeneic HCT recipients Abbreviation: HCT haematopoietic cell transplant aCurrent Advisory Committee on Immunisation Practices (ACIP) and American Academy of Pediatrics guidelines for post-exposure human rabies Ig and vaccine administration should be followed, which include administering five doses of rabies vaccine administered on days 0, 3, 7, 14 and 28 post-exposure

mine the level of cover that has been achieved • It directly aids the individual. and the need for any boosters. • It contributes to a ‘herd effect’ by maintaining Following transplant, patients will have spe- cover within the community. cific predisposition to some opportunistic or community-acquired infections such as S. pneu- Live vaccines that are theoretically contraindi- moniae, H. influenzae, measles, varicella or influ- cated post-transplant are BCG, smallpox, VZV, enza and will have a normal predisposition of yellow fever, oral polio and typhoid. Ljungman contracting regular pathogens such as tetanus, et al. (1995) published limited data for adminis- polio or diphtheria. Patients are susceptible to tration of MMR at 2 years post-transplant in chil- these organisms for a variety of reasons, poor dren with no GvHD and who were not on any antibody levels, low CD4 and concurrent immu- immunosuppression. They recorded a response nosuppression especially corticosteroid use in the rate for those who were seronegative of 65–75%. presence of GvHD (Flowers et al., 2015). It is generally accepted that patients who are 2 There is good evidence that having a low anti- years post-transplant and at least 1 year from body level to vaccine-preventable disease post- receiving any immunosuppression are able to transplant and the occurrence of encapsulated receive MMR vaccine. bacterial infection such as S. pneumoniae and H. Family members should continue to have all influenzae are linked which further bolsters the of their routine vaccinations. It is suggested that need to have vaccines. inactivated polio vaccine is used in family mem- The benefits of revaccination are twofold: bers. If this is not possible, then isolation and 290 M. Kenyon et al. avoidance of patient and family member (usually return home to continue living their lives, some a child) for 4 to 6 weeks are recommended as the of the adults and children cared for in this set- live virus may be shed for this time period in ting may die, while a patient within the hospi- body fluids (saliva, vomit, urine, faeces, etc.). If tal or be discharged home to die. In the highly this is not possible, then strict hand hygiene needs clinical and technical setting of HSCT, this to be applied with regard to faeces (nappies or reality can sometimes be overlooked and diapers) and avoidance of saliva and shared uten- avoided leaving the patient and family feeling sils to reduce risk of transmission (Tomblyn et al. abandoned and alone. In a study exploring the 2009). experience of living with advanced cancer, Separate guidelines initially existed and some participants spoke of feeling misunder- were developed by EBMT and the CDC, the stood and left alone with their advanced dis- IDSA and ASBMT. In order to amalgamate all ease, a large part of their suffering and distress of the recommendations, an expert group con- arose from the interpretation of their personal vened in 2009 and produced guidelines for pre- pain that was not easily visible to others, and venting infectious complications among HSCT many participants felt that often people did not recipients: a global perspective. From this fully understand what they were going through, group, a schedule for revaccination has been leaving them feeling ultimately alone (Quinn agreed as laid out in these two tables and is the 2011). adopted practice in most major centres across In reality, the delivery of good end-of-life care the world. can be achieved through each member of the HSCT team (clinical and non-clinical), who have often got to know the patient over a prolonged 14.9 End-of-Life Care period of time recognising their important role in in the Haematopoietic Stem supporting patients and their families at this time Cell Transplant (HSCT) in their lives. When curative treatment is no lon- Setting ger an option and the focus moves to compas- sionate care and addressing symptoms, the 14.9.1 Background trusting relationship between the patient, family and the HSCT team is crucial. The famous German philosopher Martin Heidegger once wrote that every human being is a person who is moving towards their own 14.9.2 End-of-Life Care death. Rather than seeing this as something negative, Heidegger suggests that if we truly End-of-life care and care of the dying have been acknowledge that reality, then it sets us free to defined as care that helps all those with advanced, live life as we truly want. For many nurses progressive, incurable illness to live as well as working in the field of HSCT, Heidegger’s possible until the day they die (GMC 2007). call to live life to the full is often the driving Unfortunately, in many parts of the world includ- force in delivering person-centred care and ing some healthcare and HSCT settings, the team helping people to recover or to live well until may find it difficult to discuss the reality of dying they die. due to a lack of exposure, avoidance, fear of Amidst the great advances in HSCT includ- upsetting the patient and sometimes the over- ing increasing cure rates, people living longer medicalisation and over-specialisation of caring and better management of toxicities, the reality for those who are dying. In reality, care for those still remains that some people will die of their moving towards the end of life in the HSCT set- advancing disease and/or treatment-related ting calls for a combination of clinical and human factors. While the majority of the patients will skills, built on sensitivity and humility, coupled 14 Late Effects and Long-Term Follow-Up 291 with good symptom management – core values care at the end of life, in particular the impor- of nursing care. tance of excellence in communicating. Things have improved, but the challenge • We will participate in research in order to remains with some nurses and medical staff in improve patient and family care at the end of the HSCT setting still reluctant to have a conver- life in the HSCT setting. sation about the reality that the treatment is no longer working and exploring what the patient This commitment from the HSCT team and family would like as they approach the end of relies on identifying when a patient may have life. This may be a result of living in a society incurable disease and/or untreatable complica- that tends to distance itself from this sensitive tions, having the courage to sensitively broach subject, coupled with a fear of upsetting people the subject of dying with the patient and fam- with what is indeed a very sensitive but human ily, working with the patient and family to subject that, as Heidegger says, touches us all. identify and address their physical, social The following principles of good end-of-life emotional and spiritual needs and planning care or commitments to those moving towards care together. These core principles will the end of life are worth considering in the HSCT enable nurses, doctors and the HSCT team to setting: support the person to receive, the right care, in the right place, at the right time, every time • When you are moving towards the end of life, (GSF 2016). we will be honest with you and sensitively support you and your family to ensure your needs and wishes are met, and you are enabled 14.9.3 Caring for Those to die in your preferred place of care. Who Are Dying • When you are approaching the end of your life, we will offer you the opportunity to be Caring for those who are dying to identify their involved in your care planning. This will needs, beliefs and values requires taking the time include an assessment of your needs and pref- to hear what they need to say, a process that has erences and an agreed set of actions reflecting been described as an art (Table 14.7). these choices. All nurses and doctors working in HSCT will • We will work to ensure that you and your fam- be required to use the principles of palliative or ily receive excellent care in accordance with supportive care in their care of those with your wishes, at all times of day and night. We will work with our community partners to Table 14.7 The art of assessment (Quinn 2014) ensure this happens. • We will offer you personalised care, based on Paying attention to the person and hearing their priorities your wishes and needs. This will include Thinking beyond the symptom to how it affects the attending to your physical, social, emotional, person spiritual and religious needs. Creating time and being present • We recognise the importance of your family, Cocreating a plan of care with the person and family your friends and your support network, and Applying ‘skilled companionship’a they have the right to have their own needs Intervening and reviewing to monitor symptom support assessed and reviewed and to have a carer’s and management plan. aSkilled companionship has been described by Alastair • In order to care for you and your family, we Campbell (1984) as the ability to use our clinical skills as nurses and doctors and our humanity to support a person will ensure that all staff and volunteers working as they strive to cope with the reality of living with in our team are aware of the issues surrounding advanced disease. 292 M. Kenyon et al.

