Amino acid substitution at peptide-binding pockets of HLA class I molecules increases risk of severe acute GVHD and mortality

HLA disparity has a negative impact on the outcomes of hematopoietic cell transplantation (HCT). We studied the independent impact of amino acid substitution (AAS) at peptidebinding positions 9, 99, 116, and 156, and killer immunoglobulin-like receptor binding position 77 of HLA-A, B, or C, on the risks for grade 3-4 acute graft-versus-host disease (GVHD), chronic GVHD, treatment-related mortality (TRM), relapse, and overall survival. In multivariate analysis, a mismatch at HLA-C position 116 was associated with increased risk for severe acute GVHD (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.15-1.82, P =.0016). Mismatch at HLA-C position 99 was associated with increased transplantrelated mortality (HR = 1.37, 95% CI = 1.1-1.69, P =.0038). Mismatch at HLA-B position 9 was associated with increased chronic GVHD (HR=2.28, 95%CI =1.36-3.82, P=.0018).No AAS were significantly associated with outcome at HLA-A. Specific AAS pair combinations with a frequency >30 were tested for association with HCT outcomes. Cysteine to tyrosine substitution at position 99 of HLA-C was associated with increased TRM (HR = 1.78, 95% = CI 1.27-2.51, P =.0009). These results demonstrate that donor-recipient mismatch for certainpeptide-binding residues of the HLA class Imoleculeis associated with increased risk for acute and chronic GVHD and death.