Key Points• HLA-identical sibling transplantation for SCD offers excellent long-term survival. • Mortality risk is higher for older patients; event-free survival has improved in patients transplanted after 2006.Despite advances in supportive therapy to prevent complications of sickle cell disease (SCD), access to care is not universal. Hematopoietic cell transplantation is, to date, the only curative therapy for SCD, but its application is limited by availability of a suitable HLA-matched donor and lack of awareness of the benefits of transplant. Included in this study are 1000 recipients of HLA-identical sibling transplants performed between 1986 and 2013 and reported to the European Society for Blood and Marrow Transplantation, Eurocord, and the Center for International Blood and Marrow Transplant Research. The primary endpoint was event-free survival, defined as being alive without graft failure; risk factors were studied using a Cox regression models. The median age at transplantation was 9 years, and the median follow-up was longer than 5 years. Most patients received a myeloablative conditioning regimen (n 5 873; 87%); the remainder received reduced-intensity conditioning regimens (n 5 125; 13%). Bone marrow was the predominant stem cell source (n 5 839; 84%); peripheral blood and cord blood progenitors were used in 73 (7%) and 88 (9%) patients, respectively. The 5-year event-free survival and overall survival were 91.4% (95% confidence interval, 89.6%-93.3%) and 92.9% (95% confidence interval, 91.1%-94.6%), respectively. Eventfree survival was lower with increasing age at transplantation (hazard ratio [HR], 1.09; P < .001) and higher for transplantations performed after

Summary Background The standard for selecting unrelated umbilical cord blood units for transplantation for nonmalignant diseases rely on antigen-level (lower resolution) human leukocyte antigen (HLA) typing for HLA-A and –B and allele-level for HLA-DRB1. Our aim was to study the effects of allele-level matching at HLA-A, -B, -C and –DRB1, the standard for adult unrelated volunteer donor transplantation for nonmalignant diseases for umbilical cord blood transplantation. Methods We retrospectively studied 1199 pediatric donor-recipient pairs with allele-level HLA matching who received a single unit umbilical cord blood transplant for nonmalignant diseases reported to the Center for International Blood and Marrow Transplant Research or Eurocord/European Group for Blood and Marrow Transplant. Transplantations occurred between January 1, 2000 and December 31, 2012. The primary outcome was overall survival. The effect of HLA matching on survival was studied using a Cox regression model. Findings Compared to HLA-matched transplants, mortality was higher with transplants mismatched at two (hazard ratio [HR] 1·55, 95% CI 1·08 – 2·21, p=0·018), three (HR 2·04, 95% CI 1·44 – 2·89, p=0·0001) and ≥four alleles (HR 3·15, 95% CI 2·16 – 4·58, p<0·0001). There were no significant differences in mortality between transplants that were matched and mismatched at one allele (HR 1·18, 95% CI 0·80 – 1·72, p=0·388). Other factors associated with higher mortality included recipient cytomegalovirus seropositivity (HR 1·40, 95% CI 1·13 – 1·74, p=0·002), reduced intensity compared to myeloablative conditioning regimens (HR 1·36, 95% CI 1·10 – 1·68, p=0·004), transplantation of units with total nucleated cell dose >21 × 107/kg compared to ≤>21 × 107/kg (HR 1·47, 95% CI 1·11 – 1·95, p=0·008) and transplants performed in 2000 – 2005 compared to 2006 – 2012 (HR 1·64, 95% CI 1·31 – 2·04, p<0·0001). The 5-year overall survival adjusted for recipient cytomegalovirus serostatus, conditioning regimen intensity, total nucleated cell dose and transplant period was 79% (95% CI 74 – 85) after HLA matched, 76% (95% CI 71 – 81) after 1 allele mismatched, 70% (95% CI 65 – 75) after 2 allele mismatched, 62% (95% CI 57 – 68) after 3 allele mismatched and 49% (95% CI 41 – 57) after ≥4 allele mismatched transplants. Graft failure was the predominant cause of mortality. Conclusion These data support a change from current practice in that selection of unrelated umbilical cord blood units for transplantation for nonmalignant diseases must consider allele-level HLA matching at HLA-A, -B, -C and –DRB1. Funding National Cancer Institute, National Heart, Lung, and Blood Institute, National Institute for Allergy and Infectious Diseases, US Department of Health and Human Services - Health Resources and Services Administration and US Department of Navy