Table 14.8 Principles of palliative/supportive care Table 14.9 Common symptoms in end-of-life care Providing relief from pain and other distressing Pain (physical, social, emotional, spiritual)a symptoms Nausea Intention not to hasten or postpone death Vomiting Integrating the physical, psychosocial and spiritual Oral problems (dryness, ulcers, mucositis)a needs of patients and family Anorexia/cachexia Offering a support system to support the family before Agitation/restlessness and after death Diarrhoea Using a team approach including counselling and Excessive secretionsa chaplaincy Ascites Improving quality of life Breathlessnessa Directing treatment, preventing unnecessary and a distressing tests or treatments Anxiety/distress Supporting the HSCT team Depression Confusion Adapted from Watson et al. (2011) Feelings of loss and grief Aloneness advanced or incurable disease including the fol- Spiritual/religious abandonmenta lowing (Table 14.8): aCommonly seen in the last days of life

14.9.4 Managing Pain Table 14.10 Pain as a disturbance or disruptions in key relationships and Other Symptoms Physical pain A disturbance or disruption in the relationship between the person and Mindful that good end-of-life care requires the their body team to attend to the person and their physical, Social pain A disturbance or disruption in the social, spiritual and emotional needs, some of the relationship between the person and common symptoms seen in the end-of-life care their world including their family, setting include those seen in Table 14.9. work and society Emotional pain A disturbance or a disruption in the Pain continues to be one of the symptoms that relationship between the person and people with advanced disease fear and yet their emotions or how they see research clearly shows that pain management is themselves not always achieved in a consistent and a robust Spiritual pain A disturbance or disruption in the manner. This may be as of a result of a number of relationship between the person and their beliefs and values reasons including lack of knowledge around – Managing Advanced Cancer Pain Together – An expert what is meant by pain, which drugs to use, the guidance. MACPT (2016) http://www.macpt.eu most therapeutic doses, non-pharmacological [Accessed 13 Nov 2016] approaches and failing to understand what pain means to the individual. While pain is often classified as nociceptive, neuropathic, refractory, pain and how other challenging symptoms can breakthrough, chronic or acute and this is impor- impact on the individual (Tables 14.9 and 14.10). tant to consider when assessing pain and choos- Rarely will the person’s experience of pain ing treatment options, pain can also be understood happen in isolation from other symptoms/factors as a disturbance or a disruption in personal rela- including anxiety, fear, loss, fatigue, breathless- tionships which should be considered ness and the inability to sleep or eat. While pain (Table 14.4). This approach helps the HSCT team can exacerbate a person’s anxiety and their to appreciate some of the more hidden aspects of inability to sleep, the inability to sleep and worry 14 Late Effects and Long-Term Follow-Up 293 can increase the personal experience of pain and costeroid, anti-depressant, anti-epileptic, anti- make the pain harder to manage; all of these need muscarinic and benzodiazepine should be to be considered. By taking a more person- considered and reviewed and increased as centred approach (physical, social, emotional and required. Pain relief should be prescribed on a spiritual) to symptom management, better con- regular basis and prescribed as needed for ‘break- trol may be achieved (Fig. 14.2). through pain’. The HSCT team should also con- Following the principles of the WHO pain lad- sider the best route of administration (oral der (Fig. 14.3), a combination of pharmacologi- transdermal, subcutaneous, sublingual, buccal cal approaches which may include paracetamol, mucosa, intravenous) for the patient and derived non-steroidal anti-inflammatories, opiates, corti- benefit. Pharmacological approaches can be complemented with non-pharmacological interventions including massage, touch, pastoral/spiritual support, hearing the patient’s concerns, music and relaxation approaches. A combination What may of both is often the best approach to managing Pain be observed total pain or indeed any symptom in advanced disease. ‘To ignore psychological and spiritual aspects of care may often be the reason for seem- Emotional ingly intractable pain’ (Watson et al. 2011. 18) The following tool (Fig. 14.4) has been Physical ? Social designed to encourage patients to talk about their personal experience of pain and what it means to Spiritual them, but it may also be used to help the patient to talk about their experience of other symptoms. The tool is designed to invite the patient to talk Fig. 14.2 Aspects of pain/other symptoms and what they about what is important to them including the mean to the individual are often hidden from view and take longer to identify and manage (Managing Advanced reality of their own dying and their fears and Cancer Pain Together – An expert guidance. MACPT concerns. (2016) http://www.macpt.eu [Accessed 13 Nov 2016])

Adjuvant options

• Corticosteroid • Antidepressant • Anti-epileptic • Anti-muscarinic • Benzodiazepine

Fig. 14.3 Using the World Health Organization. Cancer pain ladder for WHO approach to pain adults; http://www.who.int/cancer/palliative/painladder/en/. management in the th HSCT setting [Accessed 13 Nov 2016] 294 M. Kenyon et al.

