Evaluation of Human Leukocyte Antigen (HLA) Matching Requirements for Unrelated Peripheral Blood Stem Cell (PBSC) Transplantation
Authors: Woolfrey Ann E , Klein John , Haagenson Michael D , Spellman Stephen R , Battiwalla Minoo , Gajewski James L. , Hale Gregory A. , Horan John , Hurley Carolyn K , Kollman Craig , Marino Susana , Oudshoorn Machteld , Petersdorf Effie W , Ringdén Olle , Setterholm Michelle , Lee Stephanie J. 
Published: April 2020

Abstract
Criteria for the selection of HLA mismatched donors are needed when an HLA matched unrelated donor is not available. To define the risks associated with mismatching at HLA loci, and the impact of number of HLA mismatches on outcome, we studied 1933 patients receiving URD peripheral blood stem cell (PBSC) transplants facilitated by the National Marrow Donor Program between 1999–2006 for treatment of AML, ALL, CML or MDS. Myeloablative (65%) and reduced intensity (35%) regimens were included. The transplanted PBSC grafts were T cell-replete, and most patients received calcineurin-inhibitor based GVHD prophylaxis (99%) with T replete grafts. Median follow-up was 2 years. Pairs were typed for HLA-A, B, C, DRB1, DQA1 and DQB1 by high resolution typing methods. Matching was classified as low resolution (antigen-equivalent) or high resolution (allele) involving HLA-A, B, C, and DRB1 (8/8 match). Because of multiple comparisons, p-values &lt;0.01 were considered significant. All analyses were adjusted for patient and transplant characteristics.
Results: No effect of HLA-DQ mismatching was found for 8/8 or 7/8 matched transplant pairs, henceforth DQ mismatch was removed from subsequent models. Matching for 8/8 alleles was associated with better survival at one year (56% vs. 47%, p=0.001) compared with 7/8 matched pairs. Using patients with 8/8 match for comparison (n=1243), a single HLA-antigen mismatch (n=293) was associated with a significantly higher risk for overall mortality (OM), (relative risk (RR)=1.32, 95% confidence interval [CI] 1.12–1.55, p=0.0007), transplant-related mortality (TRM), (RR 1.54 [1.24–1.91] p=0.0001), grades III-IV graft-vs.-host disease (GVHD), (RR 1.93 [1.53–2.44] p&lt;0.0001), and lower disease-free survival (DFS), (RR 1.29 [1.10–1.51] p=0.0013). No statistically significant decrement in survival was seen for those with a single (n=208) or double (n=28) HLA-allele mismatches involving HLA-A, B, C, and/or DRB1, although small sample size limits the power of the analysis. Two antigen or antigen plus allele mismatches [6/8 pairs] were associated with 2 to 3 times the risk for OM and TRM compared with 8/8 matched pairs, all p&lt;0.001. Comparing 8/8 to 7/8 donor-recipient pairs mismatched at specific loci, only HLA-C antigen mismatches (n=187) were significantly associated with lower DFS (RR=1.36 [1.13–1.64] p=0.0010), and increased risk for OM (RR=1.41 [1.16–1.70], p=0.0005), TRM (RR=1.61 [1.25–2.08], p=0.0002), and GVHD grades III-IV (RR=1.98 [1.50–2.62], p&lt;0.0001). No differences in outcome were observed for HLA-C allele mismatch (n=61), nor for mismatches at HLA-A antigen/allele (n=136), -B antigen/allele (n=73), -DRB1 allele (n=39) or -DQ antigen/allele (n=114) compared to 8/8 matching. HLA mismatching was not associated with relapse or chronic GVHD.
Conclusion: These data suggest that when 8/8 matched PBSC donors are not available; HLA-C antigen mismatched donors should be avoided. The effects of HLA-mismatching in URD PBSC may be distinct from marrow transplants, although additional studies with larger numbers of patients may increase the power to detect effects of other specific locus mismatches.