Recommended Screening and Preventive Practices for Long-Term Survivors After Hematopoietic Cell Transplantation

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SPECIAL REPORT Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation

NS Majhail1,2, JD Rizzo3, SJ Lee4, M Aljurf5, Y Atsuta6, C Bonﬁm7, LJ Burns8, N Chaudhri5, S Davies9, S Okamoto10, A Seber11, G Socie12, J Szer13, MT Van Lint14, JR Wingard15 and A Tichelli16, for the Center for International Blood and Marrow Transplant Research, American Society for Blood and Marrow Transplantation, European Group for Blood and Marrow Transplantation, Asia-Paciﬁc Blood and Marrow Transplantation Group, Bone Marrow Transplant Society of Australia and New Zealand, East Mediterranean Blood and Marrow Transplantation Group and Sociedade Brasileira de Transplante de Medula Ossea

1National Marrow Donor Program, Minneapolis, MN, USA; 2Center for International Blood and Marrow Transplant Research, Minneapolis, MN, USA; 3Center for International Blood and Marrow Transplant Research, Milwaukee, WI, USA; 4Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 5King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; 6Nagoya University Graduate School of Medicine, Nagoya, Japan; 7Universidade Federal do Parana´, Curitiba, Brazil; 8University of Minnesota, Minneapolis, MN, USA; 9Cincinnati Children’s Hospital, Cincinnati, OH, USA; 10Keio University School of Medicine, Tokyo, Japan; 11Instituto de Oncologia Pediatrica GRAACC Unifesp, Sa˜o Paulo, Brazil; 12Hoˆpital Saint-Louis, Paris, France; 13Royal Melbourne Hospital, Parkville, Victoria, Australia; 14San Martino Hospital, Genoa, Italy; 15University of Florida College of Medicine, Gainesville, FL, USA and 16University Hospital Basel, Basel, Switzerland

Advances in hematopoietic cell transplantation (HCT) Note technology and supportive care techniques have led to improvements in long-term survival after HCT. Emerging The guidelines for ‘Recommended screening and preventive indications for transplantation, introduction of newer practices for long-term survivors after hematopoietic cell graft sources (for example, umbilical cord blood) and transplantation’ are being co-published in the following transplantation of older patients using less intense journals: Biology of Blood and Marrow Transplantation, conditioning regimens have also contributed to an increase Bone Marrow Transplantation, Hematology/Oncology and in the number of HCT survivors. These survivors are at Stem Cell Therapy and Revista Brasileira de Hematologia e risk for developing late complications secondary to pre-, Hemoterapia. peri- and post-transplant exposures and risk factors. Guidelines for screening and preventive practices for HCT survivors were published in 2006. An international group Introduction of transplant experts was convened in 2011 to review contemporary literature and update the recommendations Approximately 50 000 people undergo hematopoietic cell while considering the changing practice of transplantation transplantation (HCT) worldwide each year. Advances in and international applicability of these guidelines. This transplantation techniques and supportive care practices report provides the updated recommendations for screen- have led to progressive improvements in survival for HCT ing and preventive practices for pediatric and adult recipients. As patients survive long-term after transplanta- survivors of autologous and allogeneic HCT. tion, they are at risk for developing late complications Bone Marrow Transplantation 47; doi:10.1038/bmt.2012.5 related to pre-, peri- and post-transplant exposures. These Keywords: hematopoietic cell transplantation; allogeneic; complications can cause substantial morbidity, impair autologous; late complications; screening; prevention quality of life and can contribute to late mortality in HCT recipients. Several studies have shown that the life expectancy of HCT survivors is lower than expected at 10– 30 years post transplantation, and secondary cancers, infections and organ dysfunction are common causes of late deaths in this population.1–6 Recognizing the need for guidance about appropriate systematic long-term follow-up of HCT survivors, the Correspondence: Dr NS Majhail, National Marrow Donor Program, Center for International Blood and Marrow Transplant 3001 Broadway Street NE, Suite 100, Minneapolis, MN 55413-1753, USA. E-mail: [email protected] Research, the European Group for Blood and Marrow Received 21 October 2011; revised 2 December 2011; accepted 7 Transplantation and the American Society for Blood and December 2011 Marrow Transplantation convened a group of experts in Late effects guidelines for HCT survivors NS Majhail et al 2 2006 and provided consensus recommendations for screen- experience unusual toxicity or immune impairment following and preventive practices for autologous and allogeneic ing transplantation that places them at risk similar to HCT survivors.7,8 To update these previous guidelines, the allogeneic recipients (for example, exposure to prolonged international working group was reconvened in 2011 to corticosteroids or other drugs that may cause prolonged review the prevailing literature on late effects of transplan- lymphopenia post transplantation). Therefore, although tation and to suggest revised guidelines, if applicable. To some of the following recommendations do not generally ensure international applicability, the working group apply to autologous recipients, providers should remain included participants from the Asia-Pacific Blood and alert to these complications in all patients. Marrow Transplantation Group, the Bone Marrow Trans- The guidelines are summarized in Tables 1 and 2. The plant Society of Australia and New Zealand, the East Supplementary Appendix includes tables that highlight Mediterranean Blood and Marrow Transplantation Group recommendations for post-transplant immunizations (Sup- and Sociedade Brasileira de Transplante de Medula Ossea. plementary Appendix Table A) and recommendations by The proposed guidelines focus on risks faced by children selected exposures/risk factors (TBI, chronic GVHD, and adults who have survived 6 months or more following pediatric recipients; Supplementary Appendix Table B). transplantation and address autologous and allogeneic Supplementary Appendix Table C lists other guidelines that HCT recipients. As long-term HCT recipients may no have been referenced in this manuscript along with current longer be under the care of transplant centers and may have links to their website. Readers can also refer to guidelines returned to the care of community health-care providers, developed by the Children’s Oncology Group for follow-up the guidelines are geared toward providers who routinely of pediatric cancer survivors, which include information on care for HCT recipients as well as those who do not. pediatric HCT recipients (http://www.survivorshipguideli- The working group recognized the general lack of clinical nes.org). Representative references are included in this trials focused on screening and preventive practices among document to guide readers who would like more informa- HCT recipients and the need for more research in this area. tion on individual topics. Hence, many of these recommendations are not based on The National Marrow Donor Program publishes a evidence derived from randomized or other controlled patient version of the follow-up guidelines (http:// trials, but are supported by retrospective studies that have www.BeTheMatch.org/Patient); we recommend that pa- identified specific complications in long-term survivors and tients use these guidelines to establish a long-term follow- their associated risk factors. When such studies are not up care plan in consultation with their health-care provider available, the guidelines are based on knowledge derived based on their individual exposures and risk factors. The from non-transplant patients as well as on the consensus National Marrow Donor Program also makes a summary opinion of the working group participants. Taking into of the guidelines available for physicians (online, mobile account the risks and potential consequences of late app and in print at http://www.marrow.org/md-guidelines). complications, they represent sensible practices to optimize outcomes. The recommendations should not be interpreted as mandatory for all recipients; good medical practice and judgment dictate that certain recommendations may not be Immunity and infections applicable or may even be contraindicated in individual patients or groups of patients. International consensus guidelines for preventing infectious It was also recognized that the practice of HCT is complications among HCT recipients were published in continuously changing. Some examples of such changes 2009; these guidelines comprehensively address late infec- include emerging indications for transplantation (for tious complications of transplantation and provide recom- example, autoimmune diseases, sickle cell disease), in- mendations for vaccination of HCT recipients.9–11 creased utilization of newer donor sources (for example, Environmental risks, safe sex, water and food safety and umbilical cord blood and haploidentical donors) and travel safety among HCT recipients have also been covered decreased use of TBI for conditioning and evaluation of by these guidelines. Patients who are immune compromised novel therapies as part of HCT (for example, post- should be educated regarding their immune status and of transplant maintenance therapy in myeloma). With the the warning symptoms of infection and advised to seek advent of non-myeloablative and reduced intensity con- early medical attention if they have symptoms. ditioning regimens, a larger number of older patients now Infectious complications are frequent in the period soon receive transplantation. The risks and constellation of late after HCT because of cytopenias, immune ablation and/or complications may change as newer practices in transplan- immunosuppression. Immune reconstitution occurs gradu- tation become more prevalent. Providers should be ally over time (generally 12–18 months) and is slower for cognizant of any unique exposures and risks associated allogeneic recipients, particularly those receiving umbilical with these practices (for example, delayed immune recon- cord blood, HLA-mismatched or T-cell–depleted grafts stitution in umbilical cord blood recipients) when consider- and in survivors with GVHD or those who have received ing a long-term follow-up care plan for their patients. prolonged immunosuppression.12 T-helper lymphocyte A broad constellation of medical issues faced by late (CD4) counts and CD4/CD8 ratios are good markers of survivors of transplantation is presented. Most of the late immune reconstitution, and some experts use these assess- complications discussed here pertain particularly to allo- ments as surrogate markers of the completeness of immune geneic recipients. However, autologous recipients are at reconstitution to guide duration of viral or other infection risk for many of the same late complications and may prophylaxis after HCT.

Bone Marrow Transplantation Table 1 Summary recommendations for screening and prevention of late complications in long-term HCT survivors

Tissues/ Late complications General risk factors Monitoring tests Monitoring tests and preventive measures Monitoring tests and preventive measures in organs in all HCT recipients special populations

Immune Infections Donor source CMV Ag or PCR in PCP prophylaxis for initial 6 months after HCT Patients with cGVHD: antimicrobial prophylaxis system HLA disparity patients at high risk for Immunizations post transplant according to published targeting encapsulated organisms and PCP for the T-cell depletion CMV reactivation guidelines duration of immunosuppressive therapy GVHD Administration of antibiotics for endocarditis Patients with cGVHD: screening for CMV reactivation Prolonged prophylaxis according to American Heart Association should be based on risk factors, including intensity of immunosuppression guidelines immunosuppression. Venous access devices

Ocular Cataracts TBI/radiation Ophthalmological Routine clinical evaluation at 6 months and 1 year Patients with cGVHD: routine clinical evaluation, and if Sicca syndrome exposure to head examination after HCT and at least yearly thereafter indicated, ophthalmological examination more Microvascular and neck Ophthalmological examination with measurement of frequently retinopathy Corticosteroids visual acuity and fundus examination at 1 year after GVHD HCT, subsequent evaluation based on ﬁndings and risk factors Prompt ophthalmological examination in patients with visual symptoms

Oral Sicca syndrome GVHD Dental assessment Education about preventive oral health practices Pediatric recipients: yearly assessment of teeth Caries TBI/radiation Clinical oral assessment at 6 months and 1 year after development exposure to head HCT and at least yearly thereafter with particular Patients with cGVHD: consider more frequent oral and and neck attention to intra-oral malignancy evaluation dental assessments with particular attention to intra-oral Dental assessment at 1 year after HCT and then malignancy evaluation aeefcsgieie o C survivors Majhail HCT NS for guidelines effects Late at least yearly thereafter

Respiratory Idiopathic pneumonia TBI/radiation PFT’s Routine clinical evaluation at 6 months and 1 year Patients with cGVHD: some experts recommend earlier syndrome exposure to chest Radiological studies after HCT and at least yearly thereafter and more frequent clinical evaluation and PFT’s tal et Bronchiolitis GVHD (e.g., chest X-ray, Assessment of tobacco use and couseling against obliterans syndrome Infectious agents CT scan) smoking Cryptogenic Allogeneic HCT PFT’s and focused radiological assessment for allogeneic organizing BU exposure HCT recipients with symptoms or signs of lung pneumonia compromise Sino-pulmonary infections