Please circle three words that best best describe your recent experience of pain

igonored controlled confused distressed

scared numbness exhausted heavy frightened uncontrolled alone

gnawing radiating abandoned empty ache connected dull positive searching peaceful supported tired disbelieving held throbbing normal helpless isolated lost distant hopeful angry burning understood content anxious focused worried sharp

depressed

Managing Advanced Cancer Pain Together ‒ An expert guidance. MACPT (2016). http://www.macpt.eu [Accessed 13thNov 2016].

Fig. 14.4 Everyone experiences pain differently – you (Managing Advanced Cancer Pain Together – An expert might find it has an impact on your body, on your sense of guidance. MACPT (2016). http://www.macpt.eu [Accessed well-being and how you feel about yourself, and on your 13 Nov 2016]) relationships with others and the world around you

14.9.5 Examples of Drugs Used knowing when the person may require more in the Last Days of Life expert help including pastoral care, psychological support and specialist palliative care for chal- Pain: Morphine/diamorphine/oxycodone/alfent- lenging aspects of symptom management and/or anil/fentanyl/Buscopan +/- adjuvant drugs support/advice for the HSCT team. Pastoral, psy- Excessive secretions: Glycopyrronium chological and palliative/supportive care should Nausea: Levomepromazine/ondansetron/metoclo- be seen as a core part of HSCT care and intro- pramide/cyclizine duced to the patient earlier so that these Agitation: Midazolam approaches are seen as complementing the treat- The management of other symptoms commonly ment approach of HSCT. While an individual seen in this setting including nausea, agitation may not have any religious affiliation or religious and excessive secretions should also take both a needs, many patients will require someone to lis- pharmacological (Table 14.7) and non-ten to their hopes and dreams, their concerns and pharmacological approach focussing on what fears. The HSCT team with careful planning, suits the individual patient. support and working with the patient’s community medical and nursing team can in many cases enable patients with advanced disease to be cared 14.9.6 Support for in their own home if that is the patient’s wishes. While focussing on the person with As previously stated, an important aspect of end- advanced disease, the team is well placed to sup- of-life care is recognising the HSCT team’s role port family members including children and in supporting the patient and their family but also parents. 14 Late Effects and Long-Term Follow-Up 295

14.9.7 Conclusion vivors having at least one late effect with a median follow-up of only 7 years (Bresters et al. 2010). Although the current public message appears to Children who undergo HSCT with TBI have a be one of delivering more care with less significant risk of both growth hormone defi- resources, this in no way negates the central ciency (GHD) and the direct effects of radiation focus on delivering truly holistic patient-centred on skeletal development. The risk is increased care. We can no longer continue to talk about with single-dose TBI as opposed to fractionated patient-centred care without a willingness to TBI, pre-transplant cranial irradiation, female engage with all aspects of the person we support gender and post-treatment complications such as and care for including their physical, emotional, graft versus host disease (GVHD). social, existential and spiritual needs. It is time Late side effects and complications can to move away from a medical approach only to include chronic immunosuppression and infec- care in the HSCT setting to one of attending to tions, chronic GvHD, bronchiolitis obliterans, the person. With nursing leadership and the real- endocrine dysfunction, cataracts, disease recur- ity of dying in the HSCT setting, there is no rence and secondary malignancies (Tomlinson more urgent time to take forward the reality of and Kline 2010). person-centred care. Often the greatest gift we The endocrine system is highly susceptible to can give to those who are dying is our attention damage by high-dose chemotherapy and/or irra- and presence. Amidst the uncertainty and the diation prior to haematopoietic stem cell trans- painful realities each person has to face, caring is plantation (HSCT) during childhood. often perceived as occurring when another per- Insufficiency of thyroid hormone is one of the son carries out a simple act of kindness with a most common late sequelae of HSCT and occurs caring attitude, which requires us to be attentive more often in young children. Deficiency in the to them. pituitary’s production of growth hormone is a problem of unique concern to the paediatric population (Dvorak et al. 2011). 14.10 Late Effects and Long-Term Follow-Up in Paediatric Patients 14.10.1 Specific Late Effects After HSCT in Childhood The study of late effects after paediatric haematopoietic stem cell transplantation (HSCT) offers 14.10.1.1 Growth Impairment unique opportunities and challenges, magnified Impaired linear growth after HSCT is multifac- by the fact that children going through each devel- torial in origin and can be due to growth hor- opmental stage (infant, toddler, child preadoles- mone deficiency (GHD), hypothyroidism, cent and young adult) have different sensitivities hypogonadism, corticosteroid treatment as well to therapies, resulting in different complications. as poor nutritional status, genetic factors and For instance, infants and toddlers are susceptible metabolic status. Because of these confounding to neurocognitive damage with radiation, and factors, the reported prevalence of growth adolescents are at high risk of joint/bone issues impairment varies widely (9–84%) between with steroid therapy (Baker et al. 2011). studies (Baker et al. 2011). Paediatric HSCT survivors have a higher Treatment includes thyroid replacement ther- cumulative incidence of late effects compared to apy and growth hormone therapy, respectively, the studies of cancer survivors who did not receive for thyroid dysfunction and growth delays HSCT as part of their treatment, with 93% of sur- (Tomlinson and Kline 2010). 296 M. Kenyon et al.

