HLA-DQ G1/G2 Heterodimer Genotype Impacts Relapse and Survival Following Haploidentical Donor Transplantation Using Post-Transplant Cyclophosphamide

The importance of the HLA-DR and HLA-DP class II loci following post-transplant cyclophosphamide (PTCy)-based haploidentical donor transplantation (HIDT) has been firmly established. In contrast, the significance of HLA-DQ loci variation remains unclear. Whereas genetic diversity of HLA-DR and -DP alleles is primarily defined by their β chains, both DQα and DQβ show extensive polymorphism. Furthermore, DQB1 alleles can be grouped into group 1 (DQB1*02/03/04) or group 2 (DQB1*05/06) based on the ability of their corresponding β chains to form stable heterodimers with α chains of specific DQA1 alleles (Petersdorf et al. Blood 2022). Given the expected differences in immunopeptidome presentation based on group 1 and 2 alleles, we hypothesized that the HLA-DQ G1/G2 genotype of recipient and donor might impact relapse and survival post PTCy-based HIDT. A total of 242 consecutive patients with ALL (n=71), AML (n=125) or MDS (n=46) receiving a PTCy-based HIDT were analyzed (median age 51 (19,80), 38% non-White, 32% DRI high/v. high). PBSC was the graft source in 87%, and conditioning was myeloablative in 57%. Recipient HLA-DQ genotype was G1G2, G1G1, and G2G2 in 50%, 29% and 21%, respectively; corresponding donor genotype was 50%, 34% and 16%, respectively. In 24% of transplants, neither donor nor recipient possessed a G1G2 genotype (G1G2-negative), whereas donor, recipient or both were G1G2 in 76% (G1G2-positive). Median follow-up was 62 [23, 199] months. In univariate analysis, 5-year OS, DFS and relapse was 57% vs. 44%, p=0.022, 55% vs. 34%, p=0.002, and 32%% vs. 49%, p=0.029, for HLA-DQ G1G2-postive vs. -negative transplants, respectively. In contrast, there were no differences in the incidence of non-relapse mortality, acute or chronic GVHD. In multivariable analysis, controlled for disease risk index, regimen intensity, donor age, and sex match, the presence of an HLA-DQ G1G2 genotype in donor and/or recipient was associated with significantly improved OS (HR 0.51, p=0.001), DFS (HR 0.49, p<0.001) and relapse risk (HR 0.46, p<0.001), when compared with transplants in which neither donor nor recipient possessed a G1G2 genotype. In summary, the presence of an HLA-DQ G1G2 genotype significantly decreases relapse risk and improves survival following PTCy-based HIDT. We hypothesize that the HLA-DQ G1G2 genotype may present a more diverse immunopeptidome compared with the G1G1 or G2G2 genotype, leading to a better graft-versus-leukemia response. In addition, our results may have importance for haploidentical donor selection. Lastly, our findings reinforce the existing literature, suggesting that HLA-DQ matching may follow a different paradigm than other class II antigens.