NKG2D gene polymorphism has a significant impact on transplant outcomes after HLA-fully-matched unrelated bone marrow transplantation for standard risk hematologic malignancies

Abstract

Background: NKG2D, an activating and co-stimulatory receptor expressed on natural killer cells and T cells, plays pivotal roles in immunity to microbial infections as well as in cancer immunosurveillance. This study examined the impact of donor and recipient polymorphisms in the NKG2D gene on the clinical outcomes of patients undergoing allogeneic T-cell-replete myeloablative bone marrow transplantation using an HLA-matched unrelated donor.

Design and methods: The NKG2D polymorphism was retrospectively analyzed in a total 145 recipients with hematologic malignancies and their unrelated donors. The patients underwent transplantation following myeloablative conditioning; the recipients and donors were matched through the Japan Marrow Donor Program.

Results: In patients with standard-risk disease, the donor NKG2D-HNK1 haplotype, a haplotype expected to induce greater natural killer cell activity, was associated with significantly improved overall survival (adjusted hazard ratio, 0.44; 95% confidence interval, 0.23 to 0.85; p=0.01) as well as transplant related mortality (adjusted hazard ratio, 0.42; 95% confidence interval, 0.21 to 0.86; p=0.02), but had no impact on disease relapse or the development of grade II-IV acute graft-versus-host disease or chronic graft-versus-host disease. The NKG2D polymorphism did not significantly influence the transplant outcomes in patients with high-risk disease.

Conclusions: These data suggest an association between the donor HNK1 haplotype and better clinical outcome among recipients, with standard-risk disease, of bone marrow transplants from HLA-matched unrelated donors.

Figure 1.

Kaplan-Meier analysis of (A) overall survival, (B) cumulative incidence of transplant-related mortality and (C) disease relapse after transplantation according to the donor NKG2D polymorphism in patients with standard-risk disease. Patients with donors with the HNK1 haplotype had better overall survival and lower transplant-related mortality. Donor haplotype had no significant impact on disease relapse.

Figure 2.

Main causes of death after transplantation according to the NKG2D polymorphism in patients with (A) standard-risk disease (B) high-risk disease.

Figure 3.

Cumulative incidence of deaths due to (A) acute GVHD and (B) interstitial pneumonia after transplantation in patients with standard-risk disease. The HNK1 haplotype in donors was associated with a significantly lower incidence of deaths due to acute GVHD (p=0.006) as well as a trend toward a lower incidence of deaths due to interstitial pneumonia (p=0.09).