Increased donor inhibitory KIR with known HLA interactions provide protection from relapse following HLA matched unrelated donor HCT for AML.

Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell-mediated graft versus leukemia effect (GVL) after hematopoietic cell transplant (HCT) for AML. Accounting for known KIR-KIRL interactions may identify donors with optimal NK cell-mediated alloreactivity and GVL. A retrospective study of 2359 donor-recipient pairs (DRP) who underwent unrelated donor (URD) HCT for AML was performed. KIR-KIRL combinations were determined and associations with clinical outcomes examined. Relapse risk was reduced in DRP with both higher inhibitory KIR-KIRL (iKIR) and missing KIRL (mKIR) scores, with HR 0.86 (P = 0.01) & HR 0.84 (P = 0.02) respectively. The iKIR and mKIR score components were summed to give a maximal inhibitory KIR ligand (IM-KIR) score for each donor, which if it was 5, as opposed to <5, was also associated with a lower relapse risk, SHR 0.8 (P = 0.004). All IM = 5 donors possess KIR Haplotype B/x. Transplant-related mortality was increased among those with IM-KIR = 5, HR, 1.32 (P = 0.01). In a subset analysis of those transplanted with 8/8 HLA-matched DRP, anti-thymocyte globulin recipients with IM-KIR = 5, had a lower relapse rate HR, 0.61 (p = 0.001). This study demonstrates that HLA-matched unrelated donors with the highest inhibitory KIR content confer relapse protection, albeit with increased TRM. These donors all have KIR haplotype B. Clinical trials utilizing donors with a higher iKIR content in conjunction with novel strategies to reduce TRM should be considered for URD HCT in recipients with AML to optimize clinical outcomes.