Bone marrow transplantation from unrelated donors: the impact of mismatches with substitutions at position 116 of the human leukocyte antigen class Iheavy chain

The hypothesis was tested that amino acid substitutions in specific positio ns within human leukocyte antigen class I heavy chain would have different impacts on transplant-related mortality (TRM) in patients receiving transpl anted bone marrow from unrelated donors. One hundred patients and their unr elated donors were typed by sequence-based typing for the human leukocyte a ntigen (HLA)-A, -B, and -C loci. All pairs were matched for DRB1, DRB3, DRB 4, DRB5, DQA1, and DQB1 loci. Forty pairs were also matched at class I, and 60 pairs had one or more mismatches at class I loci. It was found that sub stitutions at positions 116 and 114 of class I heavy chain significantly in creased the risk for TRM in univariate and bivariate Cox analyses. Converse ly, no association between number of multiple mismatches or number of amino acid substitutions and TRM was seen when positions 116 and 114 were adjust ed for. Variables predictive of TRM in multivariate Cox analysis were numbe r of cells infused, diagnosis (chronic myeloid leukemia [CML] or non-CML), and amino acid substitution at position 116 or 152. The only variable predi ctive of severe acute graft-versus-host disease (GVHD) in multivariate Cox analysis was substitution at position 116. Actuarial risk for acute GVHD gr ade III-IV, TRM, and relapse in pairs with substitutions at position 116 (n = 37) compared to other pairs (n = 63) was, respectively, 36% versus 14% ( P = .01), 59% versus 28% (P = .001), and 25% versus 31 % (P = .4). In concl usion these data suggest that substitutions at position 116 of class I heav y chain increase the risk for acute GVHD and TRM in patients who receive tr ansplanted bone marrow from unrelated donors. Blood. (C) 2001 by The Americ an Society of Hematology.