Loss-Prone HLA Class I Alleles Inform Outcomes of Early Hematopoietic Cell Transplantation in Acquired Aplastic Anemia.

HLA class I allele loss in acquired aplastic anemia (AA) represents an immune escape from the T cell-mediated pathogenesis. We investigated the impact of loss-prone HLA alleles on the hematopoietic cell transplantation (HCT) outcomes using registry data of 875 Japanese patients with acquired AA. HLA associations were evident exclusively among 399 patients who received HCT within 1 year of the diagnosis, consistent with the predominance of HLA loss in this group. A set of five HLA alleles with the highest propensity for loss (HLA-A*02:01, HLA-A*02:06, HLA-A*31:01, HLA-B*40:02, and HLA-B*54:01) was the strongest predictor of post-transplant survival among all possible allele combinations (5-year survival, 80.3% vs. 54.4%; p < 0.0001), partly due to improved engraftment and pre-transplant conditions. Another set (HLA-A*33:03, HLA-B*07:02, HLA-B*44:03, HLA-B*52:01, and HLA-B*54:01)-less frequently lost in AA and underrepresented in Epstein-Barr virus (EBV)-related diseases outside AA-was associated with an increased risk of post-transplant lymphoproliferative disorders (5-year incidence, 10.2% vs. 1.8%; p = 0.00019), suggesting that the loss of protective alleles against EBV during AA pathogenesis may predispose to EBV-driven lymphoproliferations. These associations were determined by recipient, not donor, HLA. Therefore, specific HLA class I alleles and their potential loss significantly influence the HCT outcomes in acquired AA.