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The effect of inter-unit HLA matching in double umbilical cord blood transplantation for acute leukemia.

ABSTRACT: The effects of inter-unit HLA-match on early outcomes with regards to double cord blood transplantation have not been established. Therefore, we studied the effect of inter-unit HLA-mismatching on the outcomes of 449 patients with acute leukemia after double cord blood transplantation. Patients were divided into two groups: one group that included transplantations with inter-unit mismatch at 2 or less HLA-loci (n=381) and the other group with inter-unit mismatch at 3 or 4 HLA-loci (n=68). HLA-match considered low resolution matching at HLA-A and -B loci and allele-level at HLA-DRB1, the accepted standard for selecting units for double cord blood transplants. Patients', disease, and transplant characteristics were similar in the two groups. We observed no effect of the degree of inter-unit HLA-mismatch on neutrophil (Hazard Ratio 1.27, P=0.11) or platelet (Hazard Ratio 0.1.13, P=0.42) recovery, acute graft-versus-host disease (Hazard Ratio 1.17, P=0.36), treatment-related mortality (Hazard Ratio 0.92, P=0.75), relapse (Hazard Ratio 1.18, P=0.49), treatment failure (Hazard Ratio 0.99, P=0.98), or overall survival (Hazard Ratio 0.98, P=0.91). There were no differences in the proportion of transplants with engraftment of both units by three months (5% after transplantation of units with inter-unit mismatch at ?2 HLA-loci and 4% after transplantation of units with inter-unit mismatch at 3 or 4 HLA-loci). Our observations support the elimination of inter-unit HLA-mismatch criterion when selecting cord blood units in favor of optimizing selection based on individual unit characteristics.

SUBMITTER: Brunstein C

PROVIDER: S-EPMC5477613 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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The effect of inter-unit HLA matching in double umbilical cord blood transplantation for acute leukemia.

Brunstein Claudio C Zhang Mei-Jie MJ Barker Juliet J St Martin Andrew A Bashey Asad A de Lima Marcos M Dehn Jason J Hematti Peiman P Perales Miguel-Angel MA Rocha Vanderson V Territo Mary M Weisdorf Daniel D Eapen Mary M

Haematologica 20170125 5

The effects of inter-unit HLA-match on early outcomes with regards to double cord blood transplantation have not been established. Therefore, we studied the effect of inter-unit HLA-mismatching on the outcomes of 449 patients with acute leukemia after double cord blood transplantation. Patients were divided into two groups: one group that included transplantations with inter-unit mismatch at 2 or less HLA-loci (n=381) and the other group with inter-unit mismatch at 3 or 4 HLA-loci (n=68). HLA-ma ...[more]

PMID: 28126967

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Project description:BACKGROUND:The standard for selecting unrelated umbilical cord blood units for transplantation for non-malignant diseases relies on antigen-level (lower resolution) HLA typing for HLA-A and HLA-B, and allele-level for HLA-DRB1. We aimed to study the effects of allele-level matching at a higher resolution-HLA-A, HLA-B, HLA-C, and HLA-DRB1, which is the standard used for adult unrelated volunteer donor transplantation for non-malignant diseases-for umbilical cord blood transplantation. METHODS:We retrospectively studied 1199 paediatric donor-recipient pairs with allele-level HLA matching who received a single unit umbilical cord blood transplantation for non-malignant diseases reported to the Center for International Blood and Marrow Transplant Research or Eurocord and European Group for Blood and Marrow Transplant. Transplantations occurred between Jan 1, 2000, and Dec 31, 2012. The primary outcome was overall survival. The effect of HLA matching on survival was studied using a Cox regression model. FINDINGS:Compared with HLA-matched transplantations, mortality was higher with transplantations mismatched at two (hazard ratio [HR] 1·55, 95% CI 1·08-2·21, p=0·018), three (2·04, 1·44-2·89, p=0·0001), and four or more alleles (3·15, 2·16-4·58, p<0·0001). There were no significant differences in mortality between transplantations that were matched and mismatched at one allele (HR 1·18, 95% CI 0·80-1·72, p=0·39). Other factors associated with higher mortality included recipient cytomegalovirus seropositivity (HR 1·40, 95% CI 1·13-1·74, p=0·0020), reduced intensity compared with myeloablative conditioning regimens (HR 1·36, 1·10-1·68, p=0·0041), transplantation of units with total nucleated cell dose of more than 21?×?107 cells per kg compared with 21?×?107 cells per kg or less (HR 1·47, 1·11-1·95, p=0·0076), and transplantations done in 2000-05 compared with those done in 2006-12 (HR 1·64, 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 transplantation period was 79% (95% CI 74-85) after HLA matched, 76% (71-81) after one allele mismatched, 70% (65-75) after two alleles mismatched, 62% (57-68) after three alleles mismatched, and 49% (41-57) after four or more alleles mismatched transplantations. Graft failure was the predominant cause of mortality. INTERPRETATION:These data support a change from current practice in that selection of unrelated umbilical cord blood units for transplantation for non-malignant diseases should consider allele-level HLA matching at HLA-A, HLA-B, HLA-C, and HLA-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.