Growth hormone deficiency (GHD) replace- 14.10.2 Return to School ment therapy provides the benefit of optimising height outcomes among children who have not A diagnosis of cancer during the teenage years reached skeletal maturity (Chemaitilly and arrives at an important stage of development, Robison 2012). where issues of normality, identity and indepen- Even though myeloablative conditioning regi- dence are crucial. Education provides opportu- mens for HSCT are known to affect endocrine nity for peer contact, achievement and function, Myers et al. (2016) recently evidenced development for teenagers. that ‘poor growth, thyroid dysfunction and vita- Key areas involved in the impact of a cancer min D deficiency remain prevalent despite diagnosis on teenagers’ educational engagement reduced intensity chemotherapy for haematopoi- include school attendance, reintegration and peer etic stem cell transplantation in children and relationships. Long-term school absences are a young adults’. concern for teenagers but do not necessarily lead to a reduction in educational and vocational 14.10.1.2 Neurocognitive Impairment attainment. It is important to involve healthcare There is limited evidence of neurocognitive and and education professionals, as well as parents academic outcomes in paediatric HSCT: and teenagers themselves, in school matters (Pini et al. 2012). • HSCT seems to pose a low risk overall. Factors that may place children and teens at • Risk increases for children of age <5years at increased risk for difficulties in school (Landier the time of SCT who received TBI (Phipps et al. 2013) include: et al. 2008). • Diagnosis of cancer at a very young age The procedure of SCT entails probably mini- • Numerous prolonged school absences mal risk of late cognitive and academic sequelae. • A history of learning problems before being Subgroups of patients are at relatively higher diagnosed with cancer risk: patients undergoing unrelated donor trans- • Cancer treatment that results that reduced plantation, receiving TBI and those who experi- energy levels ence GVHD. No significant changes are seen in • Cancer treatment that affects hearing or vision global intelligence quotient and academic • Cancer treatment that results in physical achievement (Phipps et al. 2008). disabilities Despite substantial exposure to potentially • Cancer treatment that includes treatment to neurotoxic agents, studies have generally shown the central nervous system survivors of paediatric HSCT to be within normal limits in cognitive and academic function- Collaborative education planning should be ing, and with stable performance over time, initiated on diagnosis and aim to include nonaca- although children who are younger at the time demic variables, such as peer groups, which can of transplantation may be at increased risk for influence successful maintenance of education. cognitive impairment (Phipps et al. 2008). Further research is needed to understand the rela- Phipps et al. (2008) reported 158 patients who tionship between education engagement and survived and were evaluated at 1, 3 and 5 years’ teenagers’ cancer experiences as a whole, as well post-transplant and concluded that HSCT, even as gaining a more in depth understanding of how with TBI, poses low to minimal risk for late cog- teenagers experience their education after a diag- nitive and academic deficits in patients who are at nosis of cancer (Pini et al. 2013). least 6 years old at the time of transplantation. It will therefore be imperative that we con- However, socio-economic status was found to be tinue to follow our HSCT survivors on a long- a significant determinant of all cognitive and aca- term basis and continue research efforts to study demic outcomes. long-term outcomes (Baker et al. 2011). 14 Late Effects and Long-Term Follow-Up 297

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Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Nursing Research and Audit in the Transplant Setting 15

Corien Eeltink, Sarah Liptrott, and Jacqui Stringer

Abstract Nursing research is a systematic inquiry that uses disciplined methods to answer questions or solve problems in order to expand the knowledge base within a given field. There are various issues to address in order to complete a successful study. The aim of this chapter is to provide the reader with an overview of the key topics for consideration and give guidance as to where to go for further information. Providing best care to patients undergoing HSCT is the moral and ethical duty of all nurses. As a consequence, awareness of, and involvement in, research as the vehicle to ensuring best practice is also our moral duty.

Keywords Nursing research • Audit • Methodology • Quantitative • Qualitative Mixed methods • Cross-sectional • Longitudinal • Prospective Retrospective

15.1 Introduction/Background

Nursing research is a systematic inquiry that uses C. Eeltink disciplined methods to answer questions or solve Department of Hematology, Cancer Center Amsterdam/ VU University Medical Center, problems. It has only been in the last four decades Amsterdam, The Netherlands that nurses have had access to knowledge from e-mail: [email protected] nursing research to inform their practice. S. Liptrott Nowadays nurses are expected to use the best Division of Haemato-oncology, type of evidence to base their nursing care on, European Institute of Oncology, Milan, Italy so-called evidence-based practice (EBP). e-mail: [email protected] In 1859, Florence Nightingale’s book Notes J. Stringer (*) on Nursing was first published, with the aim of Clinical Lead Complementary Health and Wellbeing, The Christie NHS Foundation Trust, Manchester, UK providing guidance to women who have personal e-mail: [email protected] charge of the health of others. At this time, there

© EBMT and the Author(s) 2018 301 M. Kenyon, A. Babic (eds.), The European Blood and Marrow Transplantation Textbook for Nurses, https://doi.org/10.1007/978-3-319-50026-3_15 302 C. Eeltink et al. were no nursing schools and no trained nurses. guidance on carrying out research and information She was the pioneer of modern nursing. She com- about the types of methodology, which can be bined knowledge, her systematic approach, used in nursing research and what support may be developing instruments, and statistics into an required to complete a successful project. early form of evidence-based practice. Based on her analysis and presentations, she was able to make changes in nursing care with the effect of 15.2 Service Evaluation: reducing mortality and morbidity. Audit or Research? In 1997, Molassiotis reported the lack of nursing training in research techniques, problems Before focusing on research as a topic, it is worth with funding nursing research, staff shortages, first clarifying the differences between service and language barriers as the reasons for the lim- evaluation, audit, and research. These are all valid ited contribution of nursing research and the uti- methods nurses can use to review, benchmark, or lization of research findings to the field of bone enhance their practice, but there are differences in marrow transplantation (BMT) in Europe. the way they are performed, and these differences However, he also reported that nursing research have resource implications (financial, staff, and was moving forward and starting to be integrated time). Probably the key difference between the into many European BMT centers. three strategies is the overall aim of the work. Both Currently, huge progress is being made. JACIE service evaluation and audit are looking at assess- accreditation, demonstrating excellence of prac- ing or confirming the quality of the care being pro- tice, is a legal requirement for transplant centers vided to patients, whereas research aims to add in many countries (more information about JACIE new information to the field. It is often the case in Chap. 1), and as a consequence, nurses have an that a service evaluation or audit will trigger ques- important role in validating protocols of care. The tions, which become the basis of a research study. EBMT nurses group is making it possible to form multi-institutional collaborative models of Box 15.1 Definitions of Service Evaluation, research. An example of this is the many surveys Audit and Research our nurses have developed looking at current practice in relation to, for example, mouth care, Service evaluation: service evaluation seeks to assess how well a service is achieving its intended CVCs, isolation, low bacterial diet, nutrition, aims. It is undertaken to benefit the people using a medication adherence, and patient information. particular healthcare service and is designed and Such surveys are the ideal baseline from which to conducted with the sole purpose of defining or explore where there is inconsistency in nursing judging the current service. The results of service evaluations are mostly used to generate information practice across Europe and whether further work that can be used to inform local decision-making is required to clarify what can be seen as best Audit (clinical): the English Department of Health practice. Patient-focused research looking at states that clinical audit involves systematically mouth care, sexuality, and quality of life has been looking at the procedures used for diagnosis, care, extensively explored and indicates an increasing and treatment, examining how associated resources are used and investigating the effect care has on the use of evidence-based practice. Finally, the num- outcome and quality of life for the patient. Audit ber of PhDs among registered nurses is growing, usually involves a quality improvement cycle that which is increasing the capacity of the nursing measures care against predetermined standards community to carry out independent research. (benchmarking), takes specific actions to improve care, and monitors ongoing sustained improvements Nursing research is moving in the right direction. to quality against agreed standards or benchmarks However, we have been undertaking hemato- Research: research involves the attempt to extend poietic transplantation for over 60 years with the available knowledge by means of a increasing success, and the longer HSCT survivors systematically defensible process of enquiry live, the more long-term effects they report. Much Adapted from Twycross and Shorten (2014) remains to be done. This chapter aims to provide 15 Nursing Research and Audit in the Transplant Setting 303

