Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes

Abstract

Inhibitory killer immunoglobulin (Ig)-like receptors (KIRs) recognize HLA-C and -B epitopes on target cells, thereby regulating natural killer (NK) cell activity. In 178 patients receiving T-cell-depleted HLA-identical sibling transplants for acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS), analysis of donor KIR genotype with HLA genotype demonstrated that 62.9% of the patients lacked an HLA ligand for donor-inhibitory KIR. Lack of HLA ligand for donor-inhibitory KIR (missing KIR ligand) had no effect on disease-free survival (DFS), overall survival (OS), or relapse in patients receiving transplants for CML and ALL. In patients with AML and MDS, however, there was a significant missing KIR ligand effect on DFS (P = .014; hazard ratio [HR], 0.53; 95% confidence interval [95% CI], 0.28-0.88) and OS (P = .03; HR, 0.53; 95% CI, 0.3-0.93). Incidence of relapse was also lower in patients with AML and MDS who lacked the HLA ligand for donor-inhibitory KIR (P = .04; HR, 0.41; 95% CI, 0.18-0.97). AML and MDS patients lacking 2 HLA ligands for donor-inhibitory KIR had the highest DFS (P = .002) and OS (P = .003). There was no significant contribution of donor-activating KIR to transplantation outcome in these patients. These data indicate that the absence of class I ligand in the recipient for donor-inhibitory KIR can be a prognostic factor for transplantation outcome in HLA-identical sibling transplantation and that the lack of HLA-C or -B ligands for donor-inhibitory KIR can contribute to improved outcomes for patients with AML and MDS.

Figure 1.

Disease-free survival of leukemia patients with HLA ligands present or missing for donor-inhibitory KIR. Kaplan-Meier estimates for the probability of disease-free survival in (A) AML patients and (B) AML and MDS patients.

Figure 2.

Risk for relapse in AML and MDS patients with HLA ligands present or missing for donor-inhibitory KIR. Cumulative incidence estimates for the probability of relapse in (A) AML patients and (B) AML and MDS patients.

Figure 3.

Disease-free survival of AML and MDS patients according to specific KIR ligand absence. Kaplan-Meier estimates for the probability of disease-free survival in patients lacking the HLA-CAsn80 ligand for donor KIR2DL2/2DL3 (HLA-C group 1 absent; n = 10), patients lacking the HLA-CLys80 ligand for donor KIR2DL1 (HLA-C group 2 absent; n = 12), patients lacking the HLA-Bw4 ligand for donor KIR3DL1 (HLA-Bw4 absent; n = 6), patients lacking both an HLA-Bw4 ligand and an HLA-C ligand for donor KIR (HLA-C and HLA-Bw4 absent; n = 16), or patients with all ligands present for donor-inhibitory KIR (n = 28). Comparison of survival between patients lacking 1 KIR ligand and patients with all ligands present (P = .16), between patients lacking 2 ligands and patients lacking 1 (P = .06), and between patients lacking 2 ligands and patients with all ligands present (P = .002). Significance for heterogeneity between the study groups was tested by the log-rank statistic.