Donor killer cell Ig-like receptor B haplotypes, recipient HLA-C1, and HLA-C mismatch enhance the clinical benefit of unrelated transplantation for acute myelogenous leukemia

Abstract

Killer cell Ig-like receptors (KIRs) interact with HLA class I ligands to regulate NK cell development and function. These interactions affect the outcome of unrelated donor hematopoietic cell transplantation (HCT). We have shown previously that donors with KIR B versus KIR A haplotypes improve the clinical outcome for patients with acute myelogenous leukemia by reducing the incidence of leukemic relapse and improving leukemia-free survival (LFS). Both centromeric and telomeric KIR B genes contribute to the effect, but the centromeric genes are dominant. They include the genes encoding inhibitory KIRs that are specific for the C1 and C2 epitopes of HLA-C. We used an expanded cohort of 1532 T cell-replete transplants to examine the interaction between donor KIR B genes and recipient class I HLA KIR ligands. The relapse protection associated with donor KIR B is enhanced in recipients who have one or two C1-bearing HLA-C allotypes, compared with C2 homozygous recipients, with no effect due to donor HLA. The protective interaction between donors with two or more, versus none or one, KIR B motifs and recipient C1 was specific to transplants with class I mismatch at HLA-C (RR of leukemia-free survival, 0.57 [0.40-0.79]; p = 0.001) irrespective of the KIR ligand mismatch status of the transplant. The survival advantage and relapse protection in C1/x recipients compared with C2/C2 recipients was similar irrespective of the particular donor KIR B genes. Understanding the interactions between donor KIR and recipient HLA class I can be used to inform donor selection to improve outcome of unrelated donor hematopoietic cell transplantation for acute myelogenous leukemia.

Trial registration: ClinicalTrials.gov NCT01288222.

Figure 1. Interactions between KIR-Better/Best donors and recipient HLA-C1 improve LFS and protect against relapse, especially in HLA-mismatched transplants

Donors were assigned to KIR-Neutral and KIR-Better/Best groups based on KIR genotyping. Probabilities of LFS are provided by Kaplan Meier curves (A) and cumulative incidence probabilities are shown for relapse (B). Each outcome is shown comparing KIR-Neutral donors with KIR-Better/Best donors in HLA-C1/x recipients for all transplants (1), HLA-matched transplants (2) and the HLA-mismatched transplants (3). The estimated rates are presented for LFS and relapse at 5 years. P values were calculated from multivariate analyses comparing relative risks of outcomes for KIR-Neutral and KIR-Better/Best donor groups.

Figure 2. HLA-C2/C2 recipients do not experience enhanced protection from KIR-Better/Best donors

Donors were assigned to KIR-Neutral and KIR-Better/Best groups based on KIR genotyping and recipients were designated based on their HLA-C allotypes (C1/x and C2/C2). Probabilities of LFS are provided by Kaplan Meier curves (A) and cumulative incidence probabilities are shown for relapse (B). Each outcome is shown comparing KIR-Neutral donors with KIR-Better/Best donors in HLA-C2/C2 recipients for all transplants in all transplants (1), HLA-matched transplants (2) and the HLA-mismatched transplants (3). The estimated rates are presented for LFS and relapse at 5 years. P values were calculated from multivariate analyses comparing relative risks of outcomes for KIR-Neutral and KIR-Better/Best donor groups.