Table 15.1 Key criteria to consider when deciding whether your project is service evaluation, audit, or research Criteria Service evaluation Audit Research Overall aim (intent) To judge the quality of To measure clinical To generate new knowledge/ the current service practice against a add to the body of knowledge standard Initiated by Service providers Service providers Researchers Involves a new treatment No No Sometimes Randomization No No Sometimes Allocates patients to treatment No No Sometimes groups Adapted from Twycross and Shorten (2014)

Because research may change the care that a aim is to learn and increase knowledge in a par- patient is currently receiving, there is a signifi- ticular field. When initiating research, it can be cant amount of preparation required and manda- challenging to know where to begin. Planning and tory approvals from statutory bodies (e.g., ethics organization are key concepts in research perfor- committee) to be obtained prior to starting a mance, in order get started and keep focus with study. This is to ensure the patient is protected the project. For novice researchers, those looking from poor study design and unethical research to undertake research in a new field or using a practice. The situation can become confusing as methodology that they may not be familiar with, research methodologies are often used for both there is usually help at hand. It is important to service evaluation and audit. Equally, there may build a team to undertake the research, which may not always be clear standards available against begin within the local organization itself; many which to audit practice. However, there are papers hospitals have research and development depart- offering guidance on how to confidently decide ments (particularly those with links to academic which category a specific project falls into. The institutions) and/or access to statisticians and sup- following table provides a succinct set of criteria port for analysis where necessary. Often difficul- for assessing any new project (Table 15.1): ties arise when there is a lack of resources or time It is beyond the remit of this chapter to go fur- to undertake research. Getting support from man- ther into the issue. However, there are resources agement and senior clinical staff to undertake available to support nurses to make decisions research can aid in getting some protected time. regarding what classification their work falls into, Financial support for undertaking research is which is not always obvious. The Health Research an important consideration and may be available Authority (HRA) in the UK, for example, has an from a variety of sources. Registration for a per- online tool which has been designed to help clini- sonal postgraduate degree (either a master’s or a cians with exactly this challenge: http://www.hra. doctorate) is supported by some institutions and nhs.uk/research-community/before-youapply/ has the added benefit of ongoing training and determine-whether-your-study-is-research/. supervision. Nursing associations/organizations – both national and international such as the European Oncology Nursing Society – provide 15.3 Performing/Undertaking the possibility of applying for research grants. Research Information on other available resources can be obtained from, for example, national departments Few people are born as researchers. The majority of health and health research boards; however, become researchers through education and train- this will vary from country to country and will ing, practical experience, and always hard work. need investigation. Research is demanding yet rewarding – even Issues of interest for investigation through when results are not what were expected, as the research and development of the research ques- 304 C. Eeltink et al. tion can be the work of a team. All healthcare pro- and provide a focus for where research can aid in fessionals will have their own views of what is developing our understanding. important and potentially how it can be investi- To interpret and evaluate the significance of gated. By involving other members of staff in the nursing research, knowledge of the various meth- research process, there is a “buy-in” where the odologies is required. This will provide the poten- project becomes the property and interest of all tial researcher with confidence to know whether rather than just one individual. This is important the methodology and study design selected were when thinking about the practicalities of under- appropriate to answer the research question and, as taking research as it is particularly challenging if a consequence, will provide an indicator as to the one person has to do everything. Research plan- quality and reliability of the results presented. ning can also benefit from user (e.g., patient) Evaluating the quality of existing literature can involvement in terms of advising on, for example, be complex and time-consuming, but a thorough study design, strategies for recruitment, and data review can inform future research direction and collection methods that may or may not work. methodological choices. There are a variety of Support can also be sought from a wider field appraisal checklists available that can facilitate such as via local academic institutions, universi- evaluation of research such as the CONSORT ties, or other centers for multicenter studies. statement for randomized controlled trial (RCT) Knowledge of the literature and contacting those reporting, Critical Appraisal Skills Programme who are the experts in the field can be useful (CASP) tools, and PRISMA Statement. A pub- when questions or ideas are unclear. Other pro- lished paper will usually have a title, abstract, fessional groups that may be disease or interven- introduction (including study aims), methods tion focused such as the EBMT Nurses Group (including statement of ethical approval), results, can also be a useful resource. The EBMT NG discussion, acknowledgment of funding sources, Research Committee is one such group that pro- and a reference section. The abstract is concise motes collaboration with researchers in order to while communicating key information and will encourage presentation of ideas and aspirations give the reader an indication of whether the paper for research within a wider setting. Please see the is relevant to their field of interest. The main arti- website for more details: http://www.ebmt.org/ cle will provide a more detailed description. The Contents/Nursing/WhoWeAre/ introduction, for example, should provide an NursingCommittes/Pages/default.aspx. overview of previous literature to “set the scene” and state the study rationale and consequent aims/ objectives. The methodology and results sections 15.4 Interpreting Nursing require the reader to undertake a critical appraisal Research of sampling and recruitment strategies. This includes where appropriate, whether the correct In order to complete a successful project, regard- calculation has been made to ensure sufficient less of which criteria it comes under (audit, ser- subjects were entered, the “power calculation,” to vice evaluation, or research), it is important to provide meaningful results and data collection identify any work that has already been performed methods and analysis of results to inform them of within the field of interest. A scoping exercise to the overall methodological quality and therefore identify key relevant research and a critical reliability of the study results. The discussion sec- appraisal of existing literature will facilitate the tion will provide a summary of the results and identification of current knowledge and as such, their interpretation, often comparing with other which studies can be used as a baseline for further pertinent research. It should also describe the lim- work (e.g., to audit against as best practice). It itations of the research and implications for both will also identify where gaps in knowledge exist future research and clinical practice. 15 Nursing Research and Audit in the Transplant Setting 305

