HLA Genotyping Does Not Predict Outcomes in Hematopoietic Cell Transplantation (alloHCT)

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Certain HLA genotypes bind peptide epitopes with varying degrees of efficiency [Figure 1]. High-efficiency MHC presentation of minor histocompatibility antigens to the lymphocytes that mediate GVHD could predict differences in GVHD development across patients with fully matched alloHCT. A small single center analysis [n=177] examining this in Class I failed to identify differences in GVHD prevalence across high-, medium- and low- peptide binding groups. However, the cohort was small and heterogeneous in disease and donor type. To better test the hypothesis, we utilized the CIBMTR database to determine whether differences in peptide binding by HLA genotypes predicted outcomes in allogeneic transplant. Adult patients receiving a fully matched unrelated donor alloHCT [n=2775] from 01-01-2005 to 12-31-16 for AML [n=1565], ALL [n=424], and MDS [n=786] reported to the CIBMTR were stratified into three groups (low-, moderate-, and high-affinity) according to the average cumulative peptide binding fraction of each patient's major histocompatibility complexes determined by HLA typing. There were separate analyses for Class I [low: n=957; moderate: n=919; high: n=899] and Class II [low: n=897; moderate: n=960; high: n=918] requiring 4/6 and 1/2 informative alleles respectively for patient inclusion. We created multivariable models for overall and disease-free survival, relapse, transplant related mortality, and acute and chronic GVHD. Figures 2 and 3 show the main effect variables of Class I and Class II binding affinity on transplant outcomes. There were no significant associations seen comparing low, moderate, and high binding. Analyzing the cumulative peptide-binding fraction as a continuous variable was also negative. Factors such as age, disease, disease risk index, HCT-CI, KPS, and GVHD prophylaxis impacted outcomes as expected and previously known. This analysis tested whether the variation in outcomes in matched unrelated alloHCT is associated with the differences in cumulative peptide binding to MHCs, T cell activation, and GVHD development. This negative study may provide indirect evidence for the hypothesis that a smaller number of immunodominant minor histocompatibility antigens disproportionately affect T cell activation and alloHCT outcomes.