A trial of unrelated donor marrow transplantation for children with severe sickle cell disease

Abstract

• Children with sickle cell disease engrafted unrelated donor marrow after reduced intensity conditioning.• A high incidence of GVHD and associated mortality compromised safety of the trial.Children with sickle cell disease experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplant from an HLA-matched sibling can halt disease progression but is limited by donor availability. A Blood and Marrow Transplant Clinical Trials Network (BMT CTN) phase 2 trial conducted from 2008 to 2014 enrolled 30 children aged 4 to 19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C, and -DRB1 loci) unrelated donor transplant. The conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, short-course methotrexate, and methylprednisolone. Transplant indications included stroke (n 5 12), transcranial Doppler velocity >200 cm/s (n 5 2), ‡3 vaso-occlusive pain crises per year (n 5 12), or ‡2 acute chest syndrome episodes (n 5 4) in the 2 years preceding enrollment. Median follow-up was 26 months (range, 12-62 months); graft rejection was 10%. The 1-and 2-year EFS rates were 76% and 69%, respectively. The corresponding rates for overall survival were 86% and 79%. The day 100 incidence rate of grade II-IV acute GVHD was 28%, and the 1-year incidence rate of chronic GVHD was 62%; 38% classified as extensive. There were 7 GVHD-related deaths. A 34% incidence of posterior reversible encephalopathy syndrome was noted in the first 6 months. Although the 1-year EFS met the prespecified target of ‡75%, this regimen cannot be considered sufficiently safe for widespread adoption without modifications to achieve more effective GVHD prophylaxis.

Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation

“…Under the circumstances, when counseling patients for transplantation, it is important to balance the potential benefits of long-term survival as a result of a curative treatment against the risks for mortality from transplant-related complications and the potential risk for severe GVHD, which adds to the burden of morbidity and mortality. 29,30 Standard of care (ie, nontransplant therapies) has very low toxicity, but it offers no cure for the underlying disease, and the risk for death is higher later in life; the expected mortality is 4.4 per person-years. 31,32 As a consequence, the ideal comparison between these 2 very different treatments would be a randomized trial of the treatment options.…”

Cyclophosphamide improves engraftment in patients with SCD and severe organ damage who undergo haploidentical PBSCT

“…Shenoy et al 49 reported 29 patients with SCD who underwent matched unrelated donor HSCT. Patients received alemtuzumab starting 22 days before transplant, fludarabine, and melphalan.…”

Allele-level HLA matching for umbilical cord blood transplantation for non-malignant diseases in children: a retrospective analysis

“…1–6 Current standards for HLA matching for transplantation of bone marrow and peripheral blood from unrelated adult volunteer donors for non-malignant diseases support matching donors to recipients at HLA-A, -B, -C and –DRB1 at the allele-level. 7 Survival was highest after HLA matched transplants at 65%, and lower after transplants mismatched at one allele (57%; p=0·07) and two alleles (46%; p=0·001).…”