Donor activating KIR3DS1 is associated with decreased acute GVHD in unrelated allogeneic hematopoietic stem cell transplantation

Abstract

The natural killer cell receptor KIR3DS1 is associated with improved outcome in malignancies, infections, and autoimmune diseases, but data for the impact of KIR3DS1 in HSCT are inconsistent. Using genomic DNA from the National Marrow Donor Program, we performed donor KIR genotyping for 1087 patients who received an unrelated hematopoietic stem cell transplantation. A total of 33% of donors were KIR3DS1(+). Compared with KIR3DS1(-) donors, donor KIR3DS1 was associated with lower-grade II-IV acute graft-versus-host disease (GVHD; odds ratio = 0.71; 95% confidence interval, 0.55-0.92; P = .009), but not with relapse (hazard ratio = 0.97; 95% confidence interval, 0.73-1.29; P = .82). Furthermore, grade II-IV acute GVHD, overall mortality, and transplantation-related mortality all decreased as the number of copies of donor KIR3DS1 increased (P = .007, P = .03, and P = .02, respectively), with the lowest failure rate occurring among patients homozygous for donor KIR3DS1. Selection of donors with KIR3DS1 may decrease acute GVHD without compromising relapse-free survival, separating the graft-versus-tumor effect from unwanted GVHD.

Figure 1

Influence of donor KIR3DS1 on HSCT outcomes. (A) Incidence of grade II-IV acute GVHD (aGVHD) based on donor KIR3DS1 copy number and presence/absence of recipient HLA-Bw4 KIR epitope. Grade II-IV aGVHD was lower among HLA-Bw4⁺ recipients with a KIR3DS1⁺ donor. Donor KIR3DS1 homozygosity is associated with the lowest rate of grade II-IV aGVHD (39%). (B) Probability of TRM stratified by donor KIR3DS1 copy number. TRM is similarly affected by donor KIR3DS1 copy number; the lowest TRM is associated with donor KIR3DS1 homozygosity (31%, P = .02). (C) Kaplan-Meier survival analysis demonstrating an association of overall survival with donor KIR3DS1 copy number (P = .03). (D) There is no association of donor KIR3DS1 with risk of relapse (P = .82).