HLA-DPB1 mismatches between donor and recipient are commonly seen in allogeneic hematopoietic stem cell transplantation (HSCT) from an unrelated donor. HLA-DPB1 mismatch, conventionally determined by the similarity of the T-cell epitope (TCE), is associated with an increased risk of acute graft-versus-host disease (aGVHD) and a decreased risk of disease relapse. We investigated the clinical impact of HLA-DPB1 molecular mismatch quantified by mismatched eplets (ME) and Predicted Indirectly Recognizable HLA Epitopes score (PS) in a cohort of 1,514 patients receiving HSCT from unrelated donors matched at HLA-A, -B, -C, -DRB1/3/4/5, and -DQB1 loci. HLA-DPB1 alloimmunity in the GVH direction determined by high GVH ME/PS was associated with a reduced risk of relapse (HR 0.83, P= .05 for ME) and increased risk of grade 2-4 aGVHD (HR 1.44, P< .001 for ME), whereas high HVG ME/PS was only associated with an increased risk of grade 2-4 aGVHD (HR 1.26, P= .004 for ME). Notably, in the permissive mismatch subgroup classified by TCE grouping, high HVG ME/PS was associated with an increased risk of relapse (HR 1.36, P= .026 for ME) and grade 2-4 aGVHD (HR 1.43, P= .003 for PS-II). Decision curve analysis showed GVH ME outperformed other models and provided the best clinical net benefit for the modification of aGVHD prophylaxis regimen in patients with high risk of developing clinically significant aGVHD. In conclusion, molecular assessment of HLA-DPB1 mismatch enables separate prediction of HVG or GVH alloresponse quantitatively and allows further refinement of HLA-DPB1 permissiveness as defined by conventional TCE grouping.
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