It is difficult for a research study to be conducted perfectly; an open and critical reflection Box 15.2 PICO: Worked Example, Aslam of limitations will assist in judging the impact on and Emmanuel (2010) quality and perhaps generalizability of the results. P: patient, problem, or P: allogeneic HSCT Equally, suggestions of future studies which may population recipients be required and implications for clinical practice I: intervention I: psychologist C: comparison C: no psychologist can be used as validation of a proposed piece of O: outcome O: effect on research. A review of the references may identify psychological distress recent work and prevent repetition as well as Sample question using PICO: older studies, which are still relevant and can pro- In allogeneic hematopoietic stem cell recipients (P), what is the effect of a psychologist in the vide a lot of information. If the reference list con- multidisciplinary team (I) on psychological distress sists mainly of old or outdated sources, it may be (O) compared to no psychologist (C)? an indicator that the research is based on outdated information or that there is the necessity for more work to be done on the issue in question. Similarly noting the presence of peer-reviewed journals 15.5.2 Designs for Nursing Research will support evidence of reading around the topic. Once the question has been clearly defined, identifying the appropriate methodology to answer 15.5 Nursing Research the question most effectively is the next step. The research design has to be pertinent to the question 15.5.1 The Research Question itself, with the nature of the question guiding the choice of approach. Research questions may be Once the general topic has been identified, it is exploratory (i.e., with no a priori theory of out- important to refine this further to a more specific come), wanting to investigate a phenomenon that area of interest. Asking a librarian to assist with we know little about and how it is perceived by a finding the appropriate literature as a background group of individuals. This type of question lends reading exercise allows for a greater understand- itself to in-depth interviews and a qualitative ing of the topic. Narrowing the focus may be research approach. If a research question is, for helped by talking with colleagues about the topic example, interested in the efficacy of a novel and by working with a team and using sources of intervention, perhaps in comparison with to stan- support as described earlier. Formulating the dard care, then a randomized controlled trial may research question is about restating your topic as be more appropriate. a question. The research question needs to be Two overarching categories of research are clear, focused, and ethical – and obviously some- basic research, used to obtain empirical data thing that can be researched. The acronym (e.g., laboratory-based studies), which is unlikely “PICO” is a reminder used to help clarify the to be immediately translatable to clinical prac- clinical question (Box 15.2). It acts as a frame- tice, and applied research, which is usually work, requiring reflection about different aspects directly relevant to the clinical setting. Nursing of interest to investigate. Building the PICO research tends to be applied research. requires clarity and specificity, which helps in Research can also be categorized into experi- targeting the right evidence to use in practice. mental or non-experimental. Although the sug- The question must be specific. What type of gested gold standard of evidence is the patient group is of interest? Is there a specific test experimental approach of an RCT, it is not always as an intervention or a broad group? If looking possible or appropriate to use this approach, for for better outcomes, what are examples of those example, where randomization may be unethical. outcomes? This does not mean research other than that of an 306 C. Eeltink et al.

RCT is not of value; on the contrary, well-conducted research will always add to the knowledge eligible myeloablative regimen studies and base, and studies using more exploratory meth- 245 patients in 6 eligible reduced-intensity odologies often provide a foundation for clinical conditioning (RIC) regimen studies. Severe trials. Common approaches for nursing research mucositis (defined as either grades 2 to 4 or include descriptive or explorative research (e.g., grades 3 and 4, depending on the studies’ using questionnaires), correlational studies, and definition of severity) occurred among both experimental and quasi-experimental 79.7% patients treated with myeloablative approaches. regimen studies and 71.5% patients treated with reduced-intensity conditioning regimen studies. RIC regimens led to a high 15.5.3 Literature Reviews incidence of OM similar to that of MA regimens. With the ever-increasing amount of research Riley et al. (2015) reviewed the effects being produced and published, it is possible that of oral cryotherapy in patients with cancer answers to research questions already exist, but receiving treatment. For this they included they sometimes lack the culmination, critical 14 RCTs analyzing 1280 participants. appraisal, and interpretation of individual studies After high-dose melphalan before HSCT, together in one single document. This is where cryotherapy reduces considerable oral reviews of the literature to identify the evidence mucositis. However, the size of the reduc- base are sources of research in themselves. tion could not be detected. Systematic reviews have increased in number within the field of nursing care. They use strategies in order to limit bias and systematically critically appraise and synthesize pertinent studies of 15.5.4 Quantitative, Qualitative, interest (Greener and Grimshaw 1996). This and Mixed Method Research means having defined objectives for the review, criteria for study inclusion, an organized approach Research is generally divided into three groups – to searching databases, and a clearly defined quantitative, qualitative, and mixed method method for critical appraisal, analysis, and subse- approaches. Quantitative research is particularly quent synthesis of data. Systematic reviews can focused on theory testing and relationships potentially combine research findings from between variables (factors which are either smaller individual studies, in order to provide a changed within an experimental design, such as broader overview of findings in which detection mouth wash in oral care, or influenced by such of “minor” findings may be amplified or discred- changes, e.g., level of oral pain/mucositis), where ited. Box 15.3 describes two examples of system- measurement instruments (e.g., pain scale) pro- atic reviews within the HSCT setting. vide numerical data which can be subjected to statistical analysis (Creswell 2014). Examples of quantitative designs include those producing numerical data such as experiments or clinical Box 15.3 Systematic Reviews Within trials (often sponsored by pharmaceutical compa- the HSCT Setting nies or academic groups that coordinate research In the review by Chaudhry et al. (2016), the projects), observations (looking at frequencies), incidence and outcomes of oral mucositis and surveys with closed questions (using ques- (OM) in allogeneic HSCT patients and its tionnaires, in person, online, or by phone). At the association with conditioning regimens other end of the spectrum, qualitative research is were analyzed, reviewing 395 patients in 8 focused on understanding meanings and experiences of human beings, also within a given con- 15 Nursing Research and Audit in the Transplant Setting 307 text (Kielmann et al. 2011). Researchers using these methods do not have any theory on which dependence and inability to work while also to base their work; rather they may use their acknowledging support from family and results to develop a theory. Examples of qualita- healthcare professionals and a shift in pri- tive data include interviews, focus groups, and orities. By using mixed method approach, secondary data (such as written accounts or authors were able to say that the compara- reports). Both quantitative and qualitative tive quantitative and qualitative parts of the approaches have positive and negative aspects, study demonstrated corresponding results. and a more recent “mixed method” approach to research lies somewhere between these two ends. A combination of qualitative and quantitative data collection methods is aimed to benefit from 15.5.5 Classifications of Research the advantages of each approach, in order to pro- by Time vide a robust method of validating and investigating findings. Mixed methods may be used within Research can also be categorized according to the a study or over a program of research, and an time in/over which it is conducted. This can example of such is provided in Box 15.4. include retrospective studies, prospective studies, and cross-sectional and longitudinal research.

