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Confidential: for Review Only BMJ Confidential: For Review Only Unresolv ed ethical questions raised by hematopoietic stem cell transplantation using alternative donors in children with sickle cell disease Journal: BMJ Manuscript ID BMJ.2017.039766 Article Type: Analysis BMJ Journal: BMJ Date Submitted by the Author: 05-Jun-2017 Complete List of Authors: de Montalembert, Mariane; Hopital universitaire Necker-Enfants malades, 1. Department of Pediatrics Brousse, Valentine; Hopital universitaire Necker-Enfants malades, Pediatric Department Chakravorty, Subarna; Kings College Hospital, Department of Molecular Haematology Pagliuca, Antonio; King's College Hospital , Department of Haematological Medicine Porter, John; University College London, Department of Haematology Telfer, Paul; Royal London Hospital, 10. Department of Paediatric Haematology and Oncology Vora, Ajay; Great Ormond Street Hospital For Children NHS Trust, Department of Paediatric Haematology Rees, David; King's College Hospital , Department of Haematological Medicine Keywords: sickle cell disease, stem cell transplantation, paediatrics, ethics https://mc.manuscriptcentral.com/bmj Page 1 of 14 BMJ 1 2 3 Unresolved ethical questions raised by hematopoietic stem cell transplantation using 4 5 alternative donors in children with sickle cell disease 6 7 8 Confidential:Curative treatments are potentially Foravailable to Reviewall children with sickle cell Only disease 9 10 (SCD), although the risks of some procedures are very high and it is difficult to know 11 12 if, how and when these high-risk procedures should be offered. 13 14 15 Mariane de Montalembert 1, Valentine Brousse 1, Subarna Chakravorty 2, Antonio 16 17 Pagliuca 3, John Porter 4, Paul Telfer 5, Ajay Vora 6 David C Rees 2 18 19 20 21 1. Department of Pediatrics, Reference Centre for Sickle Cell Disease, Hôpital 22 Universitaire Necker-Enfants Malades, APHP, Paris, France. 23 24 2. Department of Paediatric Haematology, King’s College Hospital, London, UK. 25 26 3. Department of Haematological Medicine, King’s College Hospital, London, 27 28 UK. 29 30 4. Department of Haematology, University College London Hospitals, London, 31 UK. 32 33 5. Department of Paediatric Haematology and Oncology, Barts Health NHS 34 35 Trust, Royal London Hospital, London, UK. 36 37 6. Department of Haematology, Great Ormond Street Hospital for Children, 38 London, UK. 39 40 41 42 43 44 Address for correspondence: 45 46 David Rees, Department of Paediatric Haematology, King’s College Hospital, 47 Denmark Hill, London, SE5 9RS, UK. 48 49 Email: [email protected] 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj 1 BMJ Page 2 of 14 1 2 3 INTRODUCTION 4 5 Sickle cell disease (SCD) is one of the commonest severe inherited conditions 6 7 in the world. It is estimated that 300 000 affected babies are born each year, mostly 8 Confidential:in Africa, although there are approximately For 100 Review000 affected individuals Onlyin the USA 9 10 and up to 50 000 in Europe 1. The prognosis for children born with the condition 11 12 today varies enormously, particularly with geography: only about 20% babies born in 13 2 14 most of Africa are thought to survive to adulthood , whereas in high-income parts of 15 Europe 3 and the USA 4, more than 93% children survive to adulthood, thanks to 16 17 improved basic medical care, screening programmes, vaccinations, prophylactic 18 19 antibiotics, appropriate use of blood transfusions, primary and secondary stroke 20 1 21 prevention and the expanding use of hydroxyurea . 22 In high-income countries, despite improving survival, there remains a group 23 24 of severely affected children with SCD who fail to respond to available treatments 25 26 with hydroxyurea or regular blood transfusion. These children may suffer frequent 27 28 acute complications, including severe pain and acute chest syndrome, or have 29 30 evidence of progressive organ damage, particularly cerebrovascular disease. These 31 children are frequently admitted to hospital, with adverse affects on siblings and all 32 33 other members of the household, making it more difficult for parents to maintain 34 35 paid employment. Even in children with few overt complications, the quality of life 36 37 may be significantly impaired by complications such as reduced exercise tolerance, 38 chronic pain, nocturnal enuresis, jaundice, and delayed puberty. Additionally, 39 40 multiple comorbidities gradually develop with further reductions in quality of life 1. 41 42 In severe patients, these observations have justified the use of more high-risk 43 44 treatments, such as hematopoietic stem cell transplantation (HSCT). 