Improved survival with inhibitory Killer Immunoglobulin Receptor (KIR) gene mismatches and KIR haplotype B donors after nonmyeloablative HLA-haploidentical bone marrow transplantation

摘要

Natural killer (NK) cell alloreactivity, which may contribute to the graft-versus-leukemia effect of allogeneic hematopoietic stem cell transplantation (HSCT), is influenced by the interaction of killer-cell immunoglobulin-like receptors (KIRs) on donor NK cells and their ligands, human leukocyte antigen (HLA) Class I molecules on recipient antigen-presenting cells. Distinct models to predict NK cell alloreactivity differ in their incorporation of information from typing of recipient and donor KIR and HLA gene loci, which exist on different autosomes and are inherited independently as haplotypes. Individuals may differ in the inheritance of the two KIR haplotypes, A and B, or in the expression of individual KIR genes. Here, we examined the effect of KIR and HLA genotype, in both the recipient and donor, on the outcome of 86 patients with advanced hematologic malignancies who received nonmyeloablative, HLA-haploidentical HSCT with high-dose, post-transplantation cyclophosphamide (Cy). Compared to recipients of marrow from donors with identical KIR gene content, recipients of inhibitory KIR (iKIR) gene-mismatched marrow had an improved overall survival (HR=0.37; CI: 0.21- 0.63; p=0.0003), event-free survival (HR=0.51; CI: 0.31- 0.84; p=0.01), and relapse rate (cause specific hazard ratio, SDHR=0.53; CI: 0.31-0.93; p=0.025). Patients homozygous for the KIR “A” haplotype, which encodes only one activating KIR, had an improved overall survival (HR=0.30; CI: 0.13-10.69; p=.004), event-free survival (HR=0.47; CI: 0.22-1.00; p=.05) and non-relapse mortality (NRM; cause specific HR=0.13; CI: 0.017-0.968; p=0.046) if their donor expressed at least one KIR B haplotype, which encodes several activating KIRs. Models that incorporated information from recipient HLA typing, with or without donor HLA typing, were not predictive of outcome in this patient cohort. Thus, nonmyeloablative conditioning and T cell-replete, HLA-haploidentical HSCTs involving iKIR gene mismatches between donor and recipient, or KIR haplotype AA recipients of marrow from KIR Bx donors, were associated with lower relapse and NRM and improved overall and event-free survival. These findings suggest that selection of donors based upon inhibitory KIR gene or haplotype incompatibility may be warranted.