Highlights
- •Haploidentical transplantation expands the donor pool for sickle cell anemia patients.
- •GVHD is mitigated by two methods: 1. ex-vivo and 2. in vivo T-cell depletion.
- •Graft failure is reduced by the modifications to the conditioning regimens.
- •New desensitization protocols can reduce levels of donor-specific anti-HLA antibodies.
- •Reduced intensity conditioning, mixed chimerism reduce toxicities with good outcomes.
Abstract
For patients with high-risk sickle cell disease (SCD) without any available matched
sibling or unrelated donor, haploidentical stem cell transplantation (haploHCT) expands
the availability of this life-saving intervention to nearly all patients who may benefit
from HCT. The greatest challenge in haploHCT has been the significant risk of graft
failure. Developing a treatment modality which sustains engraftment without increasing
the incidence of debilitating graft-versus-host disease (GvHD) remains the ultimate
goal. A number of modifications have been explored to overcome the high incidence
of graft rejection and severe GvHD including: (1) ex-vivo T-cell depletion (via CD34+ selection, CD3+/CD19+, or TCRαβ+/CD19+ depletion), and (2) in vivo T-cell depletion using unmanipulated grafts followed
by post-transplant cyclophosphamide (PTCy) for GvHD prophylaxis. Furthermore, the
presence of donor-specific anti-HLA antibodies (DSA) has been associated with an increased
risk of both graft failure and poor graft function. Several approaches for desensitization
ameliorate this risk when a suitable donor without DSA is not available. In addition
to advances in supportive care, the recent demonstration that stable mixed chimerism
post-HCT sufficiently sustains symptom-free status has opened the door for less toxic
treatment approaches yielding excellent survival outcomes. Though late effects remain
uncertain, the goal of finding the least toxic conditioning regimen while providing
the highest rate of donor engraftment draws closer within reach. In this review, the
authors aim to present the latest findings, challenges, and treatment modalities of
this life-saving modality.
Keywords
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References
- Mortality in sickle cell disease. Life expectancy and risk factors for early death.N Engl J Med. 1994; 330: 1639-1644https://doi.org/10.1056/NEJM199406093302303
- Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease.Blood. 2007; 110: 2749-2756https://doi.org/10.1182/blood-2007-03-079665
- Pulmonary, gonadal, and central nervous system status after bone marrow transplantation for sickle cell disease.Biol Blood Marrow Transpl. 2010; 16: 263-272https://doi.org/10.1016/j.bbmt.2009.10.005
- Bone marrow transplantation in sickle cell anemia.Curr Opin Oncol. 2001; 13: 85-90https://doi.org/10.1097/00001622-200103000-00001
- Pulmonary complications of sickle cell disease.N Engl J Med. 2008; 359: 2254-2265https://doi.org/10.1056/NEJMra0804411
- Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients.Med (Baltim). 2005; 84: 363-376https://doi.org/10.1097/01.md.0000189089.45003.52
- Definitions of the phenotypic manifestations of sickle cell disease.Am J Hematol. 2010; 85: 6-13https://doi.org/10.1002/ajh.21550
- Circumstances of death in adult sickle cell disease patients.Am J Hematol. 2006; 81: 858-863https://doi.org/10.1002/ajh.20685
- Cardiopulmonary complications leading to premature deaths in adult patients with sickle cell disease.Am J Hematol. 2010; 85: 36-40https://doi.org/10.1002/ajh.21569
- Hematopoietic cell transplantation: a curative option for sickle cell disease.Pedia Hematol Oncol. 2007; 24: 569-575https://doi.org/10.1080/08880010701640531
- Blood and marrow transplantation for sickle cell disease: overcoming barriers to success.Curr Opin Oncol. 2009; 21: 158-161https://doi.org/10.1097/CCO.0b013e328324ba04
- Disparities in the diagnosis and pharmacologic treatment of high serum cholesterol by race and ethnicity: data from the Third National Health and Nutrition Examination Survey.Arch Intern Med. 2002; 162: 929-935https://doi.org/10.1001/archinte.162.8.929
- Unequal treatment: confronting racial and ethnic disparities in health care.J Natl Med Assoc. 2002; 94: 666-668
- Sickle cell disease summit: from clinical and research disparity to action.Am J Hematol. 2009; 84: 39-45https://doi.org/10.1002/ajh.21315
- Do children with sickle cell disease receive disparate care for pain in the emergency department.J Emerg Med. 2010; 39: 691-695https://doi.org/10.1016/j.jemermed.2009.06.003
- HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry.N Engl J Med. 2014; 371: 339-348https://doi.org/10.1056/NEJMsa1311707
- Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma.N Engl J Med. 1989; 320: 197-204https://doi.org/10.1056/NEJM198901263200401
- Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia.Biol Blood Marrow Transpl. 2001; 7: 665-673https://doi.org/10.1053/bbmt.2001.v7.pm11787529
- Haploidentical bone marrow transplantation with post-transplantation cyclophosphamide plus thiotepa improves donor engraftment in patients with sickle cell anemia: results of an international learning collaborative.Biol Blood Marrow Transpl. 2019; 25: 1197-1209https://doi.org/10.1016/j.bbmt.2018.11.027
- HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease.Blood. 2012; 120: 4285-4291https://doi.org/10.1182/blood-2012-07-438408
- Effect of increased dose of total body irradiation on graft failure associated with HLA-haploidentical transplantation in patients with severe haemoglobinopathies: a prospective clinical trial.Lancet Haematol. 2019; 6: e183-e193https://doi.org/10.1016/S2352-3026(19)30031-6
- Cyclophosphamide improves engraftment in patients with SCD and severe organ damage who undergo haploidentical PBSCT.Blood Adv. 2017; 1: 652-661https://doi.org/10.1182/bloodadvances.2016002972
- Haploidentical peripheral blood stem cell transplantation demonstrates stable engraftment in adults with sickle cell disease.Biol Blood Marrow Transpl. 2018; 24: 1759-1765https://doi.org/10.1016/j.bbmt.2018.03.031
Suradej Hongeng, Pakakasama S., Anurathapan U., Andersson B.S. Haploidentical Hematopoietic Stem Cell Transplantation (Haplo-SCT) with Pre-Transplant Immunosuppression and Post-Transplant Cyclophosphamide (Post-Cy) in Severe Thalassemia: A Novel Approach Transplant for Nonmalignant Diseases BMT TANDEM Meeting. San Diego, California: Biology of Blood and Marrow Transplantation; 2015. p. S32.
- HLA haploidentical stem cell transplant with pretransplant immunosuppression for patients with sickle cell disease.Biol Blood Marrow Transpl. 2018; 24: 185-189https://doi.org/10.1016/j.bbmt.2017.08.039
- The evolution of T cell depleted haploidentical transplantation.Front Immunol. 2019; 10: 2769https://doi.org/10.3389/fimmu.2019.02769
- Transplantation of CD3/CD19 depleted allografts from haploidentical family donors in paediatric leukaemia.Br J Haematol. 2014; 165: 688-698https://doi.org/10.1111/bjh.12810
- Long-term outcome and evaluation of organ function in pediatric patients undergoing haploidentical and matched related hematopoietic cell transplantation for sickle cell disease.Biol Blood Marrow Transpl. 2013; 19: 820-830https://doi.org/10.1016/j.bbmt.2013.02.010
- Immune reconstitution and strategies for rebuilding the immune system after haploidentical stem cell transplantation.Ann N Y Acad Sci. 2012; 1266: 161-170https://doi.org/10.1111/j.1749-6632.2012.06606.x
- Haploidentical HSCT for hemoglobinopathies: improved outcomes with TCRalphabeta(+)/CD19(+)-depleted grafts.Blood Adv. 2018; 2: 263-270https://doi.org/10.1182/bloodadvances.2017012005
- Haploidentical CD3 or alpha/beta T-cell depleted HSCT in advanced stage sickle cell disease.Bone Marrow Transpl. 2019; 54: 1859-1867https://doi.org/10.1038/s41409-019-0550-0
- Familial haploidentical stem cell transplant in children and adolescents with high-risk sickle cell disease: a phase 2 clinical trial.JAMA Pedia. 2020; 174: 195-197https://doi.org/10.1001/jamapediatrics.2019.4715
- High risk of graft failure in patients with anti-HLA antibodies undergoing haploidentical stem-cell transplantation.Transplantation. 2009; 88: 1019-1024https://doi.org/10.1097/TP.0b013e3181b9d710
- Complement-binding donor-specific anti-HLA antibodies and risk of primary graft failure in hematopoietic stem cell transplantation.Biol Blood Marrow Transpl. 2015; 21: 1392-1398https://doi.org/10.1016/j.bbmt.2015.05.001
- Risk and prevention of graft failure in patients with preexisting donor-specific HLA antibodies undergoing unmanipulated haploidentical SCT.Bone Marrow Transpl. 2012; 47: 508-515https://doi.org/10.1038/bmt.2011.131
- Donor-specific anti-human leukocyte antigen antibodies were associated with primary graft failure after unmanipulated haploidentical blood and marrow transplantation: a prospective study with randomly assigned training and validation sets.J Hematol Oncol. 2015; 8: 84https://doi.org/10.1186/s13045-015-0182-9
