KIR B donors improve the outcome for AML patients given reduced intensity conditioning and unrelated donor transplantation

Abstract

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 = 243) with that from a larger contemporaneous cohort of transplants (n = 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.

Umbilical Cord Blood and iPSC-Derived Natural Killer Cells Demonstrate Key Differences in Cytotoxic Activity and KIR Profiles

“…KIRs have been shown to be clinically significant in allogeneic hemopoietic stem cell transplant (HSCT) treatments for acute myeloid leukemia (AML) in cases of KIR profile mismatches where the inhibitory KIRs on the NK cells derived from the stem cell donor do not encounter their cognate ligands on the transplant recipient's AML blasts. In these cases, NK cells become activated and kill their targets more effectively leading to a survival benefit to AML patients ( 35 , 36 ). These findings have been adopted in practice, as when otherwise similarly HLA-matched allogeneic or haploidentical HSCT donors are available, HSCT donor selection algorithms consider KIR profiles as a donor selection criteria ( 35 , 37 – 39 ).…”

Phenotypic and Functional Characterization of NK Cells in αβT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia

“…On the basis of these in vitro data, NK cell populations characterized by a large size of the alloreactive subset and by a NCR bright phenotype are likely to exert an optimal anti-leukemia activity. In addition, B/x KIR genotype and high B content value, the presence of KIR2DS1 E/U, and the presence of NKG2C, indicating a receptor repertoire well equipped with activating receptors, were positively considered in our donor selection criteria [4,12,35,37,39,51,52]. Unexpectedly, no significant correlation with LFS was observed considering donor NK alloreactivity, KIR genotype, B-content score and KIR2DS1 E/U [34].…”

Influence of KIR and NK Cell Reconstitution in the Outcomes of Hematopoietic Stem Cell Transplantation

“…Cooley et al observed that patients with AML with KIR-B/x donors experienced a 30% improvement in RFS compared with those with A/A donors ( 40 ). Subsequently, many further investigations confirmed this beneficial effect of the KIR-B haplotype on relapse and survival in patients with hematological malignancies ( 50 , 51 , 57 , 67 , 72 , 76 , 79 , 81 , 85 , 88 – 92 , 96 , 98 , 101 – 104 ). Five of these studies reported that the protection effects mainly existed in the KIR Cen-B locus ( 67 , 88 , 91 , 92 , 96 ).…”