Cardiac and Cardiomyopathy Anthracycline Cumulative dose of Routine clinical assessment of cardiovascular risk factors vascular Congestive exposure anthracyclines as per general health maintenance at 1 year and at least heart failure TBI/radiation ECG with ventricular yearly thereafter Arrhythmias exposure to neck function, ECG in Education and counseling on ‘heart’ healthy lifestyle Valvular anomaly or chest patients at risk and in (regular exercise, healthy weight, no smoking, dietary Coronary artery Older age at HCT symptomatic patients counseling) disease Allogeneic HCT Fasting lipid proﬁle Early treatment of cardiovascular risk factors such as

oeMro Transplantation Marrow Bone Cerebrovascular Cardiovascular risk (including HDL-C, diabetes, hypertension and dyslipidemia disease factors before/ LDL-C and Administration of antibiotics for endocarditis Peripheral arterial after HCT triglycerides) prophylaxis according to American Heart Association disease Chronic kidney Fasting blood sugar guidelines disease Metabolic syndrome 3 4 oeMro Transplantation Marrow Bone

Table 1 Continued

Tissues/ Late complications General risk factors Monitoring tests Monitoring tests and preventive measures Monitoring tests and preventive measures in organs in all HCT recipients special populations

Liver GVHD Cumulative LFT’s LFT’s every 3 –6 months in the ﬁrst year, then Hepatitis B transfusion Liver biopsy individualized, but at least yearly thereafter Hepatitis C exposure Serum ferritin Monitor viral load by PCR for patients with known Iron overload Risk factors for Imaging for iron hepatitis B or C, with liver and infectious disease viral hepatitis overload (MRI or specialist consultation transmission SQUID) Consider liver biopsy at 8 –10 years after HCT to assess cirrhosis in patients with chronic HCV infection Serum ferritin at 1 year after HCT in patients who have

received RBC transfusions; consider liver biopsy or survivors HCT for guidelines effects Late imaging study for abnormal results based on magnitude of elevation and clinical context; subsequent monitoring is suggested for patients with elevated LFT’s, continued RBC transfusions, or presence of HCV infection

Renal and Chronic kidney TBI Urine protein Blood pressure assessment at every clinic visit, with genitourinary disease Drug exposure Serum creatinine aggressive hypertension management Bladder dysfunction (e.g., calcineurin BUN Assess renal function with BUN, creatinine and urine SMajhail NS Urinary tract inhibitors, protein at 6 months, 1 year and at least yearly thereafter infections amphotericin, Consider further workup (kidney biopsy or renal aminoglycosides) ultrasound) for further workup of renal dysfunction as CMV clinically indicated tal et Hemorrhagic cystitis

Muscle and Myopathy Corticosteroids Evaluate ability to stand Follow general population guidelines for physical activity Patients with cGVHD: physical therapy consultation in connective Fascitis/scleroderma GVHD from a sitting position Frequent clinical evaluation for myopathy in patients on patients with prolonged corticosteroid exposure, fascitis tissue Polymyositis Clinical evaluation of corticosteroids or scleroderma joint range of motion Patients with cGVHD: frequent clinical evaluation by manual muscle tests or by assessing ability to go from sitting to standing position for patients on prolonged corticosteroids

Skeletal Osteopenia/ Inactivity Dual-photon Dual-photon densitometry at 1 year for adult women, Patients with cGVHD: consider dual photon osteoporosis TBI densitometry all allogeneic HCT recipients and patients who are at densitometry at an earlier date in patients with Avascular necrosis Corticosteroids MRI to evaluate patients high risk for bone loss; subsequent testing determined prolonged corticosteroid or calcineurin inhibitor GVHD with joint symptoms by defects or to assess response to therapy exposure Hypogonadism Physical activity, vitamin D and calcium Allogeneic HCT supplementation to prevent loss of bone density

Nervous Leukoencephalopathy TBI/radiation — Clinical evaluation for symptoms and signs of Pediatric recipients: annual assessment for congnitive system Late infections exposure to head neurological dysfunction at 1 year and yearly thereafter development milestones Neuropsychological GVHD Diagnostic testing (e.g., radiographs, nerve conduction and cognitive deﬁcits Exposure to studies) for those with symptoms or signs Calcineurin ﬂudarabine neurotoxicity Intrathecal Peripheral chemotherapy neuropathy Table 1 Continued

Tissues/ Late complications General risk factors Monitoring tests Monitoring tests and preventive measures Monitoring tests and preventive measures in organs in all HCT recipients special populations

Endocrine Hypothyroidism TBI/radiation Thyroid function tests Thyroid function testing yearly post-HCT, or if relevant Pediatric recipients: clinical and endocrinologic gonadal Hypoadrenalism exposure (e.g., head FSH, LH, testosterone symptoms develop assessment for prepubertal boys and girls within 1 year Hypogonadism and neck, CNS) Growth velocity in Clinical and endocrinologic gonadal assessment for post- of transplant, with further follow-up as determined in Growth retardation Corticosteroids children pubertal women at 1 year, subsequent followup based on consultation with a pediatric endocrinologist Young age at HCT menopausal status Pediatric recipients: monitor growth velocity in children Chemotherapy Gonadal function in men, including FSH, LH and annually; assessment of thyroid, and growth hormone exposure testosterone, should be assessed as warranted by function if clinically indicated symptoms Patients with cGVHD: slow terminal tapering of corticosteroids for those with prolonged exposure Patients with cGVHD: consider stress doses of corticosteroids during acute illness for patients who have received chronic corticosteroids

Muco- Cutaneous sclerosis GVHD Pelvic examination Counsel patients to perform routine Patients with cGVHD and TBI recipients: consider more cutaneous Genital GVHD TBI/radiation self-examination of skin and avoid excessive exposure to frequent gynecological evaluation based on clinical exposure to pelvis sunlight without adequate protection symptoms Annual gynecological examination in women to detect early involvement of vaginal mucosa by GVHD

Second Solid tumors GVHD Mammogram Counsel patients about risks of secondary malignancies Patients with cGVHD: clinical and dental evaluation cancers Hematologic TBI/radiation Screening for colon annually and encourage them to perform self exam with particular attention toward oral and pharyngeal malignancies exposure cancer (e.g., colonscopy, (e.g. skin, testicles/genitalia) cancer PTLD T-cell depletion sigmoidoscopy, fecal Counsel patients to avoid high-risk behaviors TBI and chest irradiation recipients: screening

Exposure to occult blood testing) (e.g., smoking) mammography in women starting at age 25 or survivors Majhail HCT NS for guidelines effects Late alkylating agents or Pap smear Follow general population recommendations for cancer 8 years after radiation exposure, whichever etoposide screening occurs later but no later than age 40 years

Psychosocial Depression Prior psychiatric Psychological evaluation Clinical assessment throughout recovery period, at 6 al et and sexual Anxiety morbidity months, 1 year and annually thereafter, with mental Fatigue Hypogonadism health professional counseling recommended for those Sexual dysfunction with recognized deﬁcits Encouragement of robust support networks Regularly assess level of spousal/caregiver psychological adjustment and family functioning Query adults about sexual function at 6 months, 1 year and at least annually thereafter

Fertility Infertility TBI/radiation FSH, LH levels Consider referral to appropriate specialists for patients exposure who are contemplating a pregnancy or are having Chemotherapy difﬁculty conceiving exposure Counsel sexually active patients in the reproductive age group about birth control post-HCT

oeMro Transplantation Marrow Bone General Recommended screening as per general population health (see text)

Abbreviations: BUN ¼ blood urea nitrogen; cGVHD ¼ chronic GVHD; CNS ¼ central nervous system; CT ¼ computed tomography; ECG ¼ electrocardiogram; FSH ¼ follicle stimulating hormone; HCT ¼ hematopoietic cell transplantation; HDL-C ¼ high-density lipoprotein cholesterol; LDL-C ¼ low-density lipoprotein cholestero; LFT’s ¼ liver function tests; LH ¼ luteinizing hormone; MRI ¼ magnetic resonance imaging; PCP ¼ pneumocystis pneumonia; PFT’s ¼ pulmonary function tests; PTLD ¼ post-transplant lymphoproliferative disorder; SQUID ¼ superconducting quantum interference device. 5 Late effects guidelines for HCT survivors NS Majhail et al 6 Table 2 Abbreviated summary recommendations for screening and prevention of late complications in long-term HCT survivors organized by time after transplantation

Recommended screening/prevention 6 Months 1 Year Annually

Immunity Encapsulated organism prophylaxis 2 2 2 PCP prophylaxis 1 2 2 CMV testing 2 2 2 Immunizations 1 1 1

Ocular Ocular clinical symptom evaluation 1 1 1 Ocular fundus exam + 1 +

Oral complications Clinical assessment 1 1 1 Dental assessment + 1 1

Respiratory Clinical pulmonary assessment 1 1 1 Smoking tobacco avoidance 1 1 1 Pulmonary function testing + + + Chest radiography + + +

Cardiac and vascular Cardiovascular risk-factor assessment + 1 1

Liver Liver function testing 1 1 + Serum ferritin testing 1+

Kidney Blood pressure screening 1 1 1 Urine protein screening 1 1 1 BUN/creatinine testing 1 1 1

Muscle and connective tissue Evaluation for muscle weakness 2 2 2 Physical activity counseling 1 1 1

Skeletal Bone density testing (adult women, all allogeneic 1+ transplant recipients and patients at high risk for bone loss)

Nervous system Neurologic clinical evaluation + 1 1 Evaluate for cognitive development 11

Endocrine Thyroid function testing 11 Growth velocity in children 11 Gonadal function assessment (prepubertal men and women) 1 1 1 Gonadal function assessment (postpubertal women) 1 + Gonadal function assessment (postpubertal men) + +

Muco-cutaneous Skin self-examination and sun exposure counseling 1 1 1 Gynecological examination in women + 1 1

Second cancers Second cancer vigilance counseling 11 Screening for second cancers 11

Psychosocial Psychosocial/QOL clinical assessment 1 1 1 Sexual function assessment 1 1 1

Abbreviations: BUN ¼ blood urea nitrogen; HCT ¼ hematopoietic cell transplantation; PCP ¼ pneumocystis pneumonia; QOL, quality of life. 1 ¼ recommended for all transplant recipients. 2 ¼ recommended for any patient with ongoing chronic GVHD or immunosuppression. + ¼ reassessment recommended for abnormal testing in a previous time period or for new signs/symptoms.

