ALBERT

Description: Introduction: Hematopoietic Stem Cell Transplantation (HSCT) from unrelated donors (UD) is a curative therapy for many hematologic malignancies. HLA matching plays a major role in determining HSCT outcome but the relative role of incompatibilities at the different HLA loci is still debated. In particular, over 80% of UD-HSCT are performed across HLA-DPB1 mismatches (mm): a number of previous studies have devised immunogenetic models to elucidate the impact of HLA-DPB1 mm on HSCT outcome, but a comparative analysis of these models in a recent and well-characterized cohort is lacking. Methods: We selected 422 adult patients (pts) who received an 8/8 (HLA-A, B, -C and -DRB1) allele level-matched UD-HSCT from 2012 to 2015: of them, 382 (90%) had a mm at one or both HLA-DPB1 alleles. We classified functional HLA-DPB1 matching by four models, on the basis of: I) differential immunogenicity of alleles belonging to 3 groups of T-cell epitopes (TCE), as defined by functional studies (Zino, Blood, 2004) and refined by in silico prediction (Crivello, BBMT 2015); II) a similar model subdividing allelles in 4 TCE groups (TCE4, Crocchiolo, Blood 2009); III) differences in "delta functional distance" scores between the alleles of donor and pt, based on 12 polymorphic AA in HLA-DPB1 exon 2 (Crivello, Blood 2016); IV) mismatches in the rs9277534 single-nucleotide polymorphism in the HLA-DPB1 3′ UTR region, predicted on the basis of the DPB1 genotype (Schöne, Hum Immunol 2018), and previously shown to be associated to the expression levels of HLA-DPB1 molecules (HLAexp, Petersdorf, NEJM 2015). Indication for HSCT was acute leukemia (55%), lymphoma and multiple myeloma (29%), myelodysplastic and myeloproliferative syndromes (16%). According to EBMT score definition, 45% of pts were in early, 26% in intermediate, and 29% in advanced disease status. Conditioning regimens were myeloablative (64%) or reduced intensity (36%). Peripheral blood was the preferred stem cell source (81%). Graft-versus-host disease (GvHD) prophylaxis was based on anti-thymocyte globulin (ATG) in 91% of pts, mostly associated with cyclosporine and methotrexate (81%). Median follow-up was 3.2 y. Results: Among the four models adopted to classify functional HLA-DPB1 matching, the TCE4 provided the best results in predicting mm that were permissive (P) or non permissive (NP) for HSCT outcomes. By this model, P mismatched pairs (N=135) had a significantly superior 3-y overall survival (OS) and Graft-versus host disease and Relapse-Free Survival (GRFS) compared to NP pairs (N=247) (60±8% vs 49±7%, p .05; and 36±8% vs 29±5%, p .04). This was associated with a higher transplant-related mortality (TRM), 30±6% in NP mm and 21±6% in P mm, p .09 and a higher 3-y CI of extensive cGvHD in NP mm (12±4%) compared to P (4±2%), p .01 (Figure 1). No effect was found for relapse incidence. Cox multivariate analysis (adjusted for pt age, donor/host gender and CMV, disease status, Sorror score, conditioning intensity, stem cell source, ATG use, HLA matching on 5 loci, center effect), showed that a NP mm compared to P mm was associated with higher hazards for OS (HR 1.6, p .01), GRFS (HR 1.4, p .02), TRM (HR 1.9, p .01), cGvHD (HR 1.6, p .03) and extensive cGvHD (HR 3.6, p