Box 15.4 Mixed Method Research 15.5.6 Cross-Sectional Study Design in the HSCT Setting Niederbacher et al. (2012) investigated A cross-sectional study is an observational study quality of life (QoL) following allogeneic that collects data from a group of similar indi- hematopoietic stem cell transplantation viduals (cohort) or a representative population at (HSCT). Forty-four patients were moni- one specific point in time or over a period of time. tored and followed up for at least 3-month It may be descriptive and used to assess certain posttransplant. Quality of life was evalu- distress of a disease or treatment in a defined ated via the Functional Assessment of population. A cross-sectional study is quick and Chronic Illness Therapy–Bone Marrow easy to conduct and good for generating hypoth- Transplantation (version 4) questionnaire eses, and an example of such is provided in Box with all patients and semi-structured, 15.5. A weakness is that the onset of the outcome problem-oriented interviews with seven is difficult to determine and that associations may subjects. The authors compared results be difficult to interpret. from the quantitative and qualitative parts based on triangulation – a method aimed to increase confidence in findings by use of two or more independent measures (Bryman Box 15.5 Cross-Sectional Studies 2008). Findings suggested <25% were in the HSCT Setting highly satisfied with their QoL, with women Dyer et al. (2016) assessed 421 Australian scoring lower than men. The results revealed survivors (57% male, 43% female) of a positive correlation between the post- HSCT sexuality and reported sexual inac- tivity in 12% of both male and female sur- HSCT period and QOL (rs = 0.338, P = 0.025), especially regarding the social/ vivors and sexual difficulties in 51% of sexually active male survivors and 66% of family (rs = 0.411, P = 0.006) and emo- sexually active female survivors. Men tional well-being (rs = 0.306, P = 0.043) aspects. Interviews, however, revealed reported erectile dysfunction (80%) and 308 C. Eeltink et al.

decreased libido (62%), and female survi- tioning. Psychosocial assessment results vors reported loss of libido (83%), painful indicated (1) a low prevalence of behav- intercourse (73%), vaginal dryness (73%), ioral and social problems, (2) stability in less enjoyment of sex (68%), vaginal nar- functioning over time, and (3) pre-HSCT rowing (34%), and vaginal irritation (26%). functioning strongly predictive of later They also studied associations and found functioning. age and cGVHD significantly associated with sexual dysfunction. However, this study is the largest up till now; a weakness of this study is that it is not prospectively 15.5.8 Prospective Study Design examined. After all, how sexual function evolves over time cannot be concluded. For A prospective study design is a specific type of some outcomes, a prospective design is observational study that follows a group of simi- better. lar individuals (cohort) over time and ideally begins enrolling before exposure (baseline) and then follows over a period of time (longitudi- nally), to determine if and when exposure (e.g., 15.5.7 Longitudinal Study Design HSCT) changes outcomes. In this way, more associations can be identified between “risk fac- A longitudinal study is alternative to a cross- tors” and outcomes – examples of prospective sectional study in that data is gathered for the studies are provided in Box 15.6. same subjects repeatedly over the study period. As a consequence, longitudinal research can extend over many years or even decades depend- Box 15.7 Prospective Studies ing on the aims of the study. in the HSCT Setting Syrjala et al. (2008) reported the most extended longitudinal study in relation to Box 15.6 Longitudinal Study sexual function changes during 5 years in the HSCT Setting after HSCT report that 46% of males and Kupst et al. (2002) undertook a prospective 80% of the female patients have sexual longitudinal study of cognitive and psycho- problems 5 years posttransplant. Both men social functioning in pediatric HSCT and women declined in average sexual patients. They assessed the children on function from before transplantation to three occasions: pre-HSCT, 1 year post- 6 months after transplantation. Women did HSCT, and 2 years post-HSCT. 153 chil- not improve from 6-month posttransplanta- dren and adolescents were evaluated tion levels by 5 years. Men improved sig- pre-HSCT and at 1 year, with 2-year data nificantly by 2 years. A weakness of this available for 74 children. Longitudinal study is that the baseline measurement is analyses of Wechsler IQ data were com- before transplantation, ideally the baseline pleted on 100 children (longitudinal exact measurement would be carried out before test) and 52 children (repeated measures induction chemotherapy. analysis of variance). Results of cognitive Crooks et al. (2014) determined whether assessment indicated (1) stability of IQ the use of a single-item screening tool and scores over time and (2) that the strongest a problem list could monitor patients’ dis- predictor was pre-HSCT cognitive func- tress and the relations. All consecutive 15 Nursing Research and Audit in the Transplant Setting 309