Bone Marrow Transplantation Late effects guidelines for HCT survivors NS Majhail et al 7 Bacterial, fungal and viral infections may occur months Supplemental i.v. Ig is sometimes recommended for or years after transplantation in patients with delayed patients with severe infections and IgG levels below immune reconstitution. Although infectious risk is highest 400 mg/dL (4 g/L) and infusions are continued until in the first 1–2 years after transplantation, an increased risk infection has abated.9,10 The use of prophylactic i.v. Ig in of infection may continue long-term for some recipients of HCT patients in the absence of infection remains con- allogeneic transplants, such as patients with chronic troversial. GVHD requiring extended immunosuppressive therapy. Transplant recipients who reside in certain geographic In patients with chronic GVHD, opsonization is impaired, areas may be susceptible to locally prevalent infections (for and encapsulated bacteria (Neisseria meningitides, Haemo- example, tuberculosis, malaria, Chagas disease, leishmania- philus influenzae and Streptococcus pneumonia) may cause sis). Health-care providers taking care of such patients should rapidly progressive and life-threatening infection. Further- be aware of guidelines for the prevention and management of more, patients may have undergone splenectomy for the such infections.10,13,14 treatment of their underlying disease or may be function- ally asplenic secondary to GVHD or splenic irradiation. Recommendations Although patients with asplenia are at increased risk of infections, recommendations regarding antibiotic prophy- Patients with chronic GVHD should receive antibiotic laxis are inconsistent. Patients with combined risk of prophylaxis targeting encapsulated organisms given for asplenia and immunosuppression for GVHD should at least as long as immunosuppressive therapy is receive antibiotic prophylaxis as recommended below. administered. Otherwise patients with asplenia should, at a minimum, Antiviral and antifungal prophylaxis should be consid- be warned regarding the need for prompt medical attention ered in patients at high risk for viral and fungal for febrile illnesses. infections (for example, patients with chronic GVHD) Aspergillus infection of the lungs or sinuses is the according to published guidelines.9,10 Screening for CMV most commonly described late fungal infection, although reactivation should be based on risk factors, including Candida and Mucor species are late pathogens seen intensity of immunosuppression. infrequently. Late-onset CMV reactivation and infection Administration of prophylactic antibiotics for oral has been reported more frequently in recent years with the procedures should follow the American Heart Associa- increasing use of prophylactic or preemptive antiviral tion guidelines for endocarditis prophylaxis.15 Some drugs in the early post-HCT period. Late CMV infections experts recommend antibiotic prophylaxis before dental are most commonly seen in patients treated for early care in patients on immunosuppressive therapy for CMV infection or in those with chronic GVHD or late chronic GVHD and in patients with indwelling central immune manipulation (for example, DLI recipients). VZV venous catheters. infection frequently occurs in the first year after transplan- Allogeneic HCT recipients should receive PCP prophylaxis tation, especially in patients with chronic GVHD. In from engraftment until at least 6 months after transplanta- patients receiving prophylaxis against herpes virus infection or as long as immunosuppressive therapy is given (for tions, VZV reactivation is most commonly seen in the example, for the treatment or prevention of chronic 2–3 months after cessation of prophylaxis. Acyclovir GVHD). PCP prophylaxis for 3–6 months post trans- prophylaxis is recommended for 1-year post transplanta- plantation should be considered for autologous HCT tion for both autologous and allogeneic recipients at recipients with substantial immunosuppression (for exam- risk for VZV disease; prophylaxis may be continued ple, patients with lymphoma, leukemia or myeloma, beyond 1 year among patients who have chronic GVHD especially when pre-transplant treatments or conditioning or require systemic immune suppression. Recurrent HSV regimens have included purine analogs or high-dose infections can occasionally occur in patients with chronic corticosteroids). GVHD. Immunization with inactivated vaccines for all patients Although Pneumocystis jirovecii (previously Pneumocys- according to published guidelines (Supplementary Ap- tis carinii) pneumonia (PCP) generally occurs during the pendix Table A).9–11 As patients with chronic GVHD first 6 months after HCT, patients are at risk for as long as can mount responses to vaccines and are at risk for immunosuppressive therapy is given for chronic GVHD. infections, postponing vaccination in patients with Autologous HCT recipients are also at risk of PCP, GVHD is not recommended with the exception of live particularly during the first 6 months; the risk may be vaccines. When vaccinating patients with active GVHD, substantial if there has been prolonged corticosteroid it may be prudent to measure specific Ab levels before exposure before or after transplantation and in patients and after vaccination, to determine their level of who have received intensive conditioning. protection and need for booster immunizations. Sinusitis is an occasional complication, especially after allogeneic HCT, and is more frequent in patients with low Ig levels. Sinus pathogens are rarely identified because Ocular complications invasive diagnostic procedures are not frequently performed. Exposure to calcineurin inhibitors that can induce There are three main ocular late effects after HCT. mucosal hypertrophy and mucosal involvement by chronic Anterior segment ocular complications of keratoconjuncti- GVHD can increase the risk of secondary sinus infections vitis sicca syndrome and cataracts are well described. with bacteria or molds. Ischemic microvascular retinopathy is a posterior segment

Bone Marrow Transplantation Late effects guidelines for HCT survivors NS Majhail et al 8 complication that is being increasingly recognized and posterior segment include hemorrhage, optic-disc edema appears to be related to radiation exposure. and infectious retinitis (for example, from herpes viruses Ocular sicca syndrome is usually part of a more general including CMV, toxoplasma and fungi). sicca syndrome with xerostomia, vaginitis and dryness of 16 skin, and is associated with chronic GVHD. Ocular Recommendations manifestations include reduced tear flow, keratoconjunctivitis sicca, sterile conjunctivitis, corneal epithelial defects Routine clinical evaluation of visual history and and corneal ulceration. Symptoms include burning, irrita- symptoms, with attention to sicca syndrome, is recom- tion, pain, foreign body sensation, blurred vision, photo- mended at 6 months, 1 year and yearly thereafter for all phobia, and paradoxically, excessive tearing. The diagnosis HCT recipients. of keratoconjunctivitis sicca is made by the presence of Referral to an expert in ophthalmology for routine appropriate symptoms, evidence of decreased tear produc- ocular examination with measurement of visual acuity tion on Schirmer’s test, and clinical signs of keratitis. In all and fundus examination at 1 year after transplant is cases, infectious keratitis must be ruled out. The incidence recommended for all HCT recipients. Patients with is approximately 40–60% in patients with chronic chronic GVHD may be referred for ophthalmological GVHD.17 Artificial tears can provide symptomatic treat- examination sooner than 1-year post transplant. Sub- ment of dry eye. Information regarding frequency of use of sequent frequency of routine screening should be artificial teardrops can indicate severity of dry eye individualized according to recognized defects, ocular syndrome. Treatment includes systemic treatment of symptoms or the presence of chronic GVHD. chronic GVHD and topical treatment to increase lubrica- Patients experiencing visual symptoms should undergo tion, control evaporation or drainage, and decrease ocular ocular examination immediately. surface inflammation.18 Temporary or permanent occlusion of the tear-duct puncta for drainage control may provide Oral complications benefit. In general, contact lens usage is discouraged in patients with keratoconjunctivitis sicca because of an Late complications involving the oral cavity are common increased risk of abrasion; however, some lenses such as after HCT. The most important risk factors for oral late scleral lenses may be beneficial in severe cases to control effects are oral chronic GVHD, the use and dose of evaporation. Such an approach should occur only with the irradiation to head and neck region, underlying diagnosis close supervision of an ophthalmologist. Topical corticos- of Fanconi’s anemia and the age of the patient at HCT. teroids or calcineurin inhibitors may not only improve Pre-transplant evaluation should include clinical assess- symptoms but can also cause sight-threatening complica- ment of oral health status to serve as a baseline for tions when inappropriately used in HSV or bacterial monitoring post-transplant oral complications. keratitis. Ocular surface inflammation may be decreased The mouth is one of the most frequently affected organs with autologous serum, but this treatment is available in a in chronic GVHD.22,23 The oral changes involving the oral limited number of centers. mucosa, salivary glands, oral and lingual muscles, taste Cataract formation occurs frequently after TBI expo- buds and gingiva may completely regress, but some long- sure. After myeloablative single-dose TBI, almost all term sequela may continue despite the resolution of chronic patients develop cataracts within 3–4 years. Fractionation GVHD. Patients often report oral pain, dryness, odyno- of TBI delays onset and reduces the incidence of cataract to phagia, dysphagia and sensitivity (irritation from normally 40–70% at 10 years post transplant.19,20 In patients tolerated spices, foods, liquids or flavors) that may limit conditioned without TBI, the probability of cataract oral intake. The presence of lichen planus, hyperkeratotic formation at 10 years is 5–20%.20,21 Other risk factors plaques and restriction of mouth opening by peri-oral for cataract formation after HCT are older age, use of fasciitis or skin sclerosis are diagnostic signs of oral corticosteroids and allogeneic compared with autologous GVHD. Patients may also have mucosal erythema, transplantation. Approximately 45% of recipients treated atrophy, oral dryness, mucoceles (due to inflammation with corticosteroids for a prolonged period of time develop and obstruction of the salivary gland ducts), pseudomem- cataracts at 10 years. In the near future, the overall branes and ulcers. Salivary gland dysfunction and xerosto- cumulative incidence of cataracts after HCT is expected to mia increase the risk of dental caries, periodontal disease decrease as fewer patients receive TBI-based conditioning. and oral cancer.22,24 Patients with GVHD can be treated Cataracts are effectively treated surgically. Cataract ex- with topical oral steroids, systemic treatments for GVHD traction can be performed safely even when ocular sicca is and supportive care for xerostomia symptoms as outlined present. Surgery is indicated if vision is impaired and the below. impairment is interfering with daily life. Even in patients who have never had GVHD, some Ischemic microvascular retinopathy presents with cot- degree of salivary gland hypofunction may persist for ton-wool spots and optic-disc edema. Retinopathy is prolonged periods of time after receiving chemotherapy, observed almost exclusively after allogeneic transplanta- and especially after local irradiation. Oral dryness is also a tion, particularly in patients conditioned with TBI and in side effect of commonly used medications (for example, patients receiving CYA for GVHD prophylaxis. In most antidepressants, antihistamines, diuretics, muscle relaxants cases, retinal lesions resolve with withdrawal or reduction and some analgesics). Medication lists should be reviewed of immunosuppressive therapy, even in cases where visual to identify and eliminate any drugs that can cause or acuity is decreased. Other ocular complications in the exacerbate xerostomia. Depending on the severity of

