Abstract

Supportive care has improved the outlook for patients with SCD, but life expectancy remains considerably shorter than those without SCD. The major causes of mortality are end-organ failure, stroke, pulmonary disease, and acute vaso-occlusive crises (VOC). Myeloablative allogeneic HSCT in children under age 16 is curative in the majority. However organ damage that meets severity criteria for HSCT may not become evident until adulthood, at which time conventional myeloablative transplant is no longer an option. Additionally, the great majority of SCD patients do not have a 6/6 HLA-matched sibling donor available. Reduced-intensity conditioning may extend this potentially curative treatment to adults with SCD. Since non-myeloablative transplants may result in mixed donor chimerism, major ABO-mismatch may lead to red cell aplasia, and therefore should be avoided. Finally, cell dose is likely an important parameter in non-myeloablative transplant regimens, potentially further limiting donor availability. We initiated an IRB approved non-myeloablative allogeneic HSCT program for adults with severe SCD for whom a matched sibling donor is available. For those without related donors, we devised a search strategy for alternative donors to establish the feasibility of matched unrelated donor (MUD) or umbilical cord blood (UCB) HSCT. HLA typing was performed for potential donors and patients who on initial screen met at least one the following criteria: stroke, pulmonary hypertension, sickle related nephropathy, or frequent VOC/ACS not improved by HU. Typing at the serologic level was performed for HLA-A,-B, and at the allele level for HLA-DR B1. For patients without matched sibling donors, searches in the National Marrow Donor Program for marrow and cord blood donors were initiated. Since 2003, we performed initial screening in >100 patients, typed 58 potential recipients and 85 donors, and identified 13 potential recipients (age ≥ 16 years) with matched sibling donors. Two were excluded because of major ABO incompatibility. Among the remaining 43, 10 patients who met all study criteria on full screening were selected for alternative donor searching. MUD search results identified a median of 2.5 (range 0–18) 6/6 HLA-matched donor available. Five individuals had 0, four had 4–6, and one had >15 potential donors. UCB search revealed no patient had a 6/6 HLA-matched, two had 15–16 5/6 HLA-matched, and five had 11–190 4/6 potential donor UCB units. The median UCB units containing ≥ 2 × 10e7 nucleated cells per kg were 0 for 6/6 HLA-matched (range 0–1), 0 for 5/6 HLA-matched (range 0–19), and 8.5 for 4/6 HLA-matched (range 0–190). When ethnic haplotype and allelic frequency, the available ABO status, the likelihood of requiring two UCB units for each adult recipient were considered, 5 had neither MUD nor UCB units available, 2 only had potential UCB units available, and 3 had both MUD and UCB units available. The majority of adults with severe SCD who are eligible for non-ablative allo-HSCT do not have matched sibling donors. Our search shows that the minority of African-American adults have potential alternative donors, 10% and 50% MUD and UCB, respectively. These numbers will likely be reduced when major ABO mismatches are excluded. Further, unlike pediatric patients, one cord blood unit may not provide sufficient cells to overcome the barrier of graft rejection in most adults. Given these limitations, the feasibility of haplo-identical family donor allo-HSCT should be investigated.

Author notes

Disclosure: No relevant conflicts of interest to declare.