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

Abstract

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

Improved Survival after Cord Blood Transplantation: Single-Center Experience in Pediatric Patients Over a 2-Decade Period

“…Interestingly, white children were more likely to receive better HLA-matched and race-matched CB units than black and other minority children. Several previous studies have shown better outcomes in patients receiving singleunit UCBT using better HLA allele-matched CB units [4]. The results of this study support the importance of increasing the collection of CB units from racial minorities; however, the decrease in the number of UCBTs performed annually has been accompanied by a significant reduction in the number of public CB banks.…”

Effect of donor type and conditioning regimen intensity on allogeneic transplantation outcomes in patients with sickle cell disease: a retrospective multicentre, cohort study

“…Conditioning regimen intensity was not associated with graft failure. Increased mortality and prevalence of graft failure after transplantation from HLA-mismatched unrelated donors has been reported for non-malignant diseases but those studies 21,22 did not include many patients who received transplants for haemoglobinopathies. Our findings confirm the adverse effect of HLA disparity on survival outcomes and graft failure after transplantation in patients with sickle cell disease.…”

Selection of unrelated donors and cord blood units for hematopoietic cell transplantation: guidelines from the NMDP/CIBMTR

“…109 Later reports confirmed the importance of counting matches at the high-resolution level for HLA-A, HLA-B, HLA-C, and HLA-DRB1 for malignant and nonmalignant diseases. 106,110 The incidence of neutrophil recovery was lower and graft failure and mortality rates were higher when the recipient and the CB unit were mismatched at $2 HLA highresolution types. In the setting of double CB unit transplantation, the same HLA match criteria that guide single-unit selection should be applied to the selection of both units.…”