Epitope Mismatch at HLA-DRB1 Associates with Reduced Relapse Risk in Cord Blood Transplantation for Standard-Risk Hematologic Malignancy

Abstract

Cord blood transplantation (CBT) is an attractive therapeutic option for patients with hematological malignancies. CBT tolerates HLA mismatches between donors and recipients, but which HLA mismatches generate graft-versus-tumor (GVT) effects is unknown. Given that HLA molecules contain epitopes comprising polymorphic amino acids that determine their immunogenicity, we investigated associations between epitope-level HLA mismatches and relapse following single-unit CBT. A total of 492 patients with hematological malignancies who received single unit, T cell replete CBT were included in this multi-center retrospective study. HLA epitope mismatches (EM) were quantified using HLA matchmaker software from donor and patient HLA-A, B, C and DRB1 allele data. Patients were dichotomized by median EM value and divided into groups transplanted in complete/partial remission (standard stage: 62.4%) and others (advanced stage: 37.6%). Median EM numbers in the graft-versus-host direction (GVH-EM) at HLA-class I and HLA-DRB1 were 3 (range, 0-16) and 1 (range, 0-7), respectively. Higher HLA-class I GVH-EM increased non-relapse mortality (NRM) in the advanced stage group (adjusted hazard ratio [HR], 2.12; p=0.021), with no significant advantage for relapse in either stage. On the other hand, higher HLA-DRB1 GVH-EM was associated with better disease-free survival in the standard stage group (adjusted HR, 0.63; p=0.020), which was attributed to lower relapse risk (adjusted HR, 0.46; p=0.014). These associations were also observed even within HLA-DRB1 allele-mismatched transplants in the standard stage group, indicating that EM might have impacts on relapse risk independently of allele mismatch. High HLA-DRB1 GVH-EM did not increase NRM in either stage. High HLA-DRB1 GVH-EM may lead to potent GVT effects and favorable prognosis following CBT especially in the patients transplanted in the standard stage. This approach may facilitate appropriate unit selection and improve the overall prognosis of patients with hematological malignancies who receive CBT.