Comparative evaluation of biological human leukocyte antigen DPB1 mismatch models for survival and graft-versus-host disease prediction after unrelated donor hematopoietic cell transplantation

Hematopoietic cell transplantation (HCT) from unrelated donors (UD) is a curative therapy for many hematologic malignancies. Donor-recipient allele-level matching at human leukocyte antigen (HLA)-A, -B, -C, -DRB1 (8/8) is widely accepted to provide best results in terms of overall survival (OS), non-relapse mortality (NRM) and graft-versus-host disease (GvHD). Genotypic matching for HLA-DPB1 (DPB1) has been shown to hold limited, if any, impact on post-transplant OS, and would be challenging to adopt, due to the weak linkage disequilibrium between DPB1 and the remaining HLA class II loci. Therefore, more than 80% of 8/8-matched UD-HCT are currently DPB1-mismatched. A number of studies have demonstrated that biological models can be used to identify selected, permissive DPB1 mismatch combinations, associated with lower clinical risks compared to their high-risk, non-permissive, counterparts. Five different biological models for the assignment of DPB1 permissiveness have been identified to date, three of which are based on functional T-cell epitopes (TCE), while the remaining two rely on a single nucleotide polymorphism (SNP) tag for expression levels. In particular, in the TCE3 model, DPB1 alleles are classified into three structural groups based on variation in the peptide antigen-binding domain, which leads to either functionally similar or distinct behavior in terms of T-cell alloreactivity. The TCE4 model is identical to the TCE3 model, except for the assignment of DPB1*02 to a fourth, independent group 4. Another derivative of TCE3 is the "delta functional distance" (ΔFD) model, in which a functional distance (FD) score is assigned to every DPB1 allele based on key polymorphic aminoacids involved in anti-DPB1 alloreactivity, and differences between the FD of patient and donor alleles defines permissive and non-permissive pairs, respectively. The SNP models, in contrast, are based on high or low expression DPB1 alleles according to a SNP tag in the 3’ untranslated region, in which the rs9277534 A and G variant is associated with low and high DPB1 expression, respectively. In the expression model, this SNP tag is applied to all DPB1 alleles, while in the DP2/DP5 model, it is applied to 19 DPB1 alleles belonging either to the DP2 or the DP5 evolutionary clade. Currently, TCE3 matching is proposed by stem cell donor registries in the USA and Europe, because it is the only one of these models which has been validated in independent cohorts. However, a comparative evaluation of the five different biological models for DPB1 permissiveness and their association with HCT outcome has not been undertaken so far. Here, we have filled this gap by analysing the outcome of 422 patients with available second field DPB1 typing transplanted from 8/8-matched HLA-A, -B, -C and DRB1 allele matched UD in 32 centers from the Gruppo Italiano Trapianto di Midollo Osseo (GITMO), between 2012 and 2015. Of these, 43 pairs had a mismatch at HLA-DQB1, and 382 had one or two DPB1 mismatches. The availability of DPB1 typing did not introduce significant biases, since clinical outcomes were similar for the 422 transplants under analysis and those (n=522) performed in the same time-period and for which DPB1 typing was not available (Online Supplementary Table S1A-B). Patient, donor and transplant characteristics are shown in Table 1. Transplants were performed for hematologic malignancies, with mostly myeloablative conditioning and peripheral blood as stem cell source. GvHD prophylaxis included anti-T-lymphocytic globulin (ATG) in most cases. Permissive and non-permissive mismatches were assigned by the IMGT webtool version 2.0 for TCE3, and manually for the other models, using the cut-off 1.64 or 2.665 for ΔFD as described; for the Expression model, the rs9277534 SNP variant was predicted by DPB1 genotyping. Statistical methods are described in the Online Supplementary Materials and Methods.