Bone Marrow Transplantation Late effects guidelines for HCT survivors NS Majhail et al 9 xerostomia, patients may complain of oral sensitivity, Clinical oral evaluations should be performed at 6 abnormal taste and may feel a constant sore throat, or months, 1 year and yearly thereafter. More frequent have problems in speaking and swallowing. The decrease in evaluations may be needed in patients at high risk of oral salivation predisposes patients to dental decay, oral complications (for example, chronic GVHD, exposure to infections (for example, herpes simplex and oral candidia- TBI). Monitoring of oral complications post transplan- sis), mechanical and epithelial injuries, and impairs re- tation is facilitated by thorough pre-HCT baseline oral mineralization of teeth. Xerostomia can be difficult to assessment. manage. Symptom relief can be achieved with artificial Patients at high risk for squamous cell cancers of the oral saliva and oral rinses; sugar-free candies or gum can cavity (for example, oral chronic GVHD, Fanconi’s stimulate the saliva flow. Sialogogues (for example, anemia) should undergo clinical oral evaluations every 6 pilocarpine, cevimeline) may be tried in adults. Frequent months and should be educated to maintain meticulous sipping of water may help decrease symptoms, and oral hygiene and taught oral self-inspection. especially help chewing and swallowing food. Patients with All HCT recipients should receive a thorough evaluation xerostomia should receive meticulous oral hygiene, under- by a dentist or oral medicine specialist at 1 year after take preventive measures for dental and periodontal HCT and yearly thereafter. More frequent dental disease, and aggressive treatment of oral infections. Further consultations may be considered in patients with oral trauma to the oral mucosa should be avoided and mouth- GVHD or Fanconi’s anemia. At each visit it is important guards may be used, if necessary. Oral piercing should be to check for a history of xerostomia and high-risk habits, avoided. to perform a through oral, head and neck and dental Squamous cell oral cancer can arise from the buccal examination. Appropriate dental and radiological assess- mucosa, salivary glands, gingiva, lip or tongue (see section ment for tooth development should be performed in on Secondary Cancers).24 – 26 Patients with a history of oral children. chronic GVHD and patients with Fanconi’s anemia are particularly at risk and must be carefully screened throughout their lives. Frequent self and professional oral Respiratory complications examination is the mainstay for early diagnosis of oral cancer. Patients should be vigilant for and report lesions Late pulmonary complications among HCT recipients that do not heal, leukoplakia, localized pain and changes in include idiopathic pneumonia syndrome, bronchiolitis color or texture of the mucosa. Patients with Fanconi’s obliterans syndrome (BOS), cryptogenic organizing pneu- anemia should be examined every 6 months and oral monia and sino-pulmonary infections.28 Allogeneic HCT examination should be part of the standard annual recipients have higher risks than autologous HCT recipi- examination of all other HCT patients. ents. Predisposing factors can include infections, extent and Children undergoing HCT may have damage to the type of pre-transplant and conditioning regimen che- enamel layer and the teeth may have discolored patches or motherapy and radiation exposure, and GVHD. Pulmon- stain easily. Depending on the child’s age, permanent teeth ary complications can be associated with significant may start developing again within a few months of morbidity and mortality. transplantation. Normal dental development may be Idiopathic pneumonia syndrome, also known as inter- altered in 50–80% of children due to prior therapies or stitial pneumonitis, more commonly presents in the early conditioning regimen exposure.27 Tooth agenesis, hypo- post-transplant period. However, it can occur in long-term dontia, microdontia of the crowns of erupted permanent survivors and can lead to late respiratory impairment. teeth, narrowing of the pulp canal, thinning and tapering of Predisposing factors include allogeneic HCT, exposure to the roots of erupted permanent molars or incisors, delayed high-dose TBI and GVHD. Immune compromise delays eruption and primary tooth retention have been described recovery from infection, allowing greater damage to the lung and may jeopardize occlusal development. After irradia- interstitium. Certain chemotherapeutic agents (for example, tion, underdevelopment of the mandible and anomalies in BCNU, bleomycin, BU, MTX) can cause lung toxicity the mandibular joint may also occur. Young age at HCT directly or can enhance the damaging effects of radiation. and exposure to TBI are important risk factors for Fractionation of radiation and lung shielding can decrease problems with dental development. radiation toxicity. Prophylaxis strategies focus on decreas- Among HCT recipients who require dental procedures, ing the risks of infections post-HCT, especially among the American Heart Association recommendations for patients with chronic GVHD. antimicrobial prophylaxis against endocarditis should be BOS occurs in 2–14% of allogeneic HCT recipients and followed (see section on Immunity and Infections).15 is almost exclusively seen among patients with chronic GVHD; some experts classify BOS as pulmonary GVHD.29 – 31 BOS may develop in patients with no other Recommendations clinical manifestations of GVHD. BOS is characterized by the new onset of an obstructive lung defect and clinically All HCT recipients should be educated about preventive manifests as dyspnea on exertion, cough or wheezing. oral health and routine dental maintenance. Patients Patients may be asymptomatic early in the disease process. should also be counseled to avoid smoking and chewing BOS is clinically diagnosed when all of the following tobacco, decrease regular intake of sugar-containing criteria are met together with active chronic GVHD in at beverages and avoid intraoral piercing. least one organ other than the lung: (1) forced expiratory

Bone Marrow Transplantation Late effects guidelines for HCT survivors NS Majhail et al 10 volume in 1 s (FEV1)/forced vital capacity ratio o0.7 and In patients with symptoms or signs of lung compromise, FEV1 o75% of predicted, (2) evidence of air trapping or pulmonary function test’s and focused radiological small airway thickening or bronchiectasis on high-resolu- assessment should be performed as clinically indicated. tion chest computed tomography, residual volume 4120%, Follow-up evaluations should be guided by clinical or pathological confirmation of constrictive bronchiolitis, circumstances for patients with recognized defects. and (3) absence of infection in the respiratory tract, documented with investigations (for example, bronchoal- veolar lavage) directed by clinical symptoms. Some experts Cardiac and vascular complications consider a decrease in the FEV1 of 10% or greater from pre-transplant baseline as a diagnostic criterion for BOS or In comparison with other complications, clinically evident an indication for more frequent follow-up pulmonary cardiac and cardiovascular complications after HCT are function test assessments. The value of using spirometry rare. Cardiac toxicity accounts for late deaths in 2% to screen for BOS in the absence of symptoms is not well autologous and 3% of allogeneic HCT recipients. However, defined. Treatment of BOS includes immunosuppressive it is likely that cardiac and vascular complications are still agents such as corticosteroids, calcineurin inhibitors, underestimated. Experiences of cancer survivorship in the sirolimus and antithymocyte globulin. The prognosis of non-transplant setting may provide an estimate of the BOS is poor, and 5-year survival rates are o20% if patients magnitude of risk in HCT recipients. In a cohort of 1474 do not respond to initial treatment.30,31 long-term survivors with Hodgkin’s lymphoma (among Cryptogenic organizing pneumonia, previously known as whom 84% received mediastinal radiation), the risk of bronchiolitis obliterans organizing pneumonia, is a clin- cardiac and cardiovascular diseases was 3–5 times in- icopathologic syndrome that involves the bronchioles, creased compared with a general population.32 Therefore, alveolar ducts and the alveoli, and is the result of a variety cardiac and cardiovascular complications may increase of toxic, immunological or inflammatory injuries to the with longer follow-up after HCT. lungs. Cryptogenic organizing pneumonia presents typi- Late cardiac events can appear years and even decades cally in the first 6–12 months post transplantation, after HCT, and may manifest as subclinical abnormalities although later onset may occur, especially in patients with or present as overt congestive heart failure or angina. The chronic GVHD. Clinical presentation includes non-pro- cardiac complications include any cardiac dysfunction due ductive cough, low-grade fevers and dyspnea. Radiological to cardiomyopathy, valvular anomaly or conduction imaging may reveal patchy consolidation with ground glass anomaly. Many factors are involved, such as the cumula- or nodular infiltrates. Pulmonary function tests typically tive exposure to anthracyclines and chest radiation prior to show a restrictive pattern. Biopsy may be needed to confirm HCT, cardiac function before transplantation, intensity the diagnosis of cryptogenic organizing pneumonia. Main- and type of conditioning regimen used, as well as post- stay of treatment is corticosteroids and 80% of patients can transplant factors. Previous use of cardiotoxic chemother- be expected to recover, but relapses are common if steroids apy and chest radiation has a major role. For patients with are rapidly tapered. This complication is rare after non-malignant diseases such as hemoglobinopathy or transplantation and no specific screening tests are available aplastic anemia, transfusion history and the resultant iron for early diagnosis and prevention. overload may be important. With advancing age at the time Recurrent sino-pulmonary infections can occur in of HCT, common pre-existing cardiac diseases may be patients with delayed immune reconstitution and chronic increased. Assessment prior to transplantation for all HCT GVHD (see section on Immunity and Infections). Appro- recipients should include inquiry about exposure to pre- priate vaccination is recommended, and in patients with transplant chemotherapy (for example, cumulative dose of ongoing immune deficiency and infections, monitoring of anthracyclines) and chest and neck radiation therapy, and Ig levels should be considered with targeted replacement as evaluation of pre-existing cardiac and cardiovascular recommended elsewhere in these guidelines. disease. Other rare late complications involving the lung include Anthracycline cardiomyopathy is characterized by a diffuse alveolar hemorrhage, pulmonary thrombo-embo- dose-dependent progressive decrease in systolic left ven- lism, pulmonary veno-occlusive disease and pleural effu- tricular function. At total doses of less than 400 mg/m2 sions. body surface area, the incidence of congestive heart failure is 0.14%; this incidence increases to 7% at a dose of 2 2 Recommendations 550 mg/m and to 18% at a dose of 700 mg/m . Mediastinal radiotherapy applied before HCT can cause a variety of Routine clinical assessment by history and physical cardiac complications by producing inflammation and examination for pulmonary complications is recom- fibrosis of all structures of the heart. Restrictive cardio- mended for all patients at 6 months, 1 year and yearly myopathy, fibrosis of the electrical conduction pathways thereafter. with arrhythmias and autonomic dysfunction, as well Some experts recommend earlier and more frequent valvular defects, with left-sided valve regurgitation and clinical assessments including pulmonary function test’s valve thickening are the deleterious consequences. in patients with chronic GVHD. Cardiovascular disease involves changes of the whole History of smoking should be assessed and patients who arterial vascular network and can include cerebrovascular smoke or are at risk for passive smoking should be disease, ischemic heart disease and peripheral arterial counseled regarding smoking cessation. disease after HCT. These cardiovascular events may have

Bone Marrow Transplantation Late effects guidelines for HCT survivors NS Majhail et al 11 diverse clinical manifestations, such as stroke, transient and review of medications can often provide clues. In ischemic attack, myocardial infarction, angina pectoris, addition, the time course of onset and pattern of liver chronic coronary artery disease, ischemic leg pain or function test abnormalities, history of pre-transplant gangrene. hepatitis, diagnosis of GVHD at other sites and number In a retrospective single-center study, the cumulative of blood transfusions pre-transplantation and post trans- incidence of a cardiovascular complication was 22% at 25 plantation can be useful in determining the etiology of liver years after allogeneic HCT.33 The relative risk of develop- disease. ing a late arterial event was significantly higher after Chronic GVHD is a major cause of liver dysfunction allogeneic than after autologous HCT, supporting the after transplantation and can manifest with elevations of hypothesis that the allo-reaction may be involved in the serum alanine transaminase, alkaline phosphatase and g- atherosclerotic process. The established cardiovascular risk glutamyl transferase. Evaluation should exclude other factors (hypertension, dyslipidemia, diabetes, smoking, causes of liver dysfunction (for example, viral infections, physical inactivity) were associated with higher risks of drug injury). Liver biopsy should be performed to confirm cardiovascular complications post transplantation. Some the diagnosis when liver dysfunction occurs as the only conditioning regimens may have inherent cardiac toxicity manifestation of chronic GVHD and systemic immuno- with long-term cardiac consequences.34 suppression is being considered. Immunosuppressive ther- A high prevalence of metabolic syndrome, elevated apy is indicated for liver chronic GVHD; ursodeoxycholic triglycerides, elevated blood pressure, abdominal obesity acid may be used as an adjunct. Liver transplantation has and diabetes has been reported among allogeneic HCT successfully been performed in several rare cases of survivors, even when off immunosuppressive treatment. progressive liver failure.38 Prolonged and intensified immunosuppressive treatment, Long-term survivors with hepatitis B generally have post-transplant endocrine dysfunction and insulin and/or mild-to-moderate liver disease. Chronic HCV infection is leptin resistance could be some of the possible causes. often asymptomatic with fluctuating transaminase levels as Although studies supporting evidence-based guidelines are the only manifestation during the first decade following lacking in HCT, prevention and early treatment of the transplantation. However, the cumulative incidence of cardiovascular risk factors may decrease the risk of late HCV progressing to cirrhosis is 11% at 15 years and cardiovascular complications after HCT.35 24% at 20 years, being more rapid in transplant than non- transplant patients (18 vs 40 years).39 Extrahepatic HCV Recommendations disease and genotype 3 are associated with progression to cirrhosis. In patients with known HCV infection, liver Routine clinical assessment and cardiovascular risk biopsy can be considered at 8–10 years after transplanta- factor evaluation for all HCT recipients at 1 year and tion to assess for the presence of cirrhosis. yearly thereafter. More frequent assessments and if HCT recipients are at risk of developing iron overload clinically appropriate, extended cardiac evaluations (for primarily from RBC transfusions as part of their suppor- example, electrocardiogram, echocardiogram) may be tive care both pre-transplantation and post transplantation, indicated in patients at high risk for cardiac complica- although increased iron absorption due to ineffective tions (for example, patients with Hodgkin’s lymphoma erythropoiesis and a carrier state for hereditary hemochro- who have received mediastinal radiation therapy, matosis, if present, may also contribute.40 Iron overload in patients with amyloidosis and patients with pre-existing late survivors has been associated with increased infections cardiac and vascular abnormalities). and may mimic hepatic chronic GVHD. Although serum Education and counseling on ‘heart’ healthy lifestyle ferritin is a sensitive test for iron load, as an acute-phase (regular exercise, maintaining healthy weight, no smok- reactant, it is not a specific test. When iron overload is ing, dietary counseling) for all HCT recipients (see suspected, the hepatic iron content should be estimated by section on General Screening and Preventive Health). appropriate imaging (specialized magnetic resonance ima- Appropriate treatment of cardiovascular risk factors ging (MRI) protocols or superconducting quantum inter- such as diabetes, hypertension and dyslipidemia for all ference device) or liver biopsy. MRI and superconducting HCT recipients. Among patients started on drug therapy quantum interference device are noninvasive tests and have for dyslipidemia, follow-up assessments should be been shown to be sensitive and specific for quantifying liver performed based on published guidelines (fasting lipid iron content. These are the preferred methods unless a panel every 6–8 weeks till treatment goal is achieved and tissue sample is needed to assess for other potential then every 4–6 months).36 etiologies of liver dysfunction. Survivors with mild iron Endocarditis prophylaxis in HCT recipients according to overload may not require any therapy, as there are reports the recommendations of the American Heart Associa- of iron load decreasing with time, but should be counseled tion.15 to avoid iron supplements and alcohol ingestion. Although more data are needed to determine the incidence of end Liver complications organ damage from iron overload, patients with significant iron overload (for example, 47 mg/g dry weight liver iron) Late liver complications are most commonly related to and liver dysfunction are candidates for phlebotomy or medications, chronic GVHD, hepatitis B or C virus (HCV), iron-chelation therapy. Iron-chelation therapy prior to or or iron overload.37 The etiology of liver dysfunction may be early post transplant is being investigated in patients with multifactorial, and a careful history, physical examination pre-transplant iron overload. Among patients who are at

