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Role of Hematopoietic Stem Cell Transplantation for Hemoglobinopathies

Posted By CTTC, Tuesday, August 28, 2018


Author: Gregory Guilcher, MD, FRCPC, FAAP

Dr. Guilcher is an associate professor of oncology and paediatrics at the University of Calgary. His clinical and research focus is hematopoietic cell transplantation (HCT) for non-malignant diseases. He also studies acute and late effects of oncologic and BMT therapies. He serves as the Vice Chair of the Board of Directors and Clinical Operations for the Sickle Transplant Alliance for Research and is the Chair Mentee of the HCT Late Effects Taskforce for the Children's Oncology Group.

He is Program Director for Pediatric Hematology/Oncology at the University of Calgary, volunteers in several roles with the Royal College of Physicians and Surgeons of Canada and teaches regularly in Mbarara, Uganda.

Reviewed by: Kylie Lepic, MD, FRCPC

Hemoglobinopathies comprise the most common monogenetic disorders worldwide. With newborn screening programs and immigration from endemic regions, Canadian hematology clinics across the country are providing comprehensive care to more children, adolescents and adults with transfusion dependent thalassemias (TDT) and sickle cell disease (SCD) than ever before. While supportive care is improving and novel therapies are emerging, long-term complications of iron burden or sickling crises prompt patients, families and care providers to explore potential curative options. Hopefully gene therapy will become an accessible reality in the coming years. At present, allogeneic hematopoietic cell transplantation (HCT) is the only established cure for TDT and SCD.

HCT has been applied to children with TDT and SCD for over 30 years. Historically HCT was offered more routinely to children with TDT, since patients with these genotypes have, by definition, a clear phenotype with more clearly defined risks of chronic transfusion and iron burden and impact on quality of life. However, with newer chelation agents and generally good self-reported quality of life, those with TDT can maintain good health in higher resource settings for decades. Despite better supportive care, many patients and families want to explore HCT as a curative option.

HCT for Transfusion Dependent Thalassemias

The likelihood of a full sibling being an unaffected HLA-matched donor is 15-20%, with trait donors acceptable. This leaves the majority of patients with TDT without a familial match, and unrelated donor HCT carries lower rates of thalassemia-free survival (TFS) due to risks of graft rejection, graft-versus-host disease (GVHD) and transplant-related mortality (TRM). Infertility risk with myeloablation is an important consideration. We also know that children under 7 years of age have fewer transplant-related complications, with adults typically faring more poorly. Pesaro classification of iron burden is also an important prognostic factor to consider. However, with newer reduced toxicity approaches using either reduced-intensity conditioning (RIC) or less toxic myeloablative agents such as treosulfan, rates of TFS exceed 80% for both matched-sibling and matched-unrelated donors with lower iron burden. Treosulfan-based regimens and the addition of alkylating agents such as thiotepa have- in some series- negated the prognostic value of matched related vs unrelated donors, as well as Pesaro status. Our centre has adopted an Italian protocol consisting of treosulfan (14 g/m2/day x 3), fludarabine (40 mg/m2/day x 4), and thiotepa (8 mg/kg/day x 1), with ATG added for matched unrelated donor transplants. Marrow allografts are typically preferred by most centres. While haploidentical-HCT offers the hope of cure to all patients, the data is still in its infancy but is evolving quickly.

For patients with TDT I would recommend:

a) All children and adolescents with TDT be offered HLA typing of full siblings and parents (particularly if there is a history of consanguinity)
b) HLA-matched sibling donor reduced toxicity HCT be offered routinely to children and adolescents after appropriate counselling, including a discussion of best supportive care and late effects such as infertility
c) HLA-matched unrelated living donor HCT can be considered by centres with expertise, with  consideration of a reduced-toxicity conditioning approach
d) Unrelated umbilical cord blood, mismatched unrelated and haploidentical HCT remain experimental and should only be performed in the context of a well designed clinical trial
e) HCT for adults with TDT should be undertaken with caution at centres with expertise, with consideration of a reduced-toxicity conditioning approach
f) Fertility counselling and preservation options should be offered

HCT for Sickle Cell Disease

Who and when to offer HCT for SCD has been the topic of great debate since the first successful HCT was described in 1984. Phenotypes can vary, with sometimes unpredictable and devastating complications such as stroke. Better supportive care options such as penicillin prophylaxis, vaccination, transcranial Doppler screening, hydroxyurea and chronic transfusions for select patients have allowed over 95% of children to reach late adolescence and young adulthood in high income countries. Newer targeted agents hold promise to further improve quality of life by reducing crises and time in hospital. However, even with optimal supportive care in 2018, many patients still have strokes and other significant morbidities which impact quality and quantity of life into adulthood. Restrictive pulmonary disease and right-sided heart failure, while rare in childhood, are ominous predictors of mortality in adulthood.
Further complicating the debate are clearly superior outcomes when HCT is performed at a younger age, perhaps when a patient’s phenotype may not be severe. The risk of GVHD increases with age, as does potential alloimmunization with associated risk of graft rejection. With the high risk of infertility with traditional myeloablative approaches, the decision to refer a child for consideration of HCT has been difficult for hematologists and families, and HCT physicians have had appropriate reservations about offering transplantation. 

