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. 43 44 Similarly, there are few ethical analyses trying to balance the benefits of cure against 45 46 the risks of death, or studies on how to present these difficult choices to children 47 and parents. It is important that these patient-focused and ethical aspects are 48 49 developed in parallel with medical and transplantation advances. Our feeling is that 50 51 the absence of HLA-identical sibling does not justify taking considerable risks using 52 53 alternative donors in the vast majority of cases, although it is sometimes the case 54 that parents are considerably keener on very-high risk curative procedures than their 55 56 child’s clinicians. Indeed, SCD is a chronic condition with a very variable clinical 57 58 59 60 https://mc.manuscriptcentral.com/bmj 4 Page 5 of 14 BMJ

1 2 3 course, even in similar socio-economic settings; figures suggest a median survival of 4 16 5 more than 60 years in high-income countries . 6 7 Overall survival is approximately comparable to other chronic illnesses such 8 Confidential:as insulin-dependent diabetes mellitus, For and cystic Review fibrosis (CF). In CF, an Onlyequivalent 9 10 dilemma surrounds the timing of lung transplantation, as a life-saving but high-risk 11 12 procedure, which has an approximate 30% mortality at 5 years. Guidelines 13 14 recommend that lung transplantation is considered in CF when there is significant 15 impairment of lung function (FEV <30%) corresponding to a median survival of 5-6 16 1 17 years 17 . Although the situations are not directly comparable, it is notable that there 18 19 are agreed guidelines in CF, but no such guidelines in SCD. This is partly because it is 20 21 very difficult to reliably predict survival in children with SCD, although it is also true 22 that very few children with SCD in high-income countries die in childhood 3. There 23 24 will be a wide range of views on acceptable mortality rates for HSCT in SCD, although 25 26 it seems unlikely that a 1-year mortality rate of more than 10% should be acceptable 27 28 in the paediatric SCD population. 29 30 31 WHEN SHOULD ALTERNATIVE DONOR TRANSPLANTATION BE OFFERED? 32 33 The optimal time to offer hematopoietic stem cell transplantation using 34 35 alternative donors is also very uncertain. Late transplants are associated with higher 36 37 toxicity, while early transplants may be responsible for the death of children who 38 would not have suffered severe complications and could have lived more than 60 39 40 years. There is also considerable uncertainty and a lack of research on the long-term 41 42 effects of bone marrow transplantation for SCD, particularly using alternative 43 18 44 donors . Indications for entry in to these high-risk trials need to be debated and 45 46 agreed more widely, and should include input from transplanters, paediatricians, 47 haematologists, patient groups and ethicists. More work is also required to identify 48 49 prognostic factors which will reliably identify children likely to follow a severe clinical 50 51 course. 52 53 The decision is complicated by the improved and improving prognosis with 54 medical management, and emergence of new therapeutic options. A better 55 56 understanding of the pathophysiology of the disease has lead to the development of 57 19 58 drugs acting on inflammatory, coagulation, and endothelial damage pathways . 59 60 https://mc.manuscriptcentral.com/bmj 5 BMJ Page 6 of 14

1 2 3 Excitingly, there is an unprecedented number of clinical trials being undertaken, with 4 5 already promising results, such as the recent evidence for the effectiveness of P- 6 20 7 selectin inhibition , which may reduce very significantly the number of patient with 8 Confidential:refractory pain. Gene therapy and editingFor are also Review offering real promise, Onlywith active 9 10 clinical trials 21 . It is difficult to commit a child to a high risk, curative procedure now, 11 12 when within 10 years there may many more effective non-transplant options and 13 14 adult transplantation may be the preferred option; the latter offers the added 15 advantage that the patient is able to give consent themselves. 16 17 18 19 CLINICAL TRIALS IN ALTERNATIVE DONOR TRANSPLANATION 20 21 Ideally, some of these questions would be answered by multi-centre randomised 22 controlled trials comparing alternative bone marrow transplantation with optimal 23 24 medical care. Although multi-centre studies are being planned in this area, to our 25 26 knowledge there are no plans for randomised controlled trials in children. The 27 28 reasons for this are complex, not least because of the difficulties of performing such 29 30 studies. It is also complicated by the rapidly developing treatment options in this 31 area: an adequately powered, randomised controlled trial my take more than five 32 33 years to complete, and by the end of the trial both transplant and non-transplant 34 35 arms may be using redundant therapeutic approaches. It is also interesting to reflect 36 8 37 that in the Shenoy study there was a mortality of 24% , whereas in clinical trials of 38 non-transplant therapies in SCD even one procedure-related death is likely to result 39 40 in the suspension or permanent stopping of the study. It could be argued that the 41 42 same standards should apply to novel therapies whether they involve 43 44 transplantation or not. 45 46 47 CONCLUSIONS 48 49 Unfortunately, the vast majority of people with SCD live in low-income countries 50 51 with no foreseeable prospect of either medical or curative treatments being widely 52 53 available, and the development of low-cost effective interventions for these patients 54 would have the greatest impact 2. However, in theory every patient with SCD could 55 56 now be offered curative treatment for their disease by hematopoietic stem cell 57 58 transplantation, although for the majority, without an HLA-identical sibling, this 59 60 https://mc.manuscriptcentral.com/bmj 6 Page 7 of 14 BMJ

