HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1

Abstract

Background: Of the cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), acute myeloid leukemia (AML) is most sensitive to natural killer (NK)-cell reactivity. The activating killer-cell immunoglobulin-like receptor (KIR) 2DS1 has ligand specificity for HLA-C2 antigens and activates NK cells in an HLA-dependent manner. Donor-derived NK reactivity controlled by KIR2DS1 and HLA could have beneficial effects in patients with AML who undergo allogeneic HSCT.

Methods: We assessed clinical data, HLA genotyping results, and donor cell lines or genomic DNA for 1277 patients with AML who had received hematopoietic stem-cell transplants from unrelated donors matched for HLA-A, B, C, DR, and DQ or with a single mismatch. We performed donor KIR genotyping and evaluated the clinical effect of donor KIR genotype and donor and recipient HLA genotypes.

Results: Patients with AML who received allografts from donors who were positive for KIR2DS1 had a lower rate of relapse than those with allografts from donors who were negative for KIR2DS1 (26.5% vs. 32.5%; hazard ratio, 0.76; 95% confidence interval [CI], 0.61 to 0.96; P=0.02). Of allografts from donors with KIR2DS1, those from donors who were homozygous or heterozygous for HLA-C1 antigens could mediate this antileukemic effect, whereas those from donors who were homozygous for HLA-C2 did not provide any advantage (24.9% with homozygosity or heterozygosity for HLA-C1 vs. 37.3% with homozygosity for HLA-C2; hazard ratio, 0.46; 95% CI, 0.28 to 0.75; P=0.002). Recipients of KIR2DS1-positive allografts mismatched for a single HLA-C locus had a lower relapse rate than recipients of KIR2DS1-negative allografts with a mismatch at the same locus (17.1% vs. 35.6%; hazard ratio, 0.40; 95% CI, 0.20 to 0.78; P=0.007). KIR3DS1, in positive genetic linkage disequilibrium with KIR2DS1, had no effect on leukemia relapse but was associated with decreased mortality (60.1%, vs. 66.9% without KIR3DS1; hazard ratio, 0.83; 95% CI, 0.71 to 0.96; P=0.01).

Conclusions: Activating KIR genes from donors were associated with distinct outcomes of allogeneic HSCT for AML. Donor KIR2DS1 appeared to provide protection against relapse in an HLA-C-dependent manner, and donor KIR3DS1 was associated with reduced mortality. (Funded by the National Institutes of Health and others.).

Figure 1. Effect of KIR2DS1 and HLA-C Ligand in Stem-Cell Donors on Relapse in Patients with Acute Myeloid Leukemia (AML)

The cumulative incidence of AML relapse is shown for patients with KIR2DS1-negative versus KIR2DS1-positive donors (Panel A), patients with KIR2DS1-positive donors stratified according to HLA-C1 and C2 ligands (Panel B), and patients with donors stratified according to HLA-C1 and C2 ligands and KIR2DS1 status (Panel C). HSCT denotes hematopoietic stem-cell transplantation.

Figure 2. Association between Rate of Relapse after HSCT and Homozygosity for HLA-C2 Ligand in Transplant Recipients

The cumulative incidence of AML relapse is shown for patients stratified according to status with respect to HLA-C KIR ligand (Panel A) and status with respect to both HLA-C KIR ligand and donor KIR2DS1 (Panel B).

Figure 3. KIR2DS1-Mediated Graft-versus-Leukemia Effect in HLA-C–Mismatched HSCT

The cumulative incidence of AML relapse is shown for recipients of transplants from KIR2DS1-positive or KIR2DS1-negative donors with 10 of 10 HLA alleles matched (Panel A), with a single-allele mismatch at loci other than HLA-C (Panel B), or with a single-allele mismatch at the HLA-C locus (Panel C).