At present, children with a matched sibling donor can expect ~95% chance of cure with HCT. Rates of GVHD have been in the range of ~20% for aGVHD and ~5-15% for cGVHD; children over 14 years of age are at higher risk of this undesired complication, which is the main cause of TRM in HCT for SCD. While such high rates of cure are promising and position well against lifetime risks of SCD, these rates of GVHD are not insignificant. Again, only 15-20% of full siblings will be unaffected HLA-matches (HbAA or HbAS acceptable), limiting access to HCT.
Fortunately, newer RIC and nonmyeloablative offer the possibility of cure with fewer acute and late adverse effects. Fertility preservation is possible, the importance of which should not be underestimated. Experience with very low intensity regimens such as one developed at the National Institutes of Health (USA) has been administered in over 60 children and adults (many of these adults having significant co-morbidities) with very high rates of success (87-100% event-free survival) and no cases of acute or chronic GVHD. This regimen includes alemtuzumab/300 cGy total body irradiation with sirolimus for GVHD prophylaxis. The NIH regimen employs unmanipulated peripheral blood stem cells with no maximum cell dose, in contrast to most published sibling donor HCT regimens for SCD which stipulate bone marrow allografts. As regimens become safer and novel targeted supportive care agents are developed, the position of HCT against best supportive care is in constant evolution.

HCT for SCD should be undertaken with unique supportive care precautions. HbS levels should be less than 30-40% prior to HCT to avoid crisis during HCT. These HbS levels can be achieved with either simple or exchange transfusions. Platelets should be maintained greater than 50 x 109/L to avoid intracranial hemorrhage, particularly in those with neurovascular disease. Due to high rates of posterior reversible encephalopathy syndrome- as high as 20-40% when cyclosporine is used for GVHD prevention- it is advised to avoid hypertension and keep magnesium levels normal. Hb levels should be maintained between 90-110 g/L to avoid both hypoxia and hyperviscosity. G-CSF is avoided pre-engraftment due to the risk of splenic sequestration in patients with SCD. 

If engraftment is successful, it is hoped that no new sickling injury will occur, while existing organ dysfunction is unlikely to improve. Even 20-25% donor myeloid chimerism can be curative, and HbS levels of the recipient should reflect those of the donor. Sickling crises are not expected if the HbS level is less than 50%. Studies of long-term outcomes including neurocognitive measures, self-reported pain metrics and more detailed descriptions of end organ function into adulthood should be the focus of future research efforts.

All trials of alternative donor HCT have had either unacceptably high rates of GVHD or graft failure. Promising areas of research include novel GVHD prevention strategies with agents such as abatacept and haploidentical HCT with either post-HCT cyclophosphamide or ex-vivo graft manipulation. Given that many patients with SCD do not have fully matched related or unrelated donors, strategies which allow for safe HCT with mismatched unrelated or haploidentical donors are critical to expand access to cure. International consortia such as the CBMTG, Sickle Transplant Alliance for Research (STAR) and Monacord are dedicated to advancing safe curative therapies for SCD using HCT.

For patients with SCD I would recommend:

a) All patients with SCD be offered HLA typing of full siblings and parents (particularly if there is a history of consanguinity)
b) HLA-matched sibling donor HCT be offered routinely to children and adolescents after appropriate counselling, including a discussion of best supportive care and late effects such as infertility
c) HCT for adults with an HLA-matched sibling donor should be undertaken with caution at centres with expertise, with consideration of a reduced-toxicity approach
d) Alternative donor HCT should only be performed in the context of a well designed clinical trial
e) Fertility counselling and preservation options should be offered


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3. King AA, Kamani N, Bunin N, Sahdev I, Brochstein J, Hayashi RJ, et al. Successful matched sibling donor marrow transplantation following reduced intensity conditioning in children with hemoglobinopathies. Am J Hematol. 2015 Dec;90(12):1093-8.  
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9. Cappelli B, Tozatto-Maio K, Volt F, Paviglianiti A, Ferster A, Dupont S, et al.  Risk factors and outcomes according to age at transplant with an HLA Identical sibling for sickle cell disease. Blood 2017 130:3317
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11. Guilcher GMT, Truong TH, Saraf SL, Joseph JJ, Rondelli D, Hsieh MM. Curative therapies: Allogeneic hematopoietic cell transplantation from matched related donors using myeloablative, reduced intensity, and nonmyeloablative conditioning in sickle cell disease. Semin Hematol. 2018 Apr;55(2):87-93 
12. Chaudhury S, Laskowski J, Rangarajan H, Abraham A, Haight A, Guilcher G, et al. Abatacept for GVHD prophylaxis after hematopoietic stem cell transplantation (HCT) for pediatric sickle cell disease (SCD): A Sickle Transplant Alliance for Research (STAR) Trial. Biology of Blood and Marrow Transplantation, Vol. 24(3), S91

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