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Donor-recipient killer immunoglobulin like receptor (KIR) genotype matching has a protective effect on chronic graft versus host disease and relapse incidence following HLA-identical sibling hematopoietic stem cell transplantation

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Abstract

Impact of donor-recipient killer immunoglobulin-like receptor (KIR) gene-gene matching on transplant outcomes is still inconclusive. Recent data suggest that killer cell immunoglobulin-like receptor (KIR) regulated natural killer cell (NK cell) activity may contribute to graft versus leukemia (GvL) effects and graft versus host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This case-control study aims to evaluate the effects of both aKIR and iKIR donor-recipient genotype matching on the outcomes of T cell replete HLA-identical sibling allo-HSCTs in a homogenous young patient population with myeloid leukemias. Five transplant outcomes including relapse rate (RR), disease-free survival (DFS), overall survival (OS), cumulative incidences of acute GvHD (aGvHD), and chronic GvHD (cGvHD) are investigated. Out of 96 HLA-identical sibling donor-recipient pairs, 34 were matched for activating KIR (aKIR), 38 for inhibitory KIR (iKIR), and 20 for both aKIR and iKIR. Fourty-four pairs were mismatched for both iKIR and aKIR. In univariate analysis, aKIR-matching resulted with a decrease in relapse rate (RR) (hazard ratio [HR]: 0.4; p = 0.04) and an increase in disease-free survival (DFS) (HR: 0.5; p = 0.03). In addition, cGvHD ocurred less frequently in the aKIR-matched (odds ratio [OR]: 0.4; p = 0.04) or iKIR-matched (OR: 0.3; p = 0.009) cohorts. Matching for both aKIR and iKIR was also associated with a decrease in cGvHD incidence (OR: 0.3; p = 0.02). iKIR-matching had no effects on RR, OS, or DFS. Analysis of donor haplotype effects showed haplotype-BB to have a tendency towards reduced relapse rate (HR: 0.4; p = 0.08) and better OS (HR: 0.4; p = 0.04); haplotype-Bx to increase the incidence of cGvHD (OR: 4.1; p = 0.03). In multivariate analysis, DFS advantage remained significant for aKIR-matching (HR: 0.5; p = 0.04); cGvHD incidence was reduced in the presence of iKIR-match (OR: 0.3; p = 0.02) and increased in the presence of haplotype-AB and -BB donors (OR: 7.9; p = 0.02; OR: 5.1; p = 0.03, respectively). In an attempt to investigate the pathogenesis underlying KIR-matching, we searched for residual NK/T cells on day 0 peripheral blood samples of six additional recipients and noted the presence of CD3+ (7.0–91.4 × 106/L) and CD56+57+ (0.8–12.7 × 106/L) cells. In conclusion, conditioning regimen surviving recipient NK/T cells potentially influenced by KIR-matching may contribute to GvL/GvH reactions.

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Acknowledgements

Funda Gungor and Klara Dalva performed the laboratory analysis. Meral Beksac designed the research and selected subjects to be included in the study. Ugur Sahin and Celalettin Ustun analyzed the data. Ugur Sahin and Meral Beksac wrote the paper.

Authors are thankful to Dr. Daniel J. Weisdorf for his most valuable suggestions about the statistical approaches and critical review of the manuscript. We also would like to thank Atilla Halil Elhan and Ryan Shanley for their suggestions during data analysis; Dr. Erden Atilla and Didem Civit for their help in formation of the patient database.

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Authors and Affiliations

  1. Department of Hematology, Cebeci Hospital, Ankara University Faculty of Medicine, 06220, Ankara, Turkey

    Ugur Sahin, Klara Dalva, Funda Gungor & Meral Beksac

  2. Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA

    Celalettin Ustun

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  1. Ugur Sahin
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The study was performed in accordance with the Declaration of Helsinki and good clinical practice guidelines and was approved by the local institutional review board of Ankara University Medical School. Written informed consents were obtained from all participants prior to enrollment.

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Sahin, U., Dalva, K., Gungor, F. et al. Donor-recipient killer immunoglobulin like receptor (KIR) genotype matching has a protective effect on chronic graft versus host disease and relapse incidence following HLA-identical sibling hematopoietic stem cell transplantation. Ann Hematol 97, 1027–1039 (2018). https://doi.org/10.1007/s00277-018-3274-0

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