Bone Marrow Transplantation Late effects guidelines for HCT survivors NS Majhail et al 12 risk for iron overload and require vitamin supplementation, inhibitors can cause glomerular thrombosis and tubular iron-free preparations should be considered. injury. A long-term syndrome of calcineurin inhibitor– HCT recipients who have thalassemia or have been associated renal injury can affect both renal arterioles and heavily transfused pre-transplantation (for example, other tubules and can be accompanied by interstitial fibrosis. hemoglobinopathies and BM failure syndromes) are CMV infection has also been associated with glomerular particularly at risk for iron overload and acquired hepatitis injury and the use of foscarnet for CMV infection can B virus and HCV infections. further induce tubulointerstitial nephritis and irreversible damage due to crystallization within the renal tubules. Recommendations Radiation exposure (for example, TBI) can lead to degeneration and sclerosis of arterioles and secondary Liver function tests (total bilirubin, alkaline phosphatase destruction of glomeruli and tubules. and transaminases) should be performed every 3–6 Patients with substantial hemorrhagic cystitis in the early months for the first year and then at least yearly post-transplant period experience a greater risk of later thereafter. More frequent assessments may be needed bladder wall scarring and contraction. Evaluation and based on an individual patient’s medical status (for treatment of polyoma or adeno viruses may be warranted example, patients with GVHD), and particularly in in some patients with hemorrhagic cystitis, especially if they allogeneic transplant survivors. have received extended duration of immunosuppressive Patients with hepatitis B and C should have viral load therapy. Patients receiving immunosuppressive therapy for monitored by PCR and consultation with liver and chronic GVHD, particularly women with GVHD of the infectious disease specialists for antiviral therapy is vulva and vagina are at risk of recurrent urinary tract advised. Liver specialists may recommend a liver biopsy infections. in patients with chronic HCV infection to determine the Recommendations regarding complications of the genital extent of cirrhosis. This is particularly important in and reproductive organs are also addressed in the Endo- patients 8–10 years post transplant. crine Complications and Muco-cutaneous Complications Serum ferritin should be measured at 1-year post sections. transplant in patients who received RBC infusions pre- transplant or post transplant. Subsequent monitoring Recommendations with serum ferritin should be considered among patients with elevated levels, especially in the presence of Blood pressure should be checked at every clinic visit, abnormal liver function tests, continued RBC transfu- and hypertension should be investigated and managed sions or HCV infection. Additional diagnostic testing appropriately in all HCT recipients (see section on (for example, liver biopsy, MRI or superconducting General Screening and Preventive Health). quantum interference device) may be indicated if therapy Renal function should be evaluated at 6 months, 1 year is contemplated for suspected iron overload. and at least yearly thereafter for all HCT recipients. Screening should include assessment of blood urea Renal and genitourinary complications nitrogen, creatinine and urine protein. Further workup (for example, renal ultrasound, renal biopsy), as Renal dysfunction among HCT survivors can be caused by clinically indicated should be pursued in patients with a number of exposures in the pre-, peri- and post-transplant late-onset acute renal failure or CKD post transplanta- period. The incidence of chronic kidney disease (CKD), tion. More frequent assessments may be needed based on defined as sustained decrease in glomerular filtration rate an individual patient’s medical status (for example, below 60 mL/min per 1.73 m2, has been reported to range ongoing therapy with calcineurin inhibitors). from 5 to 65%.41,42 CKD usually becomes apparent 6–12 In patients with progressive CKD, avoid nephrotoxins months after transplant, although it can occur earlier as and consider early referral to a nephrologist for well as much later post transplantation. Renal dysfunction evaluation and treatment. may present as thrombotic microangiopathy, glomerulone- phritis or nephrotic syndrome, and radiation nephritis may Complications of muscle and connective tissue occur after exposure to TBI. The majority of patients have an idiopathic form of CKD, which is not associated with Major late complications affecting muscle and connective thrombotic microangiopathy or nephrotic syndrome, and tissue after HCT include steroid-induced myopathy, has a multifactorial etiology. fasciitis/scleroderma and polymyositis. One case-matched Risk factors for CKD in long-term survivors of HCT control study reported that 35% of 10-year survivors after include older age at HCT, diagnosis (for example, HSCT still complain of musculoskeletal stiffness, cramps, myeloma) and pre-transplant renal function and therapy weakness and joint swelling, and the incidence of muscu- exposures (for example, platinum compounds), acute and loskeletal problems was significantly higher than controls.44 chronic GVHD, use of TBI in conditioning regimen and Possible causes of these problems may include sedentary exposure to medications to prevent or treat GVHD (for lifestyle combined with muscle loss, myopathy or fibro- example, calcineurin inhibitors) and certain antimicrobials myalgia related to steroid treatment, or scleroderma/ (for example, acyclovir, amphotericin B, aminoglycoside fasciitis related to chronic GVHD. antibiotics).42,43 Antibiotics and antifungal agents cause Myopathy after HCT is one of the most frequent tubular rather than glomerular damage. Calcineurin complications of long-term steroid therapy for chronic

Bone Marrow Transplantation Late effects guidelines for HCT survivors NS Majhail et al 13 GVHD. It is associated with moderate-to-severe functional mal lymphocyte clones has been suggested as a possible impairment and may be associated with an increased risk of mechanism, but immune dysregulation associated with mortality. Proximal lower extremity muscles are commonly concomitant chronic GVHD might be a contributing involved with the quadriceps muscle being most severely factor. affected. The myopathy progresses insidiously in most cases. Clinical observation of a patient changing position from a supine to sitting or sitting to standing may reveal Recommendations early myopathy. The use of a questionnaire such as the All HCT recipients should follow general population Human Activity Profile may lead to its early detection.45 age-specific guidelines for physical activity (See section Post-transplant fatigue contributes to inactivity, which on General Screening and Preventive Health). exacerbates muscle atrophy. Therefore, it is also important For patients on corticosteroids, frequent clinical evalua- to encourage progressively increasing physical activity to tion is recommended for steroid-induced myopathy by stop this vicious cycle. manual muscle tests or by assessing patients’ ability to go Myositis or polymyositis is a distinctive feature of from a sitting to a standing position. chronic GVHD as defined by the National Institutes of Patients with muscle weakness, myalgias or arthralgias Health consensus criteria.29 Although the incidence of should be evaluated for possible chronic GVHD or myositis in patients with chronic GVHD is much higher steroid-associated myositis, and other muscular disor- than in the general population, it is a rare complication ders (for example, myasthenia gravis). after HCT. Chronic GVHD–associated polymyositis or Among patients with chronic GVHD, joint range of myopathy usually occurs 2–5 years after HCT and the motion should be evaluated to detect sclerotic changes. common presenting symptoms are moderate-to-severe Patients should also be instructed to perform self- proximal muscle weakness and/or myalgia. Lower extre- assessment of range of motion. mities are more commonly involved. This syndrome may be Where prolonged corticosteroid exposure is anticipated hard to distinguish from steroid-induced myopathy. The or when fasciitis or scleroderma develops, a physical majority of patients have elevated serum creatinine kinase, therapy consultation should be considered to establish a myopathic pattern on electromyography, a largely peri- baseline function and provide range of motion and fascicular lymphocytic infiltration on muscle biopsy and muscle strengthening exercises to minimize loss of very favorable response to immunosuppressive therapy.46 It function. is often a challenge to differentiate the muscular weakness of chronic GVHD–associated myositis or myopathy from that of steroid myopathy/peripheral neuropathy, as a few Skeletal complications patients with chronic GVHD–associated myopathy have a normal creatinine kinase and lack lymphocytic infiltration Bone density loss is a well-recognized complication of in the muscle biopsy. HCT. There is a wide variation in the reported incidence of Sclerosis can affect the skin and s.c. tissues, including this complication; some studies have reported incidence fasciae, joints and the musculoskeletal system with varying rates as high as 25% for osteoporosis and 50% for degrees of severity, and is a diagnostic feature of chronic osteopenia.48 – 51 Rapid loss of bone usually takes place GVHD. Early involvement of fasciae and tendons is within 6–12 months after transplantation. Certain patients associated with edema and an eosinophilic infiltrate, with are more susceptible to bone loss, including elderly, later progression to fibrosis and joint contractures, most women, patients with low body weight (body mass index commonly in fingers, wrists, shoulders, elbows and ankles. o20 to 25 kg/m2), patients who are physically inactive, and Inflammation of the synovium may produce joint effusion. patients who receive extended corticosteroid therapy for As sclerosis progresses insidiously, early detection is often their underlying disease before transplantation or for difficult. Aggressive and prolonged immunosuppressive GVHD after transplantation. Some experts consider therapy is necessary to prevent progression of contractures, prolonged corticosteroid exposure as use of X5mg but it is usually ineffective at reversing established prednisone equivalent daily for 43 months.52 Providers contractures. Early intervention and rehabilitation become should also consider corticosteroid exposure pre-transplan- essential to restore range of motion and strength. Stretch- tation when determining risk for bone loss (for example, as ing exercises and myofascial massage are important to help part of treatment regimens for lymphoma and acute improve the range of motion of affected joints and to lymphoblastic leukemia). The use of calcineurin inhibitors restore functions of daily living.18 Regular survey of range and other immunosuppressive therapy may increase the of motion at all target joints by clinicians as well as patients risk for this complication. is also essential to detect early and potentially reversible Studies suggest that both the total cumulative dose and limitation of movement. the duration of corticosteroid therapy are important factors The presence of a variety of autoantibodies such as for the development of osteopenia.48 Other possible antismooth muscle, antinuclear and antimitochondrial contributing factors include hypogonadism, secondary antibodies after HCT has been observed, but in most cases hyperparathyroidism due to the decrease in serum levels they are not associated with any clinical symptoms. of calcium and vitamin D, and direct toxicity from However, in rare cases donor-derived antiacetylcholine conditioning to bone cells and BM stromal cells. Standard receptor antibodies may be present with clinical manifesta- preventive measures include adequate physical activity in tions of myasthenia gravis.47 Adoptive transfer of abnor- the post-transplant period, use of supplemental calcium

