Higher HLA-DRB1 Evolutionary Divergence Is Associated with Reduced Relapse and Improved Survival after Matched Unrelated Hematopoietic Cell Transplantation.
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HLA evolutionary divergence (HED) can serve as a surrogate for the degree of immunopeptidome diversity of HLA phenotypes. Different degrees of HED in the patient-donor pair may influence the presentation of peptides relevant for alloreactive responses involved in graft-versus-host and graft-versus-leukemia (GvL) effects, potentially impacting outcomes after hematopoietic cell transplantation (HCT). This study was conducted to test whether higher HED scores (both class I and class II) correlate with improved GvL and survival after HLA-matched HCT. The study cohort comprised pediatric and adult patients (n = 9231) reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) database who underwent a first HCT from 8/8 matched unrelated donors between 2008 and 2018 for the treatment of acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myeloid leukemia, or lymphoma were included. HED was calculated on the amino acid sequences of HLA-A, -B, -C, and -DRB1, and class I (HLA-A, -B, and -C), and HLA-DRB1 HED scores were assigned to each patient-donor pair. The association between increasing HED (top quartile versus lower 3 quartiles) and HCT outcome was evaluated with malignant disease relapse, disease-free survival (DFS), and overall survival (OS) as primary endpoints. Secondary endpoints were transplantation-related mortality (TRM), acute and chronic graft-versus-host disease (GvHD), and engraftment. Greater HLA-DRB1 HED was associated with significantly decreased malignant disease relapse (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.79 to 0.94; P = .0014), better disease-free survival (HR, 0.92; 95% CI, 0.86 to 0.98; P = .0067), and improved OS (HR, 0.91; 95% CI, 0.85 to 0.96; P = .0019) in the total population after adjustment for other significant clinical variables. There was no significant association between HLA-DRB1 HED and TRM or the risk of acute or chronic GVHD. Conversely, higher (upper quartile) HLA class I HED did not significantly impact OS, DFS, TRM, relapse, or acute and chronic GVHD compared with the lower 3 quartiles. In addition, neither HLA-class I nor HLA-DRB1 HED significantly impacted neutrophil or platelet engraftment post-transplantation. Our findings demonstrate that higher HLA-DRB1 HED scores are associated with reduced relapse and improved DFS and OS in patients undergoing matched unrelated donor transplantation for hematologic malignancies. These findings contribute to the growing evidence supporting the importance of HED in post-transplantation outcomes; however, further refinement and validation are needed before incorporating HED into clinical transplantation risk assessment.