Prospective Identification of Unrelated Donors with Low Inhibitory Donor KIR3DL1 – Recipient HLA-B Interaction Decreases Relapse and Improves Survival after Allogeneic Hematopoietic Cell Transplantation for Myeloid Neoplasia

Abstract

Retrospective studies indicate that the use of unrelated hematopoietic stem cell donors with Killer Ig-like Receptor (KIR) genotypes resulting in low inhibitory interactions with recipient HLA are associated with lower relapse and higher survival in patients with myeloid neoplasia undergoing allogeneic hematopoietic cell transplantation (allo HCT). To validate these findings in a prospective fashion and to determine if advantageous KIR donors can readily be identified for patients with myeloid neoplasia, we prospectively KIR genotyped and provided KIR/HLA-based ranking for unrelated donors (URD) evaluated for patients with a diagnosis of acute myeloid leukemia or myelodysplastic syndrome undergoing workup at our center for allo HCT. Donors were prioritized first to minimize inhibitory KIR3DL1 - HLA-Bw4 interactions, followed by prioritization of donors with non-tolerized activating KIR2DS1, and finally prioritizing donors homozygous for the centromeric B haplotype. We evaluated 2,079 donors for 527 patients (median 4 donors per patient), among whom 263 ultimately underwent allo HCT. In a multivariate analysis adjusting for age, HCT-CI, and conditioning intensity, we found that the use of a KIR3DL1-low-inhibition donor was associated with an improved hazard for survival (HR = 0.58 (95% confidence interval (CI): 0.35 – 0.96), P = 0.035) and event-free survival (HR = 0.61 (95% CI: 0.39 – 0.93), P = 0.023) due to a decreased hazard for relapse (HR = 0.52, 95% CI: 0.30 – 0.90, P = 0.021) without increased non-relapse mortality when compared to KIR3DL1-non-interacting or -high-inhibition donors. Donor KIR2DS1/HLA-C1 status and centromeric haplotype B content were not predictive of relapse or survival in this cohort. Among 339 HLA-Bw4+ patients evaluated for transplant, 242 (71.4%) had an available KIR3DL1-low-inhibition donor and 205 (60.5%) had a mixture of KIR3DL1-low-inhibition with either -high-inhibition or -non-interacting donors facilitating a choice using donor KIR3DL1 genotyping. Evaluating greater numbers of donors associated with an increased probability of identifying an advantageous donor based on inhibitory KIR3DL1 interactions (P