Bone Marrow Transplantation Late effects guidelines for HCT survivors NS Majhail et al 14 and vitamin D, and consideration of estrogen replacement procedures is needed in younger patients with a long life therapy in deficient women. expectancy. Dual-photon densitometry is currently the best tool to assess the degree of bone loss. Osteopenia and osteoporosis Recommendations are differentiated by the degree of reduction in bone mass and can be quantified by T- and Z-scores by dual-photon A screening dual-photon densitometry should be per- densitometry. Normal values of bone density have not been formed at 1 year after transplantation in adult women, well established in children, although it is clear that the loss all allogeneic HCT recipients and patients who are at of bone density and increased risk of fracture is a significant high risk for bone loss after transplantation (for issue in children after HCT. The femur neck and lumbar example, prolonged treatment with corticosteroids or spine are the two most frequently measured sites by bone calcineurin inhibitors). Repeat densitometry should be densitometry. Studies have shown differential effects in the performed in those with recognized defects, ongoing risk extent and length of post-HCT bone density loss. Bone loss factors or to follow up response to therapy. Physicians is more severe, persistent and resistant to therapy in cortical should evaluate gonadal and other related endocrine bones, such as the femur neck, than in trabecular bones, abnormalities in patients with decline in bone density. such as the spine. Patients should be counseled about preventive measures Treatment choices for patients with established osteope- for bone loss and fractures such as physical exercise, fall nia and osteoporosis include active exercise, calcium and prevention, and vitamin D and calcium supplementation. vitamin D supplementation, use of estrogen replacement in Hormone replacement therapy should be discussed with women and minimizing the total exposure and duration of women who have estrogen deficiency. Some experts steroid and other immune-suppressive therapy, if possi- recommend the use of bisphosphonates for patients at ble.48 Bisphosphonate therapy should be considered for high risk for bone loss. treatment of patients with established osteopenia and Screening for AVN is not recommended; however, osteoporosis, patients with evidence of progressive bone clinicians should maintain a high level of suspicion for density loss and patients at high risk for bone loss (for patients with exposure to irradiation or prolonged example, patients with GVHD on extended steroid corticosteroids and evaluate patients with joint symp- therapy). The optimal schedule and duration of bispho- toms promptly. sphonate therapy in HCT is not well established. Bispho- sphonate therapy has also been used in addition to calcium Central and peripheral nervous system and vitamin D supplementation as a preventive measure for complications patients at high risk for osteopenia and osteoporosis, although the data for this intervention are less clear. Neurological complications after HCT may affect the Osteonecrosis of the jaw has been reported in patients central and peripheral nervous system, and are mostly receiving bisphosphonates for osteoporosis, especially secondary to infections, drug-related toxicity and metabolic among those undergoing oral procedures while on these encephalopathy. The effect on cognitive function and level agents.53 If appropriate, dental evaluation should be of alertness can be subclinical with white matter changes performed before starting bisphosphonates in order to detected up to a year later. The reported complication rate detect and correct any dental problems. Long-term use of is higher in allogeneic, especially alternative donor HCT, as bisphosphonates may be associated with subtrochanteric compared with autologous HCT recipients.57,58 fractures of the femur; extended duration of therapy with Complications include central nervous system infections these agents should be carefully considered until more in immunocompromised recipients and vascular complica- information about this association becomes available.54 tions, such as stroke and calcineurin inhibitor–induced Avascular necrosis (AVN) has been described in 4–19% neurotoxicity. Leukoencephalopathy may occur as sequela of HCT survivors. In addition to the risk factors for post- of intrathecal chemotherapy and cranial irradiation. HCT bone loss, inflammatory microvascular changes Patients who have received TBI or cranial irradiation are related to GVHD or other factors may contribute to this at increased risk of secondary solid tumors of the brain on complication.55,56 TBI has been associated with a higher long-term follow-up. Children exposed to TBI are also at incidence of AVN in some reports. Joint pain or discomfort risk for developmental delays. There is growing evidence of is usually the first manifestation of AVN, and standard a GVHD effect on the central nervous system. A cerebral radiographic evaluation may not detect abnormalities until angiitis-like syndrome has been described with cerebral late in the disease course. Joint symptoms in patients at risk ischemic lesions and leukoencephalopathy secondary to should prompt MRI for early detection. While the hip is GVHD. Guillain-Barre–like syndrome with peripheral the most frequently affected joint (over 80% of cases; neuropathy and chronic demyelinating polyneuropathy bilateral in more than 60%), other joints can be affected related to GVHD has been reported.47,59,60 Peripheral including the knees, wrists and ankles. Symptomatic relief neuropathy after HCT may be related to chemotherapy of pain and orthopedic measures to decrease pressure on exposure. the joint can be helpful. Most adult patients with advanced Neuropsychological deficits have been described in AVN will require surgical intervention. Orthopedic nearly 20% of recipients and cognitive deficits in B10% procedures, including core decompression in early cases of HCT recipients. Patients with a history of central and joint replacement, provide a satisfactory outcome in nervous system disease (for example, adenosine deaminase most patients. However, long-term follow-up of these deficiency–associated SCID) and children treated with

Bone Marrow Transplantation Late effects guidelines for HCT survivors NS Majhail et al 15 cranial radiation alone or in combination with chemother- for females. The degree of dysfunction is dependent on age, apy are at higher risk. Cognitive changes may be subtle and gender, pre-transplant therapy and conditioning regimen.65 difficult to detect making it imperative for the clinician to Although the risk of gonadal failure is high in all be vigilant even in patients who do not have any specific individuals, women generally experience higher rates of complaints.59,61 Neurocognitive function generally im- failure than do men. proves over time, but long-term deficits can remain in Women are at high risk of hypergonadotropic hypogo- more than 40% of survivors.62 nadism after HCT.66 Hypogonadism is nearly universal after high-dose irradiation or BU. Risk is lower with CY Recommendations alone. In general, ovarian endocrine failure is irreversible in adult women, but younger women, particularly prepubes- All HCT recipients should undergo clinical assessment cent girls, have a better opportunity for recovery of gonadal for symptoms or signs of neurologic dysfunction at 1 function. year after HCT and at least yearly thereafter. Earlier and Fractionation of radiation reduces the risk compared more frequent evaluations may be considered in high- with unfractionated radiation. Prepubertal girls should be risk patients (for example, allogeneic HCT recipients, monitored closely for onset of puberty and, if puberty is not patients receiving prolonged immune suppression with experienced by age 12–13 years, be referred for full calcineurin inhibitors, patients receiving TBI, cranial endocrinology evaluation and consideration of hormone radiation or intrathecal chemotherapy and patients with supplementation. Adult women should be evaluated by a chronic GVHD). gynecologist and may require hormone replacement ther- Evaluation for cognitive developmental milestones apy to maintain libido, sexual function and bone density. should be performed at least annually in pediatric Libido is often decreased and only partially corrected by patients. Adult patients should be queried annually for hormone replacement therapy in women. Vaginal GVHD changes in cognitive function, which may be subtle. may result in strictures and synechiae. Supplemental Further evaluation (for example, MRI, nerve conduction vaginal lubrication is available and should be discussed studies, electromyography, neuropsychiatry testing) may by the treating physician. be warranted in recipients with symptoms or signs of Most men have normal testosterone levels after trans- neurologic or cognitive dysfunction. plantation, although germ cell damage (infertility) is a near- universal finding in men exposed to high doses of radiation Endocrine complications or chemotherapy. Most reports suggest that prepubertal boys experience normal puberty and demonstrate normal Chemotherapy, radiation therapy and HCT can all result in testosterone levels following HCT.66 Testing and considera- impairment of endocrine function. The most significant tion of hormone replacement therapy for men is recom- endocrine complications are associated with exposure to mended based on symptoms. Failure to progress through radiation and chemotherapeutic agents (for example, BU), puberty in a timely manner should prompt referral for a full chronic GVHD and prolonged corticosteroid exposure.63 endocrinology evaluation. Subclinical, compensated hypothyroidism, with elevated Transplant recipients have a low incidence of primary thyroid stimulatory hormone and normal serum-free T4 adrenal failure after HCT. Chronic therapy with corticos- levels, occurs in 7–15% of patients in the first year after teroids for GVHD will suppress the pituitary–adrenal axis, transplantation. The reported incidence of frank hypothyr- but function usually recovers gradually once exogenous oidism is variable depending upon risk factors in the corticosteroid exposure ends. Greater length and intensity population studied. Single-dose ablative TBI is associated of exposure is generally associated with longer persistence with a 50% incidence of overt hypothyroidism, whereas of adrenal suppression. Patients with prolonged exposure fractionated TBI is associated with an incidence of about to corticosteroids after HCT should have adrenal axis 15%. The incidence reported after BU and CY condition- testing when withdrawing corticosteroids, particularly if ing is 11%. Treatments given before transplantation likely symptoms of adrenal insufficiency develop. Clinicians also contribute to the risk of thyroid abnormalities. The should maintain awareness of possible hypoadrenalism in median time to diagnosis of hypothyroidism is nearly 4 patients receiving long-term corticosteroids who develop years after HCT or TBI exposure. When thyroid stimula- acute illness and consider ‘stress dose’ corticosteroids. tory hormone is elevated with normal T4 levels, assessment Growth in children may be adversely affected by HCT, should be repeated in 2 months, or therapy should be depending upon their pre-transplant therapy and condi- initiated at the discretion of the treating physician. Patients tioning regimen.65,66 A large body of data suggests that who start thyroid hormone replacement should be reas- radiation is associated with growth defects in children who sessed at about 6 weeks after initiation of therapy. Further receive HCT. Cranial radiation, in particular, increases the individual dose adjustment should be based on periodic risk of diminished growth in children. Some reports suggest thyroid assessment, most often recommended at 6-month that chemotherapy alone may cause growth deficiencies. intervals. Autoimmune thyroiditis may also occur follow- Growth is a complicated process and may be adversely ing radiation. Radiation to the neck and TBI has been impacted by many additional factors, including general associated with dose-related increases in risk of thyroid illness, nutritional deficits, hormonal deficiencies, long-term malignancy, often with long latent periods.64 corticosteroids and GVHD. The risk of impaired growth is Gonadal dysfunction is highly prevalent in HCT greatest in the youngest children. Children should be recipients, with rates as high as 92% for males and 99% closely monitored for appropriate growth velocity after

