Effect of HLA-DPB1 Mismatch on Incidence and Severity of Chronic Graft-Versus-Host Disease Following Haploidentical Transplantation

Chronic graft-versus-host disease (cGVHD) is an important cause of late morbidity and mortality after haploidentical donor transplantation (HIDT), occurring in up to one-third of patients. The treatment of cGVHD can continue for years and can significantly impact quality-of-life in long-term transplant survivors. Therefore, it is important to identify risk factors that are associated with the incidence and severity of cGVHD. To this end, we investigated 335 consecutive recipients of HIDT utilizing post-transplant cyclophosphamide (PTCy) from 2005-2021, with a particular focus on class II HLA mismatches given prior published associations of HLA-DR and -DP mismatches with HIDT outcomes. HIDT recipients had a median age of 50 (19, 80). PBSC was the graft source in 81%, and conditioning was myeloablative in 49%. Whereas the incidence and severity of cGVHD did not differ between transplants with or without an HLA-DRB1 or -DQB1 allele-level mismatch, the presence of an HLA-DPB1 mismatch was associated with higher 1-yr incidence of all-grade (32% vs. 22%, p=0.07) and moderate-to-severe (22% vs. 12%, p=0.011) cGVHD (see figure). The effect of HLA-DPB1 mismatch on cGVHD was independent of permissiveness by the T cell epitope (TCE) algorithm or the vector of the mismatch (bidirectional, GVH- or HVG-only). In multivariate analysis, an HLA-DPB1 mismatch was associated with an increased risk of moderate-to-severe cGVHD (HR 2.05, p=0.044), while controlling for other covariates (CMV status, year of transplant). Other class II loci (HLA-DRB1 and HLA-DQB1) mismatching were not associated with chronic GVHD incidence in MVA. In summary, the presence of an HLA-DPB1 mismatch is associated with an increased incidence of moderate-to-severe cGVHD following PTCy-based HIDT. This effect, of course, must be balanced by the protective effect of a TCE nonpermissive HLA-DPB1 mismatch on relapse and survival, when selecting the optimal haploidentical donor.