1 2 3 currently involves procedure related mortality of 10 – 24%. It is difficult to know how 4 5 or when these high risk procedures should be offered, but we encourage the 6 7 development of randomised controlled trials and more research into offering these 8 Confidential:very difficult decisions to parents andFor children. TReviewhe medical community mustOnly work 9 10 with patients and parents on how to increase the availability of transplants, while 11 12 addressing ethical questions with the same priority as the technical ones. 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj 7 BMJ Page 8 of 14

1 2 3 4 5 6 7 Box with key messages 8 Confidential:• In high-income countries, new For treatments Review are being developed inOnly sickle cell 9 10 disease, with the likelihood that prognosis will improve significantly in the 11 12 near future using non-transplant approaches. 13 14 • Curative treatments are now potentially available to all patients using 15 16 haematopoietic stem cell transplantation from alternative donors, although 17 the risks of these procedures are very high. 18 19 • It is not known or agreed when these high-risk transplants should be offered 20 21 to children, or how parents should be counselled to give appropriate consent. 22 23 • Research is needed to develop safer transplants, and also in to the ethics of 24 offering high-risk procedures to children with sickle cell disease and other 25 26 chronic conditions. 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj 8 Page 9 of 14 BMJ

1 2 3 4 5 References 6 7 1. Brousse V, Makani J, Rees DC. Management of sickle cell disease in the 8 Confidential:community. BMJ 2014;348:g1765. For doi: 10.1136/bmj.g1765Review [published Only Online 9 First: 2014/03/13] 10 2. Makani J, Cox SE, Soka D, et al. Mortality in sickle cell anemia in Africa: a 11 prospective cohort study in Tanzania. PLoS One 2011;6(2):e14699. doi: 12 10.1371/journal.pone.0014699 [published Online First: 2011/03/02] 13 14 3. Telfer P, Coen P, Chakravorty S, et al. Clinical outcomes in children with sickle cell 15 disease living in England: a neonatal cohort in East London. Haematologica 16 2007;92(7):905-12. [published Online First: 2007/07/04] 17 4. Quinn CT, Rogers ZR, McCavit TL, et al. Improved survival of children and 18 adolescents with sickle cell disease. Blood 2010;115(17):3447-52. doi: 19 20 10.1182/blood-2009-07-233700 21 5. Gluckman E, Cappelli B, Bernaudin F, et al. Sickle cell disease: an international 22 survey of results of HLA-identical sibling hematopoietic stem cell 23 transplantation. Blood 2017;129(11):1548-56. doi: 10.1182/blood-2016-10- 24 745711 25 6. Walters MC, De Castro LM, Sullivan KM, et al. Indications and Results of HLA- 26 27 Identical Sibling Hematopoietic Cell Transplantation for Sickle Cell Disease. 28 Biol Blood Marrow Transplant 2016;22(2):207-11. doi: 29 10.1016/j.bbmt.2015.10.017 30 7. Nickel RS, Hendrickson JE, Haight AE. The ethics of a proposed study of 31 hematopoietic stem cell transplant for children with "less severe" sickle cell 32 33 disease. Blood 2014;124(6):861-6. doi: 10.1182/blood-2014-05-575209 34 8. Shenoy S, Eapen M, Panepinto JA, et al. A trial of unrelated bone marrow 35 transplantation for children with severe sickle cell disease. Blood 36 2016;128(21):2561-67. doi: 10.1182/blood-2016-05-715870 37 9. Bolanos-Meade J, Fuchs EJ, Luznik L, et al. HLA-haploidentical bone marrow 38 transplantation with posttransplant cyclophosphamide expands the donor 39 40 pool for patients with sickle cell disease. Blood 2012;120(22):4285-91. doi: 41 10.1182/blood-2012-07-438408 42 10. Dallas MH, Triplett B, Shook DR, et al. Long-term outcome and evaluation of 43 organ function in pediatric patients undergoing haploidentical and matched 44 related hematopoietic cell transplantation for sickle cell disease. Biol Blood 45 46 Marrow Transplant 2013;19(5):820-30. doi: 10.1016/j.bbmt.2013.02.010 47 11. Dhedin N, de la Fuente J, Bernaudin F, et al. Haploidentical bone marrow 48 transplant with post transplant cytoxan plus thiotepa improves donor 49 engraftment in patients with sickle cell anemia: results of an international 50 multicenter learning collaborative. Blood 2016;128:1233. 51 12. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency 52 53 of painful crises in sickle cell anemia. Investigators of the Multicenter Study 54 of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995;332(20):1317-22. 55 doi: 10.1056/NEJM199505183322001 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj 9 BMJ Page 10 of 14

