High-Risk Human Leukocyte Antigen Mismatch Combinations Responsible for Severe Acute Graft-Versus-Host Disease in Cord Blood Transplantation

In unrelated cord blood transplantation (UCBT), although cord blood units (CBUs) having multiple human leukocyte antigen (HLA) mismatches with recipients are better tolerated than other donor sources, HLA mismatches between the CBU and recipient are important factors in predicting transplant outcomes after UCBT. HLA matching for CBU selection is often considered in terms of the number of HLA allele mismatches, but the impact of each HLA mismatch combination on posttransplant immunological events may differ, and high-risk mismatch combinations that increase the risk of occurrence of severe acute graft-versus-host disease (GVHD) and lead to poor transplant outcomes may exist even in UCBT. To investigate whether high-risk mismatch combinations previously reported in unrelated bone marrow transplantation (UBMT) are also identified in UCBT; and also whether novel high-risk mismatch combinations are elucidated in UCBT. Here, we analyzed a cohort of Japanese UCBT patients (n = 7462) aged ≥16 yr who underwent their first UCBT. Primary endpoint of this study was the impact of HLA mismatch combinations on grade III to IV acute GVHD. High-risk mismatch combinations in UBMT were not identified, but a novel high-risk mismatch combination, C*03:04-C*14:02 (meaning that the CBU has HLA-C*03:04 and recipient has HLA-C*14:02), was elucidated. C*03:04-C*14:02 showed a statistically significant association with increased risk of grade III to IV acute GVHD (hazard ratio [HR] = 3.09, P < .0001) even after adjustment for multiple comparison. On multivariate analysis among the entire cohort in which acute GVHD was evaluated as a time-varying covariate, the onset of grade III to IV acute GVHD was associated with a significant worsening of overall survival (HR 1.82, P < .0001). Together, our findings suggest the prudence of avoiding selection of a CBU with C*03:04-C*14:02 when selecting CBUs for UCBT.