patients scheduled for an allogeneic trans- men (RIC) prior to HLA identical HSCT, plant between January 15, 2012, and to those after myeloablative (MA) regimen December 17, 2012, who gave informed HSCT, in patients with acute myeloblastic consent after being informed were handed leukemia (AML) over 50 years of age. a packet that included a short demographic Outcomes of 315 RIC were retrospectively sheet, distress thermometer, and problem compared with 407 MA HSCT recipients. list. The final sample included 37 patients; In multivariate analysis, acute GVHD (II– they were approximately 54 years of age, IV) and transplant-related mortality were range 32–66 years, and had more males significantly decreased (P = 0.01 and (62%) than females (38%). Distress was P < 10–4, respectively), and relapse inci- measured at the transplant talk, discharge, dence was significantly higher (P = 0.003) and 3 and 6 months post-discharge. Using after RIC transplantation. Leukemia-free the distress cutoff score of 4 as the crite- survival was not statistically different rion, 59% had clinically significant distress between the two groups. These results may at time point 1, 58% at discharge, 43% at set the grounds for prospective trials com- 3 months, and 19% at 6 months. The results paring RIC with other strategies of treat- show the use of a one-item screening tool ment in elderly AML. and problem list to monitor psychosocial distress over time as a potential method to coordinate the care to address problems. 15.6 Ethical Issues in Nursing Research

15.5.9 Retrospective Study Design Throughout the research process, the protection of those participating is paramount. Guidance on A retrospective study is one which looks back- the ethical conduct of clinical trials is provided ward, often by looking through patients’ notes or both locally within institutions and nationally registries. It will collate information and examine and internationally and is based on key docu- variables in relation to an outcome (e.g., survival) ments such as the Nuremberg Code (1947) and that is established when the protocol is written at the Declaration of Helsinki (2002). Methods to the start of the study. This methodology is useful protect human rights include the process of gain- if the outcome of interest is uncommon, and a ing informed consent from each potential subject prospective investigation would have to be too to participate in a trial, as well as the review of large to be feasible. Retrospective studies may be any study and its documentation, by an indepen- carried out prior to commencement of a more tar- dent ethics committee. geted prospective study to validate the field of The process of informed consent is more than study. a signature on a document. Participants must be aware of the implications of participating in the study, the potential risks and benefits, anonymity and protection of privacy, the voluntariness of Box 15.8 Retrospective Study in the HSCT their participation, and right to withdraw consent Setting to participate at any time without suffering Aoudjhane et al., on behalf of the Acute negative consequences. This information tends to Leukemia Working Party of EBMT (2005), be within a participant information sheet (PIS) compared the results of patients who under- and related consent form (CF). These are docu- went a reduced intensity conditioning regiments that will also be revised by the independent ethics committee. Potential participants 310 C. Eeltink et al. should be provided with these documents and teamwork is highly recommended as is sup- have time to both read and assimilate the infor- port from experts/experienced researchers. It mation, with opportunity to discuss and ask ques- is beyond the scope of this chapter to provide tions so that there is a clear and complete specific details for all aspects of the research understanding of all aspects of the study. The process, but rather the aim was to provide purpose of ethics committees, however, is to guidance on the main concepts, which require ensure the interests of the participant are thought in order to complete a successful proj- accounted for when evaluating studies for ect. Research is an integral part of the future approval. This includes evaluating whether the of HSCT, and as qualified nurses, we have a study is ethical, the completeness and appropri- duty of care to our patients to become involved ateness of documents such as the PIS and CF, and in whatever way we can. Finally, it is impor- reviewing aspects of the design to ensure its cor- tant to remember that negative results can be rect conduct. just as useful as positive ones, if not more so; Ethical considerations in nursing research are please do not let such an outcome, if it should sometimes rather complex, and just a simplified occur, put you off publishing. overview has been described in this chapter. The requirement for approval to conduct research should be discussed at a local level with research and development units or with the local ethics References committee secretary, who will usually be able to provide guidance on the types of approval for the Aoudjhane M, Labopin M, Gorin NC, Shimoni A, Ruutu T, Kolb H-J, Frassoni F, Boiron JM, Yin JL, Finke J, type of research being undertaken. This may also Shouten H, Blaise D, Falda M, Fauser AA, Esteve J, include approval from the national regulatory Polge E, Slavin S, Niederwieser D, Nagler A, Rocha bodies in some cases. Research should not be V. Comparative outcome of reduced intensity and undertaken until all necessary approvals have myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplan- been received and documented. The process of tation for patients older than 50 years of age with acute approval may be lengthy if amendments to docu- myeloblastic leukaemia: a retrospective survey from ments or even research protocols are required in the Acute Leukemia Working Party (ALWP) of the order to address concerns raised by one or more European group for Blood and Marrow Transplantation (EBMT). Leukemia. 2005;19:2304–12. of the approval bodies. This potential for delay Aslam S, Emmanuel P. Formulating a researchable should be considered when research is being question: a critical step for facilitating good clinical planned. research. Indian J Sex Transm Dis. 2010;31(1):47–50. Bryman A. Social research methods. 3rd ed. Oxford: Oxford University Press; 2008. Conclusion Chaudhry HM, Bruce AJ, Wolf RC, Litzow MR, Hogan One of the key factors for nursing research is WJ, Patnaik MS, Kremers WK, Phillips GL, Hashmi that we are aiming to produce results and SK. The incidence and severity of oral mucositis increase our knowledge base in a way that is among allogeneic hematopoietic stem cell transplantation patients: a systematic review. Biol Blood Marrow quickly translatable into clinical practice. In a Transplant. 2016;22(4):605–16. rapidly developing field such as HSCT, Creswell JW. Research design: qualitative, quantitative research helps to provide evidence on which and mixed methods approaches. 4th ed. London: Sage; to base standards for care, thus helping to 2014. Crooks M, Seropian S, Bai M, McCorkle R. Monitoring ensure the safety and efficacy of our practice patient distress and related problems before and with a very vulnerable patient population. after hematopoietic stem cell transplantation. Palliat Planning a potential study is often the aspect Support Care. 2014;12(1):53–61. of work which is most time-consuming. It is, Declaration of Helsinki. 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