1 2 3 13. Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children 4 with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY 5 HUG). Lancet 2011;377(9778):1663-72. doi: 10.1016/S0140-6736(11)60355-3 6 7 14. Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic 8 Confidential:transfusion for maintenance For of transcranial Review doppler flow velocities Only in children 9 with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea 10 (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet 11 2016;387(10019):661-70. doi: 10.1016/S0140-6736(15)01041-7 12 15. Kodish E, Lantos J, Stocking C, et al. Bone marrow transplantation for sickle cell 13 14 disease. A study of parents' decisions. N Engl J Med 1991;325(19):1349-53. 15 doi: 10.1056/NEJM199111073251905 16 16. Elmariah H, Garrett ME, De Castro LM, et al. Factors associated with survival in a 17 contemporary adult sickle cell disease cohort. Am J Hematol 2014;89(5):530- 18 5. doi: 10.1002/ajh.23683 19 20 17. Elborn JS. Cystic fibrosis. Lancet 2016;388(10059):2519-31. doi: 10.1016/S0140- 21 6736(16)00576-6 22 18. Shenoy S, Angelucci E, Arnold SD, et al. Current Results and Future Research 23 Priorities in Late Effects after Hematopoietic Stem Cell Transplantation for 24 Children with Sickle Cell Disease and Thalassemia: A Consensus Statement 25 from the Second Pediatric Blood and Marrow Transplant Consortium 26 27 International Conference on Late Effects after Pediatric Hematopoietic Stem 28 Cell Transplantation. Biol Blood Marrow Transplant 2017;23(4):552-61. doi: 29 10.1016/j.bbmt.2017.01.009 30 19. Archer N, Galacteros F, Brugnara C. 2015 Clinical trials update in sickle cell 31 anemia. Am J Hematol 2015;90(10):934-50. doi: 10.1002/ajh.24116 32 33 20. Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the Prevention of Pain Crises 34 in Sickle Cell Disease. N Engl J Med 2016 doi: 10.1056/NEJMoa1611770 35 21. Ribeil JA, Hacein-Bey-Abina S, Payen E, et al. Gene Therapy in a Patient with 36 Sickle Cell Disease. N Engl J Med 2017;376(9):848-55. doi: 37 10.1056/NEJMoa1609677 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj 10 Page 11 of 14 BMJ

