Natural killer (NK) cell recognition and killing of target cells are enhanced when inhibitory killer immunoglobulin-like receptors (KIR) are unable to engage their cognate HLA class I ligands. The genes of the KIR locus are organized into either KIR B haplotypes, containing 1 or more activating KIR genes or KIR A haplotypes, which lack those genes. Analysis of unrelated donor (URD) hematopoietic cell transplants (HCT), given to acute myeloid leukemia (AML) patients between 1988 and 2009, showed that KIR B haplotype donors were associated with better outcomes, primarily from relapse protection. Most of these transplants involved marrow grafts, fully myeloablative (MAC) preparative regimens, and significant HLA mismatch. Because the practice of HCT continues to evolve, with increasing use of reduced intensity conditioning (RIC), peripheral blood stem cell grafts, and better HLA match, we evaluated the impact of URD KIR genotype on HCT outcome for AML in the modern era (2010-2016). This analysis combined data from a prospective trial testing URD selection based on KIR genotypes (n 5 243) with that from a larger contemporaneous cohort of transplants (n 5 2419). We found that KIR B haplotype donors conferred a significantly reduced risk of leukemia relapse and improved disease-free survival after RIC, but not MAC HCT. All genes defining KIR B haplotypes were associated with relapse protection, which was significant only in transplant recipients expressing the C1 epitope of HLA-C. In the context of current HCT practice using RIC, selection of KIR B donors could reduce relapse and improve overall outcome for AML patients receiving an allogeneic HCT.
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Acknowledgments This work was supported by National Institutes of Health, National Cancer Institute (NCI) grants P01 CA111412 (D.W., T.W., T.A.F., E.K.W., S.G.E.M, P.P., L.A.G., and J.S.M.), P50 CA171963 (T.A.F.), R01 CA205239 (T.A.F.), and in part by P30 CA77598 using the Masonic Cancer Center Oncology Medical Informatics shared resource. The Center for International Blood and Marrow Transplant Research is supported primarily by Public Health Service Grant/ Cooperative Agreement U24CA076518 from the NCI, the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; a grant/cooperative agreement from NHLBI and NCI; NCI grant U24CA233032-01; NHLBI grants 5U24HL138660-02 and U01HL128568; Health Resources and Services Administration contract HHSH250201700006C; and
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