Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study

Background The risks after unrelated-donor haemopoietic-cell transplantation with matched HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 alleles between donor and recipient (10/10 matched) can be decreased by selection of unrelated donors who also match for HLA-DPB1; however, such donors are difficult to find. Classification of HLA-DPB1 mismatches based on T-cell-epitope groups could identify mismatches that might be tolerated (permissive) and those that would increase risks (non-permissive) after transplantation. We did a retrospective study to compare outcomes between permissive and non-permissive HLA-DPB1 mismatches in unrelated-donor haemopoietic-cell trans plantation. Methods HLA and clinical data for unrelated-donor transplantations submitted to the International Histo compatibility Working Group in haemopoietic-cell transplantation were analysed retrospectively. HLA-DPB1 T-cell-epitope groups were assigned according to a functional algorithm based on alloreactive T-cell crossreactivity patterns. Recipients and unrelated donors matching status were classified as HLA-DPB1 match, non-permissive HLA-DPB1 mismatch (those with mismatched T-cell-epitope groups), or permissive HLA-DPB1 mismatch (those with matched T-cell-epitope groups). The clinical outcomes assessed were overall mortality, non-relapse mortality, relapse, and severe (grade 3-4) acute graft-versus-host disease (aGvHD). Findings Of 8539 transplantations, 5428 (64%) were matched for ten of ten HLA alleles (HLA 10/10 matched) and 3111 (36%) for nine of ten alleles (HLA 9/10 matched). Of the group overall, 1719 (20%) were HLA-DPB1 matches, 2670 (31%) non-permissive HLA-DPB1 mismatches, and 4150 (49%) permissive HLA-DPB1 mismatches. In HLA 10/10-matched transplantations, non-permissive mismatches were associated with a significantly increased risk of overall mortality (hazard ratio [HR] 1 . 15, 95% CI 1 . 05-1 . 25; p=0 . 002), non-relapse mortality (1 . 28, 1 . 14-1 . 42; p<0 . 0001), and severe aGvHD (odds ratio [OR] 1 . 31, 95% CI 1 . 11-1 . 54; p=0 . 001), but not relapse (HR 0 . 89, 95% CI 0 . 77-1 . 02; p=0 . 10), compared with permissive mismatches. There were significant differences between permissive HLA-DPB1 mismatches and HLA-DPB1 matches in terms of non-relapse mortality (0 . 86, 0 . 75-0 . 98; p=0 . 03) and relapse (1 . 34, 1 . 17-1 . 54; p<0 . 0001), but not for overall mortality (0 . 96, 0 . 87-1 . 06; p=0 . 40) or aGvHD (OR 0 . 84, 95% CI 0 . 69-1 . 03; p=0 . 09). In the HLA 9/10 matched population, non-permissive HLA-DPB1 mismatches also increased the risk of overall mortality (HR 1 . 10, 95% CI 1 . 00-1 . 22; p=0 u 06), non-relapse mortality (1 u 19, 1 . 05-1 . 36; p=0 . 007), and severe aGvHD (OR 1 . 37, 95% CI 1 . 13-1 . 66; p=0 . 002) compared with permissive mismatches, but the risk of relapse was the same in both groups (HR 0 . 93, 95% CI 0 . 78-1 . 11; p=0 . 44). Outcomes for HLA 10/10-matched trans plantations with non-permissive HLA-DPB1 mismatches did not differ substantially from those for HLA 9/10-matched transplantations with permissive HLA-DPB1 mismatches or HLA-DPB1 matches. Interpretation T-cell-epitope matching defines permissive and non-permissive HLA-DPB1 mismatches. Avoidance of an unrelated donor with a non-permissive T-cell-epitope mismatch at HLA-DPB1 might provide a practical clinical strategy for lowering the risks of mortality after unrelated-donor haemopoietic-cell transplantation.