Donor KIR Genes 2DL5A, 2DS1 and 3DS1 Are Associated with a Reduced Rate of Leukemia Relapse After HLA-Identical Sibling Stem Cell Transplantation for Acute Myeloid Leukemia but Not Other Hematologic Malignancies

Abstract

Stem cell transplantation (SCT) from a healthy donor can be curative for patients with hematologic malignancies resistant to other treatments. Elimination of malignant cells through a graft-versus-leukemia (GVL) effect involves donor T and natural killer (NK) cells, but their relative contribution to this process is poorly defined. NK cell alloreactivity and GVL effects are controlled by the nature of the interaction of NK activation receptors and killer-immunoglobulin-like-receptors (KIR) with major histocompatibility locus class I antigens on the target cell. We performed KIR-genotyping of HLA-identical sibling donors in 246 T cell-depleted SCTs to identify genetic factors affecting transplant outcome (treatment-related mortality [TRM], leukemic relapse, and survival). Univariate and multivariate analysis of transplant-related risk factors and KIR genotyping was performed to identify independent variables predictive of outcome for different forms of leukemia. Further to confirming known predictive factors for TRM and survival (CD34 cell dose, patient age, disease stage), statistical analysis revealed that 3 donor B haplotype KIR genes, 2DL5A, 2DSI, and 3DSI, were associated with significantly less relapse in patients with acute myelogenous leukemia (AML) (13% versus 57%) but not in patients with other myelogenous or lymphoid malignancies. AML patients receiving SCT from donors with these KIR genes relapsed 4 times less frequently than patients transplanted from donors with other KIR genotypes. These findings suggest specific, genetically determined, interactions between NK cells and AML cells that facilitate the GVL effect, and have implications for donor selection for AML patients.

Long-term follow-up of a pilot study using a chemotherapy-alone protocol for killer Ig-like receptor-ligand-mismatched haploidentical haematopoietic SCT

“…In spite of this combination, one of the two relapsed with the other patient dying early due to transplant-related complications. Recently, Stringaris et al 38 noted that patients undergoing T-cell-depleted HLA-identical HSCT for AML from donors with all three of KIR2DL5A, KIR2DS1 and KIR3DS1 had a significantly lower relapse rate compared with patients whose donors did not have this combination. This explanation cannot be used to explain our results as the only patient in out cohort who had this combination of KIR genes was the only patient in our cohort who died of relapsed AML, and none of the three long-term survivors had this combination.…”

Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia

“…21 The benefit of donor KIR B haplotypes also has been observed for T cell-replete transplants from HLAmatched sibling donors, 47 an effect reported in other settings. 22,23 The authors of numerous other studies have reported varied effects of activating KIR on outcomes after various types of HCT, including increased rates of acute GVHD, 25,48,49 or protection against acute GVHD. 50 KIR B haplotypes are present in two-thirds of unrelated donors.…”

“…21 Similar effects have been reported by other investigators in unrelated donor and sibling donor settings. 22,23 Because KIR B haplotypes are present in approximately two-thirds of unrelated registry donors, interventions that merely increase the probability of selecting KIR B donors are unlikely to affect survival because most donors already have this characteristic by chance. Further, the specific genetic mechanism for the protective effect of B haplotype donors, perhaps attributable to the presence or absence of individual or groups of inhibitory or activating KIR, remains unknown.…”

Recognition of adult and pediatric acute lymphoblastic leukemia blasts by natural killer cells

“…[10][11][12][13] In adult patients, it has been reported that most acute myeloid leukemia (AML), 14 but only a minority of ALL cells, are susceptible to NK-cell mediated lysis. 15,16 On the contrary, recent studies of high-risk pediatric ALL undergoing haploidentical HSCT have highlighted the importance of choosing donors with alloreactive NK cells 17,18 to successfully cure these patients. The biological reasons responsible for the different susceptibility of adult and pediatric ALL blasts to the lytic effect played by alloreactive NK cells are so far still unknown.…”