Donor-Recipient Matching at the HLA-C Locus and Early Outcomes after Unrelated Umbilical Cord Blood Transplant (UCBT)
Authors: Eapen Mary , Klein John , Sanz Guillermo , Anasetti Claudio , Garcia Joan , Gluckman Eliane , Horowitz Mary M. , Koegler Gesine , Laughlin Mary , Michel Gerard , Spellman Stephen R , Smith Franklin O. , Rocha Vanderson 
Published: April 2020

Previous studies indicate unrelated donor bone marrow transplantation mismatched at HLA-C locus (antigen-level but not allele-level) result in higher acute graft-versus-host disease (GVHD) and mortality. Hematopoietic recovery is not affected by mismatching at this locus. The current selection of cord blood units is based on antigen-level HLA typing at HLA A and B and allele-level at DRB1. The relative importance of matching at HLA-C has not yet been described for unrelated UCBT. To address this question we analyzed hematopoietic recovery, acute GVHD and mortality in 619 UCBT recipients who received a single cord blood (CB) unit, a myeloablative preparative regimen and a calcinuerin inhibitor for GVHD prophylaxis. Eighty-three percent of patients received UCBT for leukemia or lymphoma and 17% for immunologic, metabolic or histiocytic diseases. Seventy percent of patients were ≤16 years of age at transplantation. HLA typing (using molecular methods) was performed for 96% (n=593) of donor-recipient pairs. Method of typing is not available for the remaining 4% (n=26). For all analysis, donor-recipient HLA matching was evaluated at the antigen-level (first 2 of 4 digits) for HLA-A, B, C and allele-level (4 digits) for DRB1. The median infused cell dose was 4 × 107/kg and median follow-up, 2 years. We first examined the effect of donor-recipient HLA matching and cell dose on hematopoietic recovery and mortality considering the current standard for selection of cord blood units. Fifteen percent (n=94) were matched at HLA A, B and DRB1, with 43% (n=265) mismatched at 1-locus and 42% (n=260) mismatched at 2-loci. As reported previously, compared to matched UCBT, neutrophil recovery at day-42 was lower after UCBT mismatched at 1-locus (RR 0.48, p=0.042) and 2-loci (RR 0.38, p=0.007). After adjusting for infused cell dose, year of transplant and disease status, platelet recovery and 1-year mortality rates were not different after matched and mismatched UCBT. We then examined whether the addition of another mismatch at the C locus impacted outcomes. The Table below shows the probabilities of hematopoietic recovery, acute GVHD and survival considering matching at the C-locus in addition to the standard criteria used for CB unit selection. The comparison groups for each of the categories below are patients who received UCBT matched at the C locus for the respective category. In conclusion, the data shown suggest HLA-C does not affect hematopoietic recovery, acute GVHD and 1-year overall survival after UCBT. However, definitive conclusions can only be achieved in a larger series. In the mean time, cord blood unit selection need not consider matching at the C-locus.

Outcomes Probability p-value Neutrophil recovery at day-42 Matched at A, B, DRB1 + mismatch at C (n=22) vs. matched at C (n=72) 82% vs. 93% 0.24 1-locus mismatch at A, B, DRB1 + mismatch at C (n=162) vs. matched at C (n=103) 81% vs. 85% 0.34 2-loci mismatch at A, B, DRB1 + mismatch at C (n=217) vs. matched at C (n=43) 77% vs. 77% 0.98 Platelet recovery at day-100 Matched at A, B, DRB1 + mismatch at C (n=22) vs. matched at C (n=72) 72% vs. 68% 0.68 1-locus mismatch at A, B, DRB1 + mismatch at C (n=162) vs. matched at C (n=103) 61% vs. 66% 0.35 2-loci mismatch at A, B, DRB1 + mismatch at C (n=217) vs. matched at C (n=43) 54% vs. 58% 0.59 Acute grade 2–4 GVHD at day-100 Matched at A, B, DRB1 + mismatch at C (n=21) vs. matched at C (n=71) 32% vs. 40% 0.48 1-locus mismatch at A, B, DRB1 + mismatch at C (n=162) vs. matched at C (n=101) 36% vs. 42% 0.39 2-loci mismatch at A, B, DRB1 + mismatch at C (n=213) vs. matched at C (n=43) 35% vs. 40% 0.61 Overall survival at 1-year Matched at A, B, DRB1 + mismatch at C (n=22) vs. matched at C (n=72) 55% vs. 59% 0.74 1-locus mismatch at A, B, DRB1 + mismatch at C (n=162) vs. matched at C (n=103) 57% vs. 59% 0.74 2-loci mismatch at A, B, DRB1 + mismatch at C (n=217) vs. matched at C (n=43) 52% vs. 53% 0.89