Impact of HLA-DQ Heterodimer Group (G1/G2) Mismatch on Relapse and Survival Following Haploidentical Donor Transplantation

The role of HLA-DQ matching in transplant outcomes after post-transplant cyclophosphamide (PTCy)-based haploidentical donor transplantation (HIDT) remains unclear. 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). For transplant recipients expressing a G1G1 or G2G2 genotype, additional HLA-DQ diversity is achieved through successful DQα-β transdimerization from the other parental chromosome, resulting in up to 4 unique HLA-DQ molecules. We hypothesized that an HLA-DQ group G1/G2 mismatch (mm) would reduce relapse and improve survival following PTCy-based HIDT, and that the effect may be more significant in G1G1 or G2G2 (vs. G1G2) recipients due to a higher number of heterodimer mismatches. A total of 242 consecutive patients with ALL (n=71), AML (n=125) or MDS (n=46) receiving a PTCy-based HIDT from a single institution 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 group genotype was G1G2, G1G1, and G2G2 in 50%, 29% and 21%, respectively. Donor-recipient HLA-DQ alleles were G1/G2 group matched in 49% of all transplant recipients (49% and 48% in G1G2 and G1G1/G2G2 recipients, respectively). Baseline patient, disease and transplant characteristics were well matched in the HLA-DQ G1/G2 group matched vs. mm transplants. Median follow-up was 62 [23, 199] months. In univariate analysis, 5-year DFS was 56% vs. 43%, p=0.12 for HLA-DQ group mm vs. matched, respectively. Corresponding rates of relapse were 31% vs. 41%, p=0.18. As predicted, the protective effect of a group mm was stronger in recipients with a G1G1 or G2G2 (vs. G1G2) genotype (see figure). In G1G1/G2G2 recipients, 5-yr DFS (55% vs. 34%, p=0.017) and relapse (29% vs. 49%, p=0.038) was improved for HLA-DQ group mm vs. matched, respectively. In multivariable analysis, controlled for disease risk index, regimen intensity, donor age, and sex match, an HLA-DQ G1/G2 group mm was associated with significantly improved OS (HR 0.64, p=0.022), DFS (HR 0.65, p=0.020) and relapse risk (HR 0.60, p=0.021), an effect even more pronounced when restricted to G1G1/G2G2 recipients - OS (HR 0.48, p=0.006), DFS (HR 0.46, p=0.002) and relapse (HR 0.41, p=0.003). In contrast, there was no beneficial effect of an HLA-DQ group mm in transplant recipients with a G1G2 genotype. In summary, an HLA-DQ G1/G2 group mm significantly decreases relapse risk and improves survival in the half of HIDT recipients characterized by a G1G1 or G2G2 genotype. Our results may have considerable importance for donor selection in these patients. Furthermore, this finding reinforces the existing literature, suggesting that HLA-DQ matching follows a different paradigm than other class II antigens.