Bone Marrow Transplantation Late effects guidelines for HCT survivors NS Majhail et al 16 HCT. A pediatric endocrinologist should evaluate children exposure, using adequate skin protection and periodic self- who do not achieve adequate growth, and assessment of examination of the skin with prompt referral to a growth hormone levels should be considered. Growth dermatologist for further evaluation and treatment of hormone deficiency following TBI has been demonstrated suspicious skin lesions. in some studies, but not in others. As growth failure is Severe genital GVHD may develop in B12% of women likely to be multifactorial, consideration must be given to with or without associated systemic GVHD.68,69 Patients causes other than inadequate growth hormone. The may present with excoriated or ulcerated mucosa, fissures, benefits of growth hormone supplementation are unclear. narrowing of introitus, or vaginal scarring and obliteration However, in children with demonstrated deficiency, sup- that may lead to hematocolpos. Initial symptoms may be plementation is commonly prescribed. mild and nonspecific, such as dryness, dyspareunia or post- coital bleeding, and if not recognized they may lead to Recommendations important sexual dysfunction. Careful questioning and examination should be performed, as patients without Thyroid function tests (thyroid stimulatory hormone, T3 sexual activity may not detect these abnormalities and and free T4) should be performed at 1 year and yearly sexually active patients may not disclose relevant symp- thereafter in all transplant recipients and additionally if toms. Biopsy may be needed to establish the diagnosis. relevant symptoms develop. Care should be taken when reducing systemic immunosup- Clinical and endocrinologic gonadal assessment at 1 year pression as reactivation of genital GVHD may occur. after HCT is recommended for all women who were Vaginal strictures may limit the performance of routine post-pubertal at the time of transplantation. Frequency Papanicolaou smears as well as sexual intercourse. Treat- of subsequent assessments should be guided by clinical ment of vaginal GVHD includes topical steroids, topical need (for example, menopausal status). Women should CY and vaginal dilators. Surgical intervention can be used have annual gynecologic evaluation as part of general to treat severe cases. In contrast to chronic GVHD, health screening, at which time, hormone replacement patients with hypoestrogenism due to premature meno- therapy should be addressed for those who are post- pause may present with thin and pale vulvar mucosa that menopausal. responds well to lubricants and topical estrogens. However, Gonadal function in men, particularly follicle stimulat- patients may have changes due to GVHD and hypoestro- ing hormone, leutinizing hormone and testosterone, genism concurrently. Genital involvement with GVHD is should be assessed if symptoms warrant (lack of libido less common in men and may result in phimosis. or erectile dysfunction). Consider referral to an endocrinologist for men who may need testosterone replacement therapy. Recommendations Clinical and endocrinologic gonadal assessment of Patients should perform routine self-examination of the prepubertal boys and girls should be initiated 6–12 skin and avoid excessive exposure to sunlight without months after transplantation, with further follow-up adequate protection. schedule determined in consultation with an endocrino- All women recipients of allogeneic HCT should have logist. clinical screening for symptoms of genital GVHD. Patients withdrawing from prolonged corticosteroid usage Women who have established chronic GVHD should should have slow terminal tapering of corticosteroids; have gynecological examination to screen for genital stress doses of corticosteroids may be warranted during involvement. acute illness in patients who have been on chronic Patients should be counseled about self-examination of corticosteroids in the past. the vaginal area, general hygiene measures and early Growth velocity should be monitored every year in all recognition of local symptoms. Application of topical children, with assessment of thyroid function and growth vaginal immunosuppressive agents, such as ultrahigh hormone if growth velocity is abnormal. potency corticosteroids or calcineurin inhibitors, pre- scription of systemic hormonal replacement therapy if Muco-cutaneous complications indicated, and the use of vaginal dilatators should be initiated early in the course of the disease. Late complications involving skin and appendages are frequent after HCT.67 Nearly 70% of patients with chronic Secondary cancers GVHD experience skin involvement. Early changes of lichen-planus–like or papulosquamous lesions may pro- Second malignancies after HCT are a devastating late gress to sclerosis or poikiloderma and can be associated complication. Patients receiving allogeneic HCT have a two with skin ulcers and subsequent infections. Alopecia, to threefold increased risk of developing solid tumors, thinning of scalp hair, nail dystrophy, sweat impairment compared with an age-, gender- and region-adjusted and skin dyspigmentation are common complications after population.59 Nearly all cancer types are described after chronic GVHD. allogeneic and autologous transplant, including oral HCT survivors, especially recipients of allogeneic HCT, cancers, as mentioned above. Risk factors include radiation are at risk for developing secondary cancers of the skin.24 therapy, length, and intensity of immunosuppression and Patients should be counseled about early detection and chronic GVHD.26 However, a recent long-term follow-up prevention of skin cancers, including avoiding excessive sun analysis of patients transplanted after myeloablative doses

Bone Marrow Transplantation Late effects guidelines for HCT survivors NS Majhail et al 17 of BU and CY found similar increased risk.25 Risk ary malignancies. Clinical examination and screening for increases with time after transplantation, particularly for secondary malignancies should follow the recommenda- radiation-related malignancies. Recent analyses suggest tions outlined under the General Health and Preventive that risk of radiation-related (sarcoma, breast and thyroid Screening section. In women with radiation exposure (for cancers) and non-radiation–related (squamous cell carci- example, TBI or radiation to the chest region), initiation noma linked to chronic GVHD) solid tumors continues to of screening mammography should occur at age 25 or 8 increase beyond 10-year post transplantation.24,26 Children years after radiation, whichever occurs later, but no later who have received cranial irradiation are at risk for than age 40 years. Particular attention to oral malig- developing brain tumors. HCT recipients with Fanconi’s nancies should be paid to patients with previous severe anemia are also at risk for developing oro-pharyngeal chronic GVHD of the oral and pharyngeal mucosa. cancers. Providers can consider vaccination against human papilloma virus according to country-specific general Psychosocial adjustment and sexual complications population recommendations.10 All patients should at least receive country-specific general population recommenda- Depressive symptoms and psychological distress are tions for screening for cancers. Screening for breast cancer frequently observed in HCT survivors. Fatigue, anger, is recommended at an earlier age (25 years or 8 years after insomnia and problems with marital relationships may also radiation, whichever occurs later) but no later than age 40 be seen. Pediatric patients may experience altered behavior years among recipients of TBI or chest irradiation. Early patterns, changes in social habits and changes in academic/ referral to a dermatologist should be considered in patients school behavior. At the transition from acute convalescence with skin lesions suspicious for cancer. to long-term follow-up, psychological distress may increase Risk of secondary leukemia or myelodysplasia after rather than abate as the patient and his/her family must autologous HCT is also higher than anticipated, with an cope with changes in roles, employment situations and overall incidence of about 4% at 7 years after transplanta- financial difficulties. Spouses and other caregivers may also tion; with a median onset of 2.5 years (range, 3 months to 7 exhibit high levels of depression and psychological distress. years) post transplantation. Risk appears to be increased They often report loneliness and low levels of perceived for patients receiving prior alkylator therapy, prolonged social support. Children may suffer from separation from administration of conventional chemotherapy and higher one or both parents and the consequences of stress and doses of pre-transplant irradiation.70 upheaval in the family. At a minimum, screening for Post-transplant lymphoproliferative disorders are a rare depression is recommended every 6–12 months after complication of allogeneic HCT associated with greater transplantation, as per the general screening and preventive donor–recipient HLA disparity, T-cell depletion and health section below. Specific tools for screening for GVHD.71 Overall incidence is 1% at 10 years after HCT. psychosocial difficulties after HCT are also available and Although these usually occur early (within 6 months of could be used with a similar frequency to depression transplantation), post-transplant lymphoproliferative dis- screening. Sexual dysfunction occurs in a significant orders is reported as late as 8 years after HCT. The number of survivors and may be multifactorial in origin, majority of post-transplant lymphoproliferative disorders from depression to gonadal hormonal deficiency. are associated with EBV infection. Quantitative PCR detection of EBV reactivation allows prompt initiation of Recommendations anti-CD20 MoAb therapy before development of frank post-transplant lymphoproliferative disorders.59 A high level of vigilance for psychological symptoms should be maintained. Clinical assessment is recommended throughout the recovery period, at 6 months, at Recommendations 1 year and at least yearly thereafter, with mental health Exposure to radiation and photosensitizing effects of professional assessment recommended for those with many commonly used transplantation-related medica- recognized deficits. tions increase the risk of skin cancers among HCT Inquiry as to the level of spousal/caregiver psychological recipients. All HCT recipients should be encouraged to adjustment and family functioning should be performed reduce UV skin exposure through use of high sun at regular intervals. protection factor sunscreens or skin coverage. In adults, sexual function should be queried at 6 months, All patients should be advised of the risks of secondary at 1 year and yearly thereafter (also see section on Muco- malignancies annually and encouraged to routinely cutaneous Complications). perform recommended screening self-examination, such as genital/testicular and skin examination. Women Fertility should discuss breast self-examination with their physicians. All patients should be encouraged to avoid high- Male and female HCT survivors are at risk for infertility risk behaviors, as recommended under General Health secondary to pre-transplant and transplant-related treat- and Preventive Screening section, including avoidance of ment exposures.72,73 Among transplant survivors of the tobacco, passive tobacco exposure or excessive unpro- child-bearing age group, loss of fertility can be associated tected skin UV exposure. with psychological consequences that can affect quality of Screening clinical assessment should be performed life. Conditioning regimens with TBI or BU plus CY can yearly, and should include symptom review for second- cause gonadal failure, although risk may be lower with