- Donor-specific anti-HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation.Blood. 2011; 118: 5957-5964https://doi.org/10.1182/blood-2011-06-362111
- The detection of donor-directed, HLA-specific alloantibodies in recipients of unrelated hematopoietic cell transplantation is predictive of graft failure.Blood. 2010; 115: 2704-2708https://doi.org/10.1182/blood-2009-09-244525
- Anti-HLA antibodies in double umbilical cord blood transplantation.Biol Blood Marrow Transpl. 2011; 17: 1704-1708https://doi.org/10.1016/j.bbmt.2011.04.013
- The European Society for Blood and Marrow Transplantation (EBMT) consensus guidelines for the detection and treatment of donor-specific anti-HLA antibodies (DSA) in haploidentical hematopoietic cell transplantation.Bone Marrow Transpl. 2018; 53: 521-534https://doi.org/10.1038/s41409-017-0062-8
- Partially mismatched transplantation and human leukocyte antigen donor-specific antibodies.Biol Blood Marrow Transpl. 2013; 19: 647-652https://doi.org/10.1016/j.bbmt.2013.01.016
- Successful engraftment in crossmatch-positive HLA-mismatched peripheral blood stem cell transplantation after depletion of antidonor cytotoxic HLA antibodies with rituximab and donor platelet infusion.Bone Marrow Transpl. 2005; 36: 555-556https://doi.org/10.1038/sj.bmt.1705070
- Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients.Transplantation. 2000; 70: 887-895https://doi.org/10.1097/00007890-200009270-00006
- Rapid hematopoietic recovery with high levels of DSA in an unmanipulated haploidentical transplant patient.Transplantation. 2013; 95: e76-e77https://doi.org/10.1097/TP.0b013e318293fcda
- Overcoming HLA-DPB1 donor specific antibody-mediated haematopoietic graft failure.Br J Haematol. 2010; 151: 94-96https://doi.org/10.1111/j.1365-2141.2010.08305.x
- Quantitatively different red cell/nucleated cell chimerism in patients with long-term, persistent hematopoietic mixed chimerism after bone marrow transplantation for thalassemia major or sickle cell disease.Haematologica. 2011; 96: 128-133https://doi.org/10.3324/haematol.2010.031013
- Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia.Biol Blood Marrow Transpl. 2003; 9: 519-528https://doi.org/10.1016/s1083-8791(03)00192-7
- Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation.Blood. 2017; 129: 1548-1556https://doi.org/10.1182/blood-2016-10-745711
- Relationship between mixed donor-recipient chimerism and disease recurrence after hematopoietic cell transplantation for sickle cell disease.Biol Blood Marrow Transpl. 2017; 23: 2178-2183https://doi.org/10.1016/j.bbmt.2017.08.038
- Using fludarabine to reduce exposure to alkylating agents in children with sickle cell disease receiving busulfan, cyclophosphamide, and antithymocyte globulin transplant conditioning: results of a dose de-escalation trial.Biol Blood Marrow Transpl. 2015; 21: 900-905https://doi.org/10.1016/j.bbmt.2015.01.015
- Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype.JAMA. 2014; 312: 48-56https://doi.org/10.1001/jama.2014.7192
- Allogeneic hematopoietic stem-cell transplantation for sickle cell disease.N Engl J Med. 2009; 361: 2309-2317https://doi.org/10.1056/NEJMoa0904971
- Nonmyeloablative stem cell transplantation with alemtuzumab/low-dose irradiation to cure and improve the quality of life of adults with sickle cell disease.Biol Blood Marrow Transpl. 2016; 22: 441-448https://doi.org/10.1016/j.bbmt.2015.08.036
- Nonmyeloablative matched sibling donor hematopoietic cell transplantation in children and adolescents with sickle cell disease.Biol Blood Marrow Transpl. 2019; 25: 1179-1186https://doi.org/10.1016/j.bbmt.2019.02.011
- Cyclophosphamide-induced immunological tolerance: an overview.Immunobiology. 1996; 195: 129-139https://doi.org/10.1016/S0171-2985(96)80033-7
- Long-term survival of ex-thalassemic patients with persistent mixed chimerism after bone marrow transplantation.Bone Marrow Transpl. 2000; 25: 401-404https://doi.org/10.1038/sj.bmt.1702151
- Mixed chimerism and transplant tolerance.Immunity. 2001; 14: 417-424https://doi.org/10.1016/s1074-7613(01)00122-4
- Induction of tolerance through mixed chimerism.Cold Spring Harb Perspect Med. 2014; 4a015529https://doi.org/10.1101/cshperspect.a015529
- Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation.Am J Transpl. 2015; 15: 695-704https://doi.org/10.1111/ajt.13091
- Use of hematopoietic cell transplants to achieve tolerance in patients with solid organ transplants.Blood. 2016; 127: 1539-1543https://doi.org/10.1182/blood-2015-12-685107
