Improved survival with inhibitory killer immunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors after nonmyeloablative, HLA-haploidentical bone marrow transplantation

Abstract

Natural killer (NK) cell alloreactivity, which may contribute to the graft-versus-leukemia (GVL) 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 (APCs). 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 2 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 (NMA), HLA-haploidentical HSCT with high-dose, posttransplantation cyclophosphamide (Cy). Compared to recipients of bone marrow (BM) from donors with identical KIR gene content, recipients of inhibitory KIR (iKIR) gene-mismatched BM had an improved overall survival (OS) (hazard ratio [HR]=0.37; confidence interval [CI]: 0.21-0.63; P=.0003), event-free survival (EFS) (HR=0.51; CI: 0.31-0.84; P=.01), and relapse rate (cause-specific HR, SDHR=0.53; CI: 0.31-0.93; P=.025). Patients homozygous for the KIR "A" haplotype, which encodes only 1 activating KIR, had an improved OS (HR=0.30; CI: 0.13-10.69; P=.004), EFS (HR=0.47; CI: 0.22-1.00; P=.05), and nonrelapse mortality (NRM; cause-specific HR=0.13; CI: 0.017-0.968; P=.046) if their donor expressed at least 1 KIR B haplotype that 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, NMA conditioning and T cell-replete, HLA-haploidentical HSCTs involving iKIR gene mismatches between donor and recipient, or KIR haplotype AA recipients of BM from KIR Bx donors, were associated with lower relapse and NRM and improved OS and EFS. These findings suggest that selection of donors based upon inhibitory KIR gene or haplotype incompatibility may be warranted.

Figure 1

Models of natural killer cell alloreactivity after allogeneic cell transplantation. A. The KIR ligand incompatibility, or ligand-ligand model predicts NK cell alloreactivity in the GVH direction (depicted by jagged arrow) when the recipient lacks expression of an inhibitory KIR ligand, in this case a member of the HLA-C1 group, that is present in the donor. This model assumes the presence of functional donor NK cells expressing KIR2DL2, the receptor for HLA-C1 molecules, as their inhibitory receptor. B. The receptor-ligand model predicts NK cell alloreactivity in the GVH direction when the recipient lacks the expression of an HLA ligand for a verified donor inhibitory KIR. The HLA type of donor cells is not considered in this model. C. The missing ligand model predicts NK cell alloreactivity in the GVH direction when recipient cells lacks expression of at least one of the HLA ligands (C1, C2, or –Bw4) for a verified donor inhibitory KIR. As in B., the HLA type of the donor is not considered in this model. D. The KIR gene-gene model predicts NK alloreactivity when the donor and recipient are mismatched for KIR gene content. This model characterizes the KIR genotype of both donor and recipient and asks whether differences in the expression of individual inhibitory or stimulatory genes between the donor and the recipient KIR (i.e. donor includes inhibitory KIR genes that the recipient is missing or vice versa) have any effect on the outcome of allogeneic SCT. Inhibitory KIR genes are shown here as unshaded boxes, whereas black boxes represent activating KIR genes. In the example shown, the donor has several activating and inhibitory genes that the recipient lacks. This example also illustrates the KIR haplotype characterization. In this case, the donor is haplotype group B, based on the presence of several activating KIR genes, while the recipient is haplotype group A based on the presence of inhibitory genes and only one activating gene.

Figure 2

Nonmyeloablative haploidentical BMT conditioning and postgrafting immunosuppresive regimen.

Figure 3

Overall outcomes among nonmyeloablative haploidentical BMT recipients. Cumulative incidence of (A) acute GVHD, grades II-IV and III-IV. (B) Non-relapse mortality. (C) Relapse. (D) Overall survival. (E) Event-free survival.

Figure 4

Gene-gene inhibitory KIR mismatches and overall survival, event free-survival, and relapse (A) Overall Survival (OS). (B) Event-Free Survival (EFS). (C) Cumulative incidence of relapse.

Figure 5

Overall survival, event free-survival, and non-relapse mortality for haplotype A recipients of B donors (A) Overall survival. (B) Event-Free survival. (C) Cumulative incidence of non-relapse mortality

Figure 6

Overall and event free-survival for haplotype B recipients of A donors (A) Overall survival. (B) event-free survival.