1 2 3 Contributors and Sources 4 5 This Analysis article arose out of concern amongst the authors following the 6 7 publication of results showing high mortality rates using alternative donor HSCT in 8 Confidential:children with HSCT. DCR wrote an initialFor draft, whiReviewch was fully revised and Only improved 9 10 by MdM. MdM summarized the results of previous trials of alternative-donor 11 12 transplantation. DCR circulated the different authors for their views, including 13 14 authors from the fields of paediatrics, haematology and transplantation. All authors 15 made significant changes and contributions, and approved the final manuscript. 16 17 18 19 Conflicts of Interest 20 21 MdM has received funding for taking part in clinical trials and advisory boards from 22 Novartis, Pfizer and Addmedica. She received funding to attend academic meetings 23 24 from Novartis and Addmedica. 25 26 VB has received funding from Addmedica for taking part in an advisory board. 27 28 SC has received funding from Novartis and Pfizer for advisory boards and other 29 30 meetings. 31 AP has received funding from Bluebirdbio for attending an advisory board. 32 33 JP has received funding for from Novartis, Celgene and Bluebirdbio for attending 34 35 advisory boards and clinical studies. 36 37 PT has received funding from Bluebirdbio, Global Blood Therapeutics and Pfizer for 38 attending advisory boards; Novartis and Apopharma for attending meetings; and 39 40 Napp and Kyora Kirin for research studies. 41 42 AV has received funding from Amgen, Pfizer, Jazz Pharmaceuticals and Medac to 43 44 attend academic meetings and take part in advisory boards. 45 46 DR has received funding for taking part in clinical trials and advisory boards from 47 Novartis, Eli Lilly and Bluebirdbio. He received funding to attend academic meetings 48 49 from Eli Lilly, Novartis, Biogen, and Addmedica. 50 51 52 53 Licence 54 The Corresponding Author has the right to grant on behalf of all authors and does 55 56 grant on behalf of all authors, an exclusive licence (or non exclusive for government 57 58 employees) on a worldwide basis to the BMJ Publishing Group Ltd ("BMJ"), and its 59 60 https://mc.manuscriptcentral.com/bmj 11 BMJ Page 12 of 14

1 2 3 Licensees to permit this article (if accepted) to be published in The BMJ 's editions 4 5 and any other BMJ products and to exploit all subsidiary rights, as set out in our 6 7 licence. 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj 12 Page 13 of 14 BMJ

1 2 3 4 5 Reference N Median Conditioning OS Rejection DFS GVH TRM 6 age 7 (years) 8 Confidential:Bolanos - 14 22 Pre: FluFor-Cy -TBI Review100% 43% 57% Only0% 0% 9 Meade Post: Cy 10 (2012) 11 12 Dallas 8 9 Flu, thiotepa, 75% 38% 38% 38%cGVH 25% 13 (2013) BU, ATG, OKT3 14 or HU, 15 azathioprine, 16 BU, thiotepa, Cy, 17 OKT3, MMF 18 De la 13SCD+3 10 Pre: 94 6% - 12.5% aGVH 6% 19 Fuente TM Flu,thiotepa, Cy, 6.3% cGVH 20 (2015) TBI 2Gy, ATG 21 Post: Cy, MMF, 22 sirolimus 23 24 Dhed in 25 (2016) 26 strategy 1 5 26.4 Pre: 60% 27 Flu,thiotepa, Cy, 28 TBI 2Gy, ATG 29 Post: Cy, MMF, 30 sirolimus 31 32 7 18.1 Idem+thiotepa 100% 28.5%aGVH 33 34 35 Strategy2 22 10 Azathioprine, 86.4% 9.1% 81.8% 18.2%aGVH+cGVH 13.6% 36 37 HU, 38 hypertransfusion 39 thiotepa 40 41 Outcome of patients receiving haploidentical haematopoietic stem cell transplant 42 43 Gluckman 1000 846 92.9% 2.3% 91.4% 14.8%aGVH 7% 44 (2016) children 14.3%cGVH 45 (median 46 age 9 47 years) 48 154 49 50 adults 51 (median 52 age 53 20 54 years) 55 Outcomes of patients receiving HLA-identical sibling hematopoietic stem cell transplant 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj 13 BMJ Page 14 of 14

1 2 3 Table 1: Summary of results from studies of haploidentical haematopoietic stem cell 4 transplantion in sickle cell disease (top panel) compared to HLA-identical sibling 5 transplantation for the same condition. 6 7 SCD, sickle cell disease; TM, thalassemia major; OS, overall survival; DFS, disease-free 8 Confidential: For Review Only 9 survival; aGVH, acute graft versus host disease; cGVH, chronic graft versus host disease; 10 TRM, transplant related mortality; Flu, fludarabine; BU, busulfan; Cy, cyclophosphamide; 11 ATG, antithymocyte globulin; OKT3, muromonab-CD3; MMF, mycophenolate mofetil; TBI, 12 total body irradiation; HU, hydroxyurea. 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj 14