Landscapes of HLA Mismatching in Contemporary Unrelated Haematopoietic Cell Transplantation

Haematopoietic cell transplantation (HCT) with HLA-mismatched unrelated donors (MMUD) offers access to curative therapy for patients lacking well-matched donors. Accumulating evidence suggests that functional matching among allele-mismatched pairs can significantly influence patient outcomes. Therefore, real-world data on mismatch frequencies in MMUD-HCT could provide fundamental information for the assessment of patient risks and donor selection strategies. Here, we analysed HLA matching in 28,376 first unrelated transplants reported to the EBMT Registry with available 6-locus high-resolution typing. Mismatches at each locus were quantified and characterised at the allelic, antigenic and functional (antigen-recognition domain, peptide-binding motif) levels. 25% of the transplants were performed across one (9/10; n = 6053) or more (< 9/10; n = 1013) high-resolution mismatches at the five main HLA loci, a proportion that was markedly higher (43.9%) among transplants performed with post-transplantation cyclophosphamide (PTCy). Median time from diagnosis to transplant was longer for MMUD compared to 10/10 transplants, but this difference decreased over time (14.9 vs. 11.3 months pre-2011, p = 0.003; 8.1 vs. 7.4 months 2021-2022, p = 0.016). Across transplant eras, single class I mismatches were three times more common than class II mismatches. Conversely, matching for HLA-DPB1 increased from 15% pre-2011 to 31% in 2021-2022. The landscapes of allelic mismatches differed markedly between HLA loci. For class II, skewed distributions dominated by frequent combinations result in significantly higher frequencies of functional matching compared to class I in both PTCy and non-PTCy pairs. Our study constitutes the first large-scale characterisation of real-world HLA mismatch frequencies in contemporary unrelated HCT, bearing implications for future clinical outcome studies.