Bone Marrow Transplantation Late effects guidelines for HCT survivors NS Majhail et al 18 regimens that include CY only. Older age at transplant and avoidance of excess alcohol intake and regular aerobic chronic GVHD are associated with low likelihood of exercise. gonadal recovery. Non-assisted natural pregnancies follow- Hypercholesterolemia: Cholesterol and high-density lipo- ing gonadal recovery in women or in partners of male protein levels should be checked every 5 years starting at transplant recipients have been reported, but the estimated age 35 years for men and 45 for women. Screening incidence is o15%. should start at age 20 years for anyone who smokes, has The outcome of pregnancy after transplantation is diabetes, hypertension, obesity (body mass index generally good, although women are at increased risk of X30 kg/m2) or a family history of heart disease before fetal and maternal complications and post-transplant age 50 years for male relatives or before age 60 years for pregnancy should be considered a high-risk pregnancy.73 female relatives. Fasting is not required for accurate The incidence of congenital anomalies is not higher than in measurement of cholesterol and high-density lipoprotein, the normal population and the rate of miscarriage is not but is required for low-density lipoprotein and triglycer- increased. Women exposed to TBI have a higher than ides. As a rough guideline, total cholesterol levels normal incidence of preterm deliveries and low or very low 4200 mg/dL (45.0 mmol/L) or high-density lipoprotein birth weight infants. Irradiation may result in uterine vessel levels o40 mg/dL (o1 mmol/L) should be followed up damage and reduce uterine volume. by a full fasting lipid panel. Treatment goals are based on A general recommendation is to delay spontaneous or overall risk of heart disease (for example, greater than a assisted pregnancies for at least 2 years after HCT, as this is 10% chance of coronary heart disease in 10 years). the period of highest risk of relapse after transplantation. Overall risk assessment will include the following risk Contraception counseling in survivors after HCT with factors: age, sex, diabetes, clinical atherosclerotic disease, gonadal recovery is recommended and contraception is hypertension, family history, low high-density lipopro- advisable if fertile or if fertility status is not known and tein (o40 mg/dL or 1.0 mmol/L) and smoking. An pregnancy is not desired. Even if infertile, barrier contra- online calculator is available at http://www.nhlbi.nih.- ception is recommended with new partners to prevent gov/guidelines/cholesterol/index.htm. sexually transmitted diseases. Colorectal cancer: Screening should start at age 50 years Women with gonadal recovery should also be advised in the absence of a family history (first-degree relative about the risks of premature menopause. diagnosed with colorectal cancer before age 60 years). The interval of testing depends on the type of testing Recommendations procedure and the prior screening results. There are several screening approaches including annual fecal Consider referral to appropriate specialists for patients occult blood testing (3 cards at home), sigmoidoscopy who are contemplating a pregnancy or are having every 5 years with fecal occult testing every 3 years or difficulty conceiving. colonoscopy every 10 years. Virtual computerized Although infertility is common, patients should be tomography is a new method, currently under investiga- counseled regarding birth control post transplantation. tion. No one approach alone or in combination has proven superior; however, a single digital rectal exam- General screening and preventive health ination with occult blood testing is not recommended. Diabetes: Screening for type 2 diabetes is indicated for In addition to transplant-specific risk factors mentioned people every 3 years after age 45 years or in those with above, HCT survivors face general risks found in the non- sustained higher blood pressure (4135/80) because transplanted population. In general, transplant survivors blood pressure targets are lower for diabetics. A fasting should be under the care of physicians comfortable with plasma glucose 4126 mg/dL (47 mmol/L), confirmed providing care for general health and hematology-oncology– by testing on another day, is diagnostic for diabetes. specific issues. Summarized below are screening and lifestyle Depression: Asking two simple questions about mood recommendations for the general adult population that are and anhedonia (‘‘Over the past 2 weeks, have you felt also relevant for HCT survivors. Further details about down, depressed, or hopeless?’’ and ‘‘Over the past 2 screening recommendations for adults and children can be weeks, have you felt little interest or pleasure in doing found at http://www.uspreventiveservicestaskforce.org.74,75 things?’’) is probably as effective as longer screening tools. Frequency of screening is not stated, but it is Recommended screening for all patients reasonable to screen every 6- to12-month post transplantation or as clinically indicated. Affirmative answers Hypertension: Blood pressure should be checked at least to the questions above should trigger in-depth evaluation every 2 years. In children, hypertension is defined as for depression to determine the need for pharmacological readings greater than the 95th percentile for age, sex and or psychotherapeutic treatments. height. Treatment is indicated for readings of greater Sexually transmitted diseases: Chlamydia screening is than 140/90 in adults on two separate visits at least 1 recommended for women under the age of 25 years who week apart, unless hypertension is mild or can be are sexually active. Screening and appropriate treatment attributed to a temporary condition or medication (for decrease the incidence of pelvic inflammatory disease and example, CYA). Non-pharmacological treatments may pregnancy-related complications, although most women also be tried for mild hypertension and include moderate will be infertile after myeloablative transplantation. Male dietary sodium restriction, weight reduction in the obese, and female survivors should be reminded that protection

Bone Marrow Transplantation Late effects guidelines for HCT survivors NS Majhail et al 19 against sexually transmitted disease is important even availability of tests and procedures. Furthermore, issues when pregnancy is unlikely or impossible. related to healthcare access (for example, distance to transplant center or health-care facility with adequate expertise and resources) may restrict the ability of some Sex-specific recommendations patients to obtain screening and preventive care. In Recommended screening for men: circumstances where resource limitations do not allow for Prostate cancer: There is no consensus about the use of comprehensive evaluation and follow-up, health-care pro- prostate-specific Ag or digital rectal examination for viders should use their best clinical judgment in determin- prostate cancer screening. ing appropriate preventive care for HCT survivors based on their individual exposures and risk factors for long-term Recommended screening for women: complications. Breast cancer: Screening with mammograms should start at age 40 years and occur every 1–2 years. Breast self- examination is not recommended. In women exposed to Long-term follow up of HCT recipients 4800 cGy radiation, screening should start at age 25 or 8 years after radiation exposure, whichever is later but no To facilitate transition of HCT recipients from one phase of later than age 40 years, based on the data from post-transplant care to another, transplant providers Hodgkin’s lymphoma survivors. should provide HCT recipients with a survivorship care Cervical cancer: Screening with pap smears should be plan that includes a treatment summary and a follow-up performed every 1–3 years in women older than 21 or care plan. This document can serve as an instrument for within 3 years of initial sexual activity, whichever occurs reminding providers about appropriate surveillance for late earlier. complications based on an individual patient’s risk factors Osteoporosis: Screening with a bone density test should and exposures. As survivors can be at risk for late relapse, start at age 65 years for women in the general the care plan should also include appropriate follow-up for population, or if the individual’s fracture risk is the disease for which HCT was performed. Survivorship equivalent to a 65-year-old woman (9.3% risk at 10 care plan instruments that are specific to HCT recipients years).76 An online calculator is available to determine are lacking. Until they are routinely available, providers the 10-year risk of fracture (http://www.shef.ac.uk/ can consider instruments that have been developed for FRAX/). Also see section on Skeletal Complications cancer survivors in general (for example, LIVESTRONG for additional recommendations for HCT recipients. Care Plan (http://www.livestrongcareplan.org), Passport for Care (http://www.txch.org/passportforcare)). In addi- Healthy lifestyle recommendations for all patients tion, providers can consider incorporating the patient version of these guidelines (available at http://www.BeThe- Eat a healthy diet with a wide variety of foods. Match.org/Patient) into a survivorship care plan document Do not smoke (passive or active exposure), chew tobacco for HCT recipients. or use illegal drugs. Long-term survivors of HCT may not receive care at Use alcohol in moderation, generally o2 drinks per day. their transplant center. Because of patient or center Maintain a healthy weight. preference, absence of immediate transplant-related com- Avoid excessive sun exposure and wear sunscreen plications, or distance from the transplant center, trans- protection for anticipated periods of long exposure. plant recipients may transition their care back to their Follow general population age-specific guidelines for hematologist-oncologists, primary care physicians or other physical activity (http://www.health.gov/paguidelines).77 health-care providers. With an increasing number of Adults (aged 18–64 years) should do 2 h and 30 min a transplant survivors, it is likely that non-transplant week of moderate-intensity, or 1 h and 15 min a week of health-care providers will have a greater role in survivor- vigorous-intensity aerobic physical activity or an equiva- ship care and may need to be aware of the unique lent combination of moderate- and vigorous-intensity exposures, risk factors and medical issues these patients aerobic physical activity. Aerobic activity should be face. The working group recognized that the models and performed in episodes of at least 10 min. Adults should primary site for long-term follow-up will vary by country also do muscle strengthening activities that involve all and available resources. On occasion, adherence to major muscle groups performed on 2 or more days per particular recommendations may be inconsistent with week. national or regional guidelines, the availability of specific procedures or medications, or local epidemiological condi- Implementation of guidelines in resource-limited countries tions. Individual clinicians should practice best clinical judgment in implementing these guidelines and when caring Although the working group has provided recommenda- for an individual patient, should consider age, gender, tions that should be applicable to all HCT recipients, they coexisting comorbidities, cancer and transplant-related recognized that resource constraints may limit their exposures and immediate side effects in determining patient implementation, especially in certain geographic regions risks for specific long-term complications. Prevention, and developing countries. Some examples of such chal- screening and management of late complications of lenges include availability of specialists with expertise and transplantation may require a multidisciplinary approach, experience in managing post-transplant complications and with involvement of the transplant center, oncologists,

Bone Marrow Transplantation Late effects guidelines for HCT survivors NS Majhail et al 20 subspecialists, primary care physicians and other health- transplantation and functional status of long-term survivors: care providers, as necessary. report from the Bone Marrow Transplant Survivor Study. Blood 2007; 110: 3784–3792. 3 Bhatia S, Robison LL, Francisco L, Carter A, Liu Y, Grant M et al. Late mortality in survivors of autologous hematopoietic- Conflict of interest cell transplantation: report from the Bone Marrow Transplant Survivor Study. Blood 2005; 105: 4215–4222. The authors declare no conflict of interest. 4 Goldman JM, Majhail NS, Klein JP, Wang Z, Sobocinski KA, Arora M et al. Relapse and late mortality in 5-year survivors of myeloablative allogeneic hematopoietic cell transplantation for Acknowledgements chronic myeloid leukemia in first chronic phase. J Clin Oncol 2010; 28: 1888–1895. We acknowledge the following members of the Late Effects 5 Martin PJ, Counts Jr GW, Appelbaum FR, Lee SJ, Sanders Working Group of the Asia-Pacific Blood and Marrow JE, Deeg HJ et al. Life expectancy in patients surviving more Transplantation Group for their review of this manuscript: than 5 years after hematopoietic cell transplantation. J Clin Mickey Koh (Singapore), Jong Wook Lee (Korea), David Ma Oncol 2010; 28: 1011–1016. (Australia) and Tahir Shamsi (Pakistan). 6 Majhail NS, Bajorunaite R, Lazarus HM, Wang Z, Klein JP, Zhang MJ et al. Long-term survival and late relapse in 2-year survivors of autologous haematopoietic cell transplantation for Hodgkin and non-Hodgkin lymphoma. Br J Haematol Sources of support 2009; 147: 129–139. 7 Rizzo JD, Wingard JR, Tichelli A, Lee SJ, Van Lint MT, The Center for International Blood and Marrow Transplant Burns LJ et al. Recommended screening and preventive Research is supported by Public Health Service Grant/Co- practices for long-term survivors after hematopoietic cell operative Agreement U24-CA76518 from the National Cancer transplantation: joint recommendations of the European Institute, the National Heart, Lung and Blood Institute and the Group for Blood and Marrow Transplantation, the Center National Institute of Allergy and Infectious Diseases; a Grant/ for International Blood and Marrow Transplant Research, Cooperative Agreement 5U01HL069294 from the National and the American Society of Blood and Marrow Transplanta- Heart, Lung and Blood Institute and the National Cancer tion. Biol Blood Marrow Transplant 2006; 12: 138–151. Institute; a contract HHSH234200637015C with Health Re- 8 Rizzo JD, Wingard JR, Tichelli A, Lee SJ, Van Lint MT, sources and Services Administration (HRSA/DHHS); two Burns LJ et al. Recommended screening and preventive grants N00014-06-1-0704 and N00014-08-1-0058 from the Office practices for long-term survivors after hematopoietic cell of Naval Research; and grants from AABB; Allos Inc.; Amgen transplantation: joint recommendations of the European Inc.; anonymous donation to the Medical College of Wisconsin; Group for Blood and Marrow Transplantation, Center for Astellas Pharma US Inc.; Be the Match Foundation; Biogen International Blood and Marrow Transplant Research, and IDEC; BioMarin Pharmaceutical Inc.; Biovitrum AB; Blood- the American Society for Blood and Marrow Transplantation Center of Wisconsin; Blue Cross and Blue Shield Association; (EBMT/CIBMTR/ASBMT). Bone Marrow Transplant 2006; Bone Marrow Foundation; Buchanan Family Foundation; 37: 249–261. CaridianBCT; Celgene Corporation; CellGenix, GmbH; Chil- 9 Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, dren’s Leukemia Research Association; ClinImmune Labs; CTI Storek J et al. 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