Influence of Human Leukocyte Antigen Haplotypes on Acute Graft Versus Host Disease Incidence after Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Gupta Sameer , Aggarwal Charu , McCarthy Philip L. , Padmanabhan Swaminathan , Battiwalla Minoo , Hahn Theresa E. 
Published: October 2019

Abstract
There is increasing evidence that the Human Leukocyte Antigen (HLA) alleles may influence the incidence of acute graft versus host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). Differential presentation of recipient antigens to donor-derived T-cells by the respective HLA molecules may be a responsible factor. We have reported a decreased rate of aGVHD in HLA DR15 positive patients (pt) undergoing alloHSCT for myeloid malignancies (Blood, 2006; 107:1970). We investigated the influence of different HLA alleles and the three most common HLA haplotypes in US Caucasians on grade 2–4 acute GVHD (graded using published criteria) in HLA matched alloHSCT. We conducted a retrospective review of 195 related and 70 unrelated consecutive first myeloablative alloHSCT pt treated from 01/1992 to 4/2005 at our center. HLA typing was determined by either molecular (n=176) or serologic (n=89) methods. Pt characteristics included: AML (n=84), CML (n=62), NHL (n=47), ALL (n=41), MDS (n=20), HD (n=7) and CLL (n=4); median age 39 years (range 6–66), < 40 years (n=130); Male (n=168), Female (n=97); Caucasian (>95%); Donor-Recipient Sex Mismatch (n=112); Total Body Irradiation (TBI) conditioning regimens (n=205); Etoposide/Cyclophosphamide(Cy)/TBI (n=122), Busulfan(Bu)/Cy (n=28), Bu/TBI (n=27), Thiotepa/TBI (n=23), Cy/TBI (n=22), Fludarabine/Melphalan (n=8), Thiotepa/Carboplatin (n=8) or other combinations (n=27) and peripheral blood stem cell source (n= 35). HLA Haplotypes analyzed for their effect on aGVHD were A1B8DR3 (n=25), A3B7DR15 (n=20) and A2B44DR4 (n=13). There was no significant difference in the pt characteristics (donor relation, conditioning regimen, donor-recipient sex match, diagnosis, age, gender, performance status, disease status at transplant, stem cell source and GVHD prophylaxis) by each of the three haplotypes. We analyzed prior published HLA alleles that were associated with an increased or decreased risk of aGVHD and pt characteristics for their effect on grade 2–4 aGVHD incidence. By univariate analysis, donor relation (unrelated vs. related, 52% vs. 38%, p=0.0002), HLA A2 (44% vs. 33%, p=0.05) and HLA B8 were associated with increased aGVHD (61% vs. 37%, p=0.005) whereas HLA B18 was associated with decreased aGVHD (19% vs. 43%, p=0.017) in contrast to prior reports using serological typing only. By multivariate analysis, HLA A2 (RR=1.5, 95%CI: 1.0 to 2.2, p=0.04), HLA B8 (RR=1.9, 95%CI: 1.1 to 3.0, p=0.01) and unrelated donor (RR= 1.9, 95%CI: 1.3 to 2.9, p=0.001) were associated with increased aGVHD. HLA haplotype multivariate analysis demonstrated increased risk of aGVHD with haplotypes A1B8DR3 and A2B44DR4 (A1B8DR3: 64% vs. 32%, RR 2.6, 95% CI: 1.1 to 5.9, p=0.012 and A2B44DR4: 61% vs. 39%, RR 3.5, 95% CI: 1.7 to 7.5, p=0.04) whereas haplotype A3B7DR15 had less aGVHD compared to others (18% vs. 42%, RR 0.31, 95%CI: 0.098 to 0.98, p=0.049). This is the first published report of the effect of HLA haplotypes on aGVHD incidence. Results of our haplotype analysis substantiate our findings of single allele effects of HLA A2, HLA B8 and HLA DR15 suggesting a differential effect on aGVHD incidence. The ability to predict aGVHD after alloHSCT using HLA haplotypes may improve outcomes by allowing for individualized GVHD prophylaxis regimens.