45 46 HSCT has indeed offered the only curative option for SCD, and has been routinely 47 performed in well-resourced countries for this indication for more than 40 years 48 49 using bone marrow donated by HLA-identical siblings. Progressive improvements in 50 51 conditioning and supportive care during the transplantation period have greatly 52 53 reduced the initial risks of death, rejection, and graft-versus-host disease. The best 54 results involve HLA-matched sibling donor transplantation, with mortality of 5% and 55 56 event-free survival of more than 90% 5 6 . These excellent outcomes have even led to 57 7 58 discuss the extension of HSCT to patients with milder forms of the disease . 59 60 https://mc.manuscriptcentral.com/bmj 2 Page 3 of 14 BMJ 1 2 3 However, this therapy is limited by the availability of suitable donors, with HLA- 4 6 5 identical siblings available in only 10 - 20% of cases . In order to expand the number 6 7 of children who might benefit from HSCT, there have been important attempts to 8 Confidential:develop new protocols using alternative For donors, Review where the donor is either Only an 9 10 unrelated HLA-identical donor or haploidentical (parent or sibling with one matched 11 12 HLA haplotype). It is starting to emerge that these alternative donor transplants are 13 14 associated with significantly higher risks of death and rejection, and here we address 15 the question of when these transplants should be used, and what risks are 16 17 acceptable when trying to cure a chronic disease like SCD. 18 19 20 21 WHAT ARE THE RISKS OF HEMATOPOIETIC STEM CELL TRANSPLANTS USING 22 ALTERNATIVE DONORS? 23 24 Two such studies have recently been presented, with both showing a 25 26 disappointingly high mortality rate. Shenoy et al published a trial of unrelated bone 27 28 marrow transplantation for children with SCD: 29 children were evaluable, of whom 29 8 30 7 died (24%), and 38% had extensive graft-versus host disease at 1 year . 31 Several reports of haploidentical hematopoietic stem cell transplants have 32 33 been published in the past 5 years 9-11 (Table 1). Although the studies are small and 34 35 outcomes are very variable, none produced a disease-free survival of more than 36 37 82%. Dhedin et al recently presented the results of the largest cohort using 38 haploidentical bone marrow donors in children with SCD, which showed slightly 39 40 more encouraging results 11 . The study was not a formal clinical trial and used 41 42 different approaches at different times, and the first five patients were adults. The 43 44 second phase involved 22 children, age 3 – 18 years, with 3 deaths (14%), 2 patients 45 46 with graft failure (9%), and an event free survival of 82%. Overall in these two trials, 47 51 children were transplanted using alternative donors and 10 died (20%). 48 49 Comparing these later results with those published by Gluckman et al on 50 5 51 HLA-identical transplants , which included several different protocols from 1986 to 52 53 2013, we observe a doubling of transplant related death (14% vs. 7%) and a dramatic 54 increase of graft rejection (see Table 1). The excellent benefit-risk ratio 55 56 characterizing transplantation with HLA-identical sibling is severely impaired when 57 58 59 60 https://mc.manuscriptcentral.com/bmj 3 BMJ Page 4 of 14 1 2 3 alternative donors are used as a source for hematopoietic stem cells. Several ethical 4 5 concerns are therefore raised. 6 7 Indications for transplantation in Shenoy’s publication were >2 episodes of 8 Confidential:acute pain per year (12 children), abnormalFor transcr Reviewanial Doppler velocities Only (2 9 10 children) and >1 episode of acute chest syndrome (4 children). Randomized 11 12 controlled trials suggest that these complications can be effectively managed with 13 12 13 14 14 hydroxyurea or regular blood transfusions , although neither of these options is 15 curative. Chronic transfusion also carries significant risks, particularly iron overload 16 17 and red cell alloimmunisation, although these can be effectively mitigated using iron 18 19 chelation and erythrocytapheresis procedures, and extensive blood group typing 20 21 respectively. 22 23 24 WHAT RISKS ARE ACCEPTABLE TO CURE A CHILD WITH SICKLE CELL DISEASE? 25 26 Our experience is that many parents value curative treatments very highly, 27 28 and are prepared to take high risks on behalf of their children to achieve a cure and 29 30 escape transfusion programmes, and the daily burden of SCD itself. This is illustrated 31 by a study in the 1990s showing that 12% parents of children with SCD were willing 32 33 to accept a short-term transplant-related mortality of more than 50% 15 . Young 34 35 children are unable to give consent, and the parents are responsible for taking this 36 37 very difficult decision. There has been little recent research in to the opinions of 38 families and children on the risks of potentially curative treatments in SCD, 39 40 particularly in the light of improving medical outcomes and the widening options for 41 42 curative treatments, which now include the possibility of transplantation as an adult.
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