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

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 x 10(6)/L) and CD56(+)57(+) (0.8-12.7 x 10(6)/L) cells. In conclusion, conditioning regimen surviving recipient NK/T cells potentially influenced by KIR-matching may contribute to GvL/GvH reactions.