Genotypic inhibitory killer immunoglobulin-like receptor ligand incompatibility enhances the long-term antileukemic effect of unmodified allogeneic hematopoietic stem cell transplantation in patients with myeloid leukemias

Abstract

It remains controversial whether alloreactive donor-derived natural killer (NK) cells display graft-versus-leukemia reactions after unmodified allogeneic hematopoietic stem cell transplantation (HSCT). The present study evaluated the role of inhibitory killer immunoglobulin-like receptor (KIR) ligand incompatibility using a welldefined and uniform setting of unmodified allogeneic HSCT in 374 patients with myeloid leukemias. The most striking finding was a significant heterogeneity in the 5-year estimates of hematologic leukemic relapse after human leukocyte antigen (HLA)-identical (n ‫؍‬ 237; 22%), HLA class I-disparate (n ‫؍‬ 89; 18%), and KIR ligandincompatible transplantations (n ‫؍‬ 48; 5%) (P < .04). Multivariate analysis confirmed that the relative relapse risk (RR) was influenced by HLA class I disparity alone (RR 0.49), but was lowest after HLA class I-disparate, KIR ligand-incompatible transplantations (RR 0.24) (P < .008). The primary graft failure rates, however, increased from 0.4% after HLA class I-identical to 2.3% after HLA class I-disparate, and to 6.3% after KIR ligandincompatible transplantations, respectively (P < .02). Unlike some other reports, no beneficial effect of KIR ligand incompatibility on other major endpoints of allogeneic HSCT (transplantation-related mortality, and overall and event-free survival) was detectable in the present study.

Activating KIR genes are associated with CMV reactivation and survival after non-T-cell depleted HLA-identical sibling bone marrow transplantation for malignant disorders

“…Giebel et al 7 supported the concept raised by Velardi et al, 4,5 Beelen et al 8 only confirmed the antileukaemic effect whereas others reported no benefit from mismatches that should have favoured NK-cell alloreactivity. [9][10][11] A recent study 12 reported an improved outcome in patients transplanted for AML and myelodysplastic syndrome (MDS) with T-depleted HLA-identical sibling bone marrow and lacking an HLA ligand for donor inhibitory KIR.…”

Relevance of C1 and C2 Epitopes for Hemopoietic Stem Cell Transplantation: Role for Sequential Acquisition of HLA-C-Specific Inhibitory Killer Ig-Like Receptor

“…In subsequent studies of related or unrelated HSCT, NK cell-mediated effects were less clear-cut. Whereas a beneficial influence of KIR ligand mismatching on leukemic relapse as well as survival was observed in some studies (8,9), similar effects were not seen in others (10,11). Recently, a combined analysis of KIR ligands together with DNAor RNA-based KIR typing was suggested as better predictors of clinical outcome (12,13).…”

“…HLA-A and -B polymorphisms were determined by low-and intermediateresolution DNA-based typing using PCR-sequence-specific primer (SSP) typing as described previously (9). Additionally, to enable unambiguous assignment of HLA-C-encoded KIR ligands, HLA-C alleles were determined by DNA-based direct sequencing in all donors and recipients included in this study.…”

Natural killer cell immune escape in acute myeloid leukemia

“…30,31 Although these findings were confirmed by some groups, others failed to show any benefit. [32][33][34][35][36][37][38] Results of those studies are discussed in more detail elsewhere by Verheyden and Demanet. 39 Another NK cell escape mechanism demonstrated in the HSCT setting is the overexpression of the inhibitory receptor CD94/ NKG2A on reconstituted NK cells that recognizes human leukocyte antigen-E on AML blasts, which is associated with a low cytotoxic capacity.…”