- High-dose sirolimus and immune-selective pentostatin plus cyclophosphamide conditioning yields stable mixed chimerism and insufficient graft-versus-tumor responses.Clin Cancer Res. 2015; 21: 4312-4320https://doi.org/10.1158/1078-0432.CCR-15-0340
- Conditioning regimens for hematopoietic cell transplantation: one size does not fit all.Blood. 2014; 124: 344-353https://doi.org/10.1182/blood-2014-02-514778
- Donor CD8 cells prevent allogeneic marrow graft rejection in mice: potential implications for marrow transplantation in humans.J Exp Med. 1993; 178: 703-712https://doi.org/10.1084/jem.178.2.703
- Graft-versus-host disease.Lancet. 2009; 373: 1550-1561https://doi.org/10.1016/S0140-6736(09)60237-3
- Effective prevention of GVHD using in vivo T-cell depletion with anti-lymphocyte globulin in HLA-identical or -mismatched sibling peripheral blood stem cell transplantation.Bone Marrow Transpl. 2014; 49: 126-130https://doi.org/10.1038/bmt.2013.143
- MHC-mismatched mixed chimerism augments thymic regulatory T-cell production and prevents relapse of EAE in mice.Proc Natl Acad Sci USA. 2015; 112: 15994-15999https://doi.org/10.1073/pnas.1521157112
- Bone marrow graft-versus-host disease: early destruction of hematopoietic niche after MHC-mismatched hematopoietic stem cell transplantation.Blood. 2010; 115: 5401-5411https://doi.org/10.1182/blood-2009-11-253559
- Contribution of CD4+ and CD8+ T cells to graft-versus-host disease and graft-versus-leukemia reactivity after transplantation of MHC-compatible bone marrow.Bone Marrow Transpl. 1991; 8: 51-58
- Ex vivo T-cell depletion in allogeneic hematopoietic stem cell transplant: past, present and future.Bone Marrow Transpl. 2017; 52: 1241-1248https://doi.org/10.1038/bmt.2017.22
- Donor CD4+ T and B cells in transplants induce chronic graft-versus-host disease with autoimmune manifestations.Blood. 2006; 107: 2993-3001https://doi.org/10.1182/blood-2005-09-3623
- Donor B cells in transplants augment clonal expansion and survival of pathogenic CD4+ T cells that mediate autoimmune-like chronic graft-versus-host disease.J Immunol. 2012; 189: 222-233https://doi.org/10.4049/jimmunol.1200677
- Thymic damage, impaired negative selection, and development of chronic graft-versus-host disease caused by donor CD4+ and CD8+ T cells.J Immunol. 2013; 191: 488-499https://doi.org/10.4049/jimmunol.1300657
- High-dose sirolimus and immune-selective pentostatin plus cyclophosphamide conditioning yields stable mixed chimerism and insufficient graft-versus-tumor responses.Clin Cancer Res. 2015; 21: 4312
- Late effects of blood and marrow transplantation.Haematologica. 2017; 102: 614-625https://doi.org/10.3324/haematol.2016.150250
- Cardiac function after hematopoietic cell transplantation: an echocardiographic cross-sectional study in young adults treated in childhood.Pedia Blood Cancer. 2015; 62: 143-147https://doi.org/10.1002/pbc.25135
- Stable to improved cardiac and pulmonary function in children with high-risk sickle cell disease following haploidentical stem cell transplantation.Bone Marrow Transpl. 2021; 56: 2221-2230https://doi.org/10.1038/s41409-021-01298-7
- Prevalence of and risk factors for cardiac, pulmonary, and neurologic dysfunction following hematopoietic cell transplant for sickle cell disease: a STAR study.Transplant Cell Ther. 2022; 28: S49-S51https://doi.org/10.1016/s2666-6367(22)00219-6
- T-cell replete haploidentical bone marrow transplantation and post-transplant cyclophosphamide for patients with inborn errors.Haematologica. 2019; 104: e478-e482https://doi.org/10.3324/haematol.2018.215285
- CTLA4Ig in an extended schedule along with sirolimus improves outcome with a distinct pattern of immune reconstitution following post-transplantation cyclophosphamide-based haploidentical transplantation for hemoglobinopathies.Biol Blood Marrow Transpl. 2020; 26: 1469-1476https://doi.org/10.1016/j.bbmt.2020.05.005
- Pre-transplant myeloid and immune suppression, upfront plerixafor mobilization and post-transplant cyclophosphamide: novel strategy for haploidentical transplant in sickle cell disease.Bone Marrow Transpl. 2021; 56: 492-504https://doi.org/10.1038/s41409-020-01054-3
- Alternative donor: alphass/CD19 T-cell-depleted haploidentical hematopoietic stem cell transplantation for sickle cell disease.Hematol Oncol Stem Cell Ther. 2020; 13: 98-105https://doi.org/10.1016/j.hemonc.2019.12.006
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Published online: August 28, 2022
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