Project description:Randomized clinical trials offer the highest-quality data for modifying clinical practice. Results of a phase III randomized trial of nonmyeloablative transplantation for adults with high-risk hematologic malignancies with 2 umbilical cord blood (UCB) units (n = 183) or HLA-haploidentical relative bone marrow (Haplo-BM; n = 154) revealed a 2-year progression-free survival (PFS) of 41% after Haplo-BM transplantation and 35% after 2-unit UCB transplantation (P = .41), with overall survival (OS) of 57% and 46%, respectively (P = .04). We sought to examine the generalizability of BMT CTN 1101 to a contemporaneous cohort beyond the trial's prespecified 2-year outcomes. All transplantations were performed between June 2012 and June 2018 in the United States. We hypothesized that the results of a rigorous phase III randomized trial would be generalizable. Changes in graft selection for HLA-haploidentical relative transplantation during the trial period allowed comparison of outcomes after transplantation with Haplo-BM with those after haploidentical peripheral blood (Haplo-PB). The trial's broad eligibility criteria were applied to the data source of the Center for International Blood and Marrow Transplant Research to select nontrial subjects. Extended follow-up of trial subjects was obtained from this data source. Three separate analyses were performed: (1) trial subjects beyond the trial's 2-year endpoint; (2) comparison of trial subjects with a contemporaneous cohort of nontrial subjects (195 2-unit UCB, 358 Haplo-BM, and 403 Haplo-PB); and (3) comparison of nontrial subjects by donor and graft type. Multivariate analyses were performed using Cox proportional hazards models for comparison of outcomes by treatment groups. With longer follow-up of the trial cohorts, 5-year PFS (37% versus 29%; P = .08) and OS (42% versus 36%; P = .06) were not significantly different between the treatment groups. We then compared the trial results with outcomes of comparable real-world transplantations. Five-year OS did not differ between trial and nontrial 2-unit UCB transplantations (36% versus 41%; P = .48) or between trial and nontrial Haplo-BM transplantations (42% versus 47%; P = .80), confirming generalizability. The randomized trial did not accrue as planned and therefore lacked the statistical power to detect a 15% difference in PFS. With substantially larger numbers of nontrial Haplo-BM transplantations, 5-year survival was higher after nontrial Haplo-BM compared with trial 2-unit UCB (47% versus 36%; P = .012). Nontrial patients who underwent Haplo-PB transplantation had higher 5-year survival (54%) compared with trial Haplo-BM (hazard ratio [HR], 0.76; P = .044) and nontrial Haplo-BM (HR, 0.78; P = .026). Similarly, survival was better after Haplo-PB compared with trial UCB (HR, 0.57; P < .0001) and nontrial UCB (HR, 0.63; P = .0002). When considering alternative donor low-intensity conditioning regimen transplantation, a haploidentical relative is preferred, and PB is the preferred graft source.

Dataset Information

The effect of inter-unit HLA matching in double umbilical cord blood transplantation for acute leukemia.

Publications

The effect of inter-unit HLA matching in double umbilical cord blood transplantation for acute leukemia.

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