Single or Multiple HLA-A, B, C or DRB1 Mismatches Limit Success of Unrelated Donor Bone Marrow Transplantation.
Authors: Lee Stephanie J. , Klein John , Haagenson Michael , Baxter-Lowe Lee Ann , Confer Dennis , Eapen Mary , Fernandez-Vina Marcelo , Flomenberg Neal , Horowitz Mary , Hurley Carolyn , Noreen Harriet , Oudshoorn Machteld , Petersdorf Effie , Setterholm Michelle , Spellman Stephen , Weisdorf Daniel , Williams Thomas M. , Anasetti Claudio 
Published: October 2019

Fewer than 50% of patients (pts) are able to identify an HLA-A, B, C, DRB1-sequence matched unrelated donor (URD); the best partially matched donor must be chosen for the remainder. National Marrow Donor Program data from 3860 US transplants performed from 1988–2003 were analyzed to provide guidance in that choice. Pts had AML, ALL, CML or MDS and received myeloablative conditioning regimens. Most received calcineurin-based GVHD prophylaxis with T replete grafts (79%). Nearly all received marrow grafts (94%). Median follow-up was 6 years. Pts and donors were retrospectively typed for HLA-A, B, C, DRB1, DQB1, DQA1, DPB1, and DPA1 by DNA sequencing and other high resolution typing methods. Matching was classified as low resolution (antigen-equivalent) or high resolution (allele sequence). Because of multiple comparisons, p-values <0.01 were considered significant. All analyses were adjusted for pt and transplant characteristics.

RESULTS: Full matching for HLA-A, B, C, and DRB1 was associated with the best survival. A single mismatch at A, B, C or DRB1 was associated with a mortality relative risk (RR) of 1.23 (95% CI 1.11–1.36, p=0.0001) with 1-yr survival of 45% compared to 52% for fully matched pairs. Mismatches detected by low or high DNA resolution testing were associated with similar survival decrements (p=0.7). Survival differences were apparent in all disease risk categories. When mismatches at individual HLA loci were analyzed, a single mismatch at HLA-A was significantly associated with increased mortality (RR 1.35, 95% CI 1.14–1.59, p=0.0004); isolated HLA-A, B, C or DP mismatches were associated with increased risk of grades III-IV GVHD. Although the data set had few DRB1 mismatches (no antigen level and 58 allele level) limiting the power of this analysis, the RR of mortality (1.31, 95% CI 0.96–1.79, p=0.085) suggests an adverse outcome for DRB1 mismatching equivalent to A mismatching. Isolated DQ mismatching had no adverse impact. Mismatches at 2 HLA loci were associated with higher mortality risk than single mismatches (37% vs. 45% 1-yr survival), with HLA-A+C and HLA-B+C being the most frequent.

CONCLUSION: High resolution DNA typing of HLA-A, B, C, and DRB1 alleles facilitates optimal URD donor selection for pts with hematological malignancies because the best survival is associated with complete matching at these loci. When selecting among donors with single mismatches, HLA-DQ or DP disparity was not associated with worse survival. Examination of risks for mortality suggests single HLA-B or C mismatches are better tolerated than HLA-A or possibly DRB1 mismatches. Disparities for 2 loci, detected by either high or low resolution testing, compound the risk of mortality.