Bone marrow transplantation from unrelated donors: The impact of mismatches with substitutions at position 116 of the class I heavy chain on graft versus host disease and transplant related mortality

We have tested the hypothesis that specific amino acid substitutions within Class I mismatched molecules would have a different impact on acute graft versus host disease (GvHD) and transplant related mortality (TRM) in patients receiving unmanipulated marrow. One hundred patients were retrospectively typed by polymerase chain reaction-sequence based typing (PCR-SBT) for the HLA-A, -B, and -C loci, together with their unrelated donors, otherwise matched by PCR-SBT for DRB1/3/4/5, DQA1, and DQB1 loci. Forty pairs were matched for HLA A, B and C loci, whereas 60 pairs had one or more mismatches at Class I. In the latter group there was no correlation between number of amino acid substitutions or number of multiple mismatches and outcome. However, substitutions involving position 116 were significantly more frequent in deceased patients (P=0.04). Mismatches were defined as non-conservative when an aromatic residue at position 116 was substituted with a smaller non-aromatic one or vice-versa, and otherwise as conservative. We then compared the three groups: matched (n=40), conservative mismatches (n=31) and non-conservative mismatches (n=29). The 3 groups were comparable for age, disease phase, gender combination, cells infused, interval diagnosis-BMT. The actuarial day +100 risk of developing grade III-IV GvHD in the group with non-conservative mismatch was 42%, significantly higher as compared to the matched (10%, P=0.003) and the conservative mismatch group (17%, P=0.02). Similarly, the actuarial 3 year risk of TRM in the group with non-conservative mismatch was 64%. significantly higher as compared to the matched (28%, P=0.002) and the conservative mismatch groups (32%, P=0.02). In a multivariate COX analysis non-conservative mismatching was a significant predictor for TRM (P=0.005). This study suggests that the replacement at position 116 of an aromatic residue with a non-aromatic one, or vice-versa, has a significant impact on acute GvHD and TRM after BMT from unrelated donors otherwise matched for Class II.