Antigen Level Matching at HLA-C Improves Long-Term Outcomes after Double Umbilical Cord Blood Transplantation
Authors: Brunstein Claudio G , Cutler Corey S , DeFor Todd E. , Spitzer Thomas R. , Bejanyan Nelli , Garfall Alfred L. , Verneris Michael R. , Chen Yi-Bin , Warlick Erica , Kim Haesook T. , Miller Jeffrey S. , Antin Joseph H. , Weisdorf Daniel J. , Soiffer Robert J , Wagner John E , Ballen Karen K. 
Published: October 2019

Abstract
Matching at HLA-C has been shown to influence outcomes and has been incorporated in selection of unrelated adult donors. In contrast, selection of UCB grafts has historically considered HLA-A and B at antigen and DRB1 at allele level resolution. Recent data in single, myeloablative pediatric UCB transplantation demonstrated that antigen level matching at HLA-C was associated with lower NRM and improved survival in patients receiving better HLA-matched units. Whether or not these same principles apply in the setting of double UCB (dUCB) transplantation has not been addressed. Thus, we retrospectively studied whether HLA-C matching would influence outcomes in 490 patients with hematological malignancies at two centers undergoing myeloablative and reduced intensity dUCB transplantation. We considered the worst HLA-matching of the 2 donor units with 316 (64%) patients receiving at least one 4/6 matched unit and 144 (29%) one or two 5/6 units, and 30 (6%) receiving two 6/6 HLA-matched units. Patients were scored considering the number of HLA-C antigen matches as 0-1 (23%), 2 (40%), 3 (18%), and 4 (19%), of 4 possible matches. The median age was 47 yrs. (range, 2-72), 59% were male, 285 (58%) had acute leukemia, 291 (59%) were CMV seropositive, 319 (66%) received RIC regimen, and 400 (82%) had CsA/MMF immunosuppression. In the overall study population, we observed no significant influence of HLA-C matching on the risk of death, treatment failure, non-relapse death, relapse, GVHD and hematopoietic recovery. However, we recognized an interaction between conventional HLA-matching at A, B, and DRB1 and number of matches at HLA-C in the survival endpoints. Thus, we analyzed two groups based on conventional HLA-matching at A, B and DRB1: those receiving at least one 4/6 HLA-matched unit (4/6 & 4-6/6; n=316) or those receiving ≥ 5-6/6 matched unit (5/6 & 5-6/6; n=174). In the ≥5/6 UCB transplants, there was no significant influence of HLA-C matching on the risk of death, treatment failure, non-relapse death, and relapse. However, in 4/6 & 4-6/6 transplants, better matching at HLA-C was associated with lower risk of death, treatment failure, and non-relapse death (Table), but there remained no association with risk of relapse. These data contrast with those reported with single UCB grafts and suggest that with 4/6 HLA-matched UCB units, additional matching at HLA-C reduces treatment failure and improves survival, and should be included in the match strategy. In better matched (≥5/6) dUCB grafts further matching at HLA-C offers no additional benefit. Table 1.Table shows multivariate analysis results in 316 patient who received 4/6 & 4-6/6 dUCB graftsMatching at HLA CNOverall mortalityTreatment failureNon-relapse deathRelapseGrade II-IV acute GVHDRelative Risk (95% CI)PRelative Risk (95% CI)PRelative Risk (95% CI)PRelative Risk (95% CI)PRelative Risk (95% CI)P4/4331.01.01.01.01.03/4521.70.121.50.163.00.100.90.781.10.83(0.8-3.5)(0.8-2.8)(0.8-10.9)(0.4-1.9)(0.4-3.2)2/41362.30.011.70.065.4<0.010.60.151.10.85(1.2-4.2)(1.0-2.9)(1.7-17.7)(0.3-1.2)(0.4-3.0)0-1/4952.30.011.80.034.40.020.90.711.10.86(1.3-4.4)(1.1-3.2)(1.3-14.4)(0.5-1.7)(0.4-3.0)

Disclosures
Chen: Bayer: Consultancy, Research Funding. Miller:Coronado: Speakers Bureau; BioSciences: Speakers Bureau; Celegene: Speakers Bureau. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.