Donors with KIR-Bx Haplotypes Improve Outcome of Unrelated Hematopoietic Stem Cell Transplantation for Recipients with a Myeloid Malignant Disease and a C1 Ligand Phenotype

Abstract

Introduction

A donor Killer Cell Ig-like Receptor (KIR) B-Haplotye has been reported to beneficially influence outcome of unrelated transplantation for patients with acute myeloid leukemia (AML) if the recipient HLA-C phenotype exhibits a C1 ligand. We validated this association in an independent cohort of German patients.

Materials and Methods

Patients treated with first unrelated transplantation between 2000 and 2009 for a malignant haematological disease, were included (n=1694, myeloid disease n=982 – 58.0%, lymphatic diseases n=712 – 42.0%). Graft sources were bone marrow (n=132 – 7.8%) or peripheral blood stem cells (n=1562 – 92.2%). All patients and donors were high resolution typed for the loci HLA-A,B,C,DRB1,DQB1. Retrospectively, the donors were typed for KIR genes using a commercial SSP kit (Invitrogen) and classified for KIR-AA or KIR-Bx haplotypes based upon the presence of one or more of the following activating KIR-receptors: 2DL2, 2DL5, 3DS1, 2DS1, 2DS2, 2DS3, 2DS5. The resulting groups were compared for the endpoints: relapse, transplant-related mortality (TRM), and overall survival (OS) using competing risks analysis and extended cox regression modelling for the subsets myeloid and lymphatic diseases. Heterogeneity of diagnosis within each subset was adjusted using stratification.

Results

For lymphatic diseases no significant difference was found between the corresponding groups regarding relapse, OS and TRM. For myeloid diseases however, a significantly lower rate of relapse was found if the donor had a KIR Bx haplotype and the patient had a C1 HLA-C ligand (5 year relapse rate 36.2% vs 28.2%, p=0.012). OS and TRM was slightly favourable for this group, but no significant differences could be found (OS: 42.2% vs. 37.9%, p=0.146; TRM: 20.8% vs. 22.9% p=0.433). The effect on relapse was independent of the HLA-matching status, and a relative risk rate of 0.73 (CI 0.57-0.92, p=0.009) for the incidence of relapse was found in multivariate competing risks regression after correction for the number of HLA-mismatches.

Conclusion

A substantially reduced relapse rate was found in our analysis for patients with myeloid diseases and the presence of an HLA-C1 ligand if their donor had a KIR-Bx Haplotype. Most patients being transplanted fall in this patient group. Approximately two thirds of all donors have a KIR-Bx haplotype. For patients with myeloid diseases and an HLA-C1 ligand, donor KIR typing should be performed if more than one well matched donors are available. Donors with KIR-AA haplotypes should be avoided for these patients if possible.