Alternative Donor/Unrelated Donor Transplants for the β-Thalassemia and Sickle Cell Disease

Abstract

Considerable progress with respect to donor source has been achieved in allogeneic stem cell transplant for patients with hemoglobin disorders, with matched sibling donors in the 1980s, matched unrelated donors and cord blood sources in the 1990s, and haploidentical donors in the 2000s. Many studies have solidified hematopoietic progenitors from matched sibling marrow, cord blood, or mobilized peripheral blood as the best source-with the lowest graft rejection and graft versus host disease (GvHD), and highest disease-free survival rates. For patients without HLA-matched sibling donors, but who are otherwise eligible for transplant, fully allelic matched unrelated donor (8/8 HLA-A, B, C, DRB1) appears to be the next best option, though an ongoing study in patients with sickle cell disease will provide data that are currently lacking. There are high GvHD rates and low engraftment rates in some of the unrelated cord transplant studies. Haploidentical donors have emerged in the last decade to have less GvHD; however, improvements are needed to increase the engraftment rate. Thus the decision to use unrelated cord blood units or haploidentical donors may depend on the institutional expertise; there is no clear preferred choice over the other. Active research is ongoing in expanding cord blood progenitor cells to overcome the limitation of cell dose, including the options of small molecule inhibitor compounds added to ex vivo culture or co-culture with supportive cell lines. There are inconsistent data from using 7/8 or lower matched unrelated donors. Before routine use of these less matched donor sources, work is needed to improve patient selection, conditioning regimen, GvHD prophylaxis, and/or other strategies.

Goal-Oriented Monitoring of Cyclosporine Is Effective for Graft-versus-Host Disease Prevention after Hematopoietic Stem Cell Transplantation in Sickle Cell Disease and Thalassemia Major

“…In SCA, matched unrelated donors also appeared to be the next best option after MSDs for HSCT, but high rates of aGVHD and cGVHD were previously reported. In these studies conditioning regimens varied from myeloablative to reduced intensity, and umbilical cord blood was used [37]. Better control of GVHD and immunosuppression by strict monitoring of CsA TBC as described herein is promising and could play a crucial role in HSCT.…”

Stem cells in the treatment of sickle cell disease

“…18 However, more recent regimens are able to successfully remove immunosuppressants within 6 months while still achieving mixed chimerism in the recipients. 18 While promising results support allogeneic matched HSCT, donor availability is among the major limitations behind stem cell transplantation as a curative therapy for SCD 17,28 Recommendations by the National Bone Marrow Donor Program recommend high-level matching at the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci or an 8/8 match. 17 An 8/8 matched donor is ideal for HSCT, but less than 20% of patients with symptomatic SCD will have an unaffected HLAmatched sibling.…”

“…25 The likelihood of two siblings being HLA-identical is only 25% which accounts for the limitation in donor availability. 28 In addition, because SCD has genetic origins, it is likely that the siblings of an affected individual are also affected. Both of these phenomena contribute to the fact that donor availability is a primary barrier preventing the use of HSCT in SCD.…”

Curative options for sickle cell disease: haploidentical stem cell transplantation or gene therapy?

“…Given the lack of eligible patients with an HLA‐matched sibling, optimizing alternative donor HSCT is critical for offering more patients an opportunity for cure (Fitzhugh et al , ; Joseph et al , ). Data regarding unrelated cord blood or bone marrow (BM) donors for patients with SCD remain limited, however, particularly given less common, more diverse haplotypes in Africans than the Caucasian population, and an underrepresentation of ethnic minorities in donor registries worldwide (Krishnamurti et al , ; Switzer et al , ).…”