Donor KIR Tel-B Haplotypes Beneficially Affect Outcome after Allogeneic Stem Cell Transplantation in Patients with Myeloid Malignancies

Introduction. Leukemia relapse after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) remains a major clinical issue. Myelogenous leukemias are the most sensitive to natural killer (NK)-cell reactivity among blood malignancies treated with allo-HSCT. NK-cell function is controlled by an array of inhibitory and activating receptors, including killer cell immunoglobulin-like receptors (KIRs), whose genes vary in number and content. Inhibitory KIRs recognize the HLA class I ligands and mediate tolerance to self when they encounter self-HLA molecules on putative target cells. HLA-C allotypes with asparagine at position 80 (C1 ligands) are recognized by KIR2DL2/3, HLA-C allotypes with lysine at position 80 (C2 ligands) are recognized by KIR2DL1. HLA-A and –B allotypes with Bw4 motif are recognized by KIR3DL1. The ligands and function of activating KIRs are not well identified with the exception of KIR2DS1which recognizes HLA-C2 ligand group. KIR A haplotypes have simple, fixed gene content; B haplotypes have variable gene content and one or more of the B-specific genes: KIR2DS1, 2, 3, 5 KIR2DL2, KIR2DL5.The KIR locus divides into centromeric (Cen) and telomeric(Tel) regions. In both regions there are two distinctive types of variable KIR gene content motif - Cen-A/Cen-B and Tel-A/Tel-B. The aim of our prospective study was to evaluate the influence of immunogenetic factors (KIRs and their HLA ligands) on the outcome after allo-HSCT in patients with myeloid malignancies.

Methods. 29 patients with different clonal myeloid disorders who underwent allo-HSCT in Research Center for Hematology (Moscow, Russian Federation) in 2011-2013 from HLA-identical related (n=19) and HLA-matched unrelated (n=10) donors were included in the study. The pre-transplantation risk category included standard or high risk. Acute myelogenous leukemia (AML) in complete remission 1 (CR1, n=15), chronic myelogenous leukemia (chronic phase 1, n=4), and myelodysplastic syndromes (n=2) classified as refractory anemia/refractory anemia with ringed sideroblasts were categorized as standard risk (n=21), whereas AML > CR1were considered as high risk (n=8). KIR genotyping was performed before allo-HSCT simultaneously with HLA-typing using a PCR-SSP kit (Invitrogen, WI, USA). Overall survival (OS) and event-free survival (EFS) were calculated by the Kaplan-Meier method, and compared with the log-rank test. OS was defined as survival without lethal event from any cause, EFS was defined as survival in complete remission without lethal event from any cause.

Results. We found that the 3-year estimated OS and EFS in all patients were 59.7 and 50.0%, respectively. Conditioning regimen and graft source (related or unrelated) had no significant effect on transplant outcome. The pre-transplantation risk category was the main factor influencing survival. The probability of the 3-year OS and EFS for standard-risk patients was 85.7 and 69.0%, respectively; all high-risk patients died during 20 months after allo-HSCT. For standard-risk patients there was better EFS in patients whose donors had KIR Tel-B haplotypes in comparison with patients whose donors had no KIR Tel-B haplotypes (87.5 vs. 58.3%, p=0.08). Standard-risk recipients with HLA-C1/C1 ligands (i.e., C1 epitope present on both HLA-C alleles) had a tendency to an improved EFS compared with patients having either C1/C2 or C2/C2 ligands (88.9 vs. 55.6%, p=0.15). Also there was a tendency to better EFS in patients lacking HLA-Bw4 ligands compared with patients having those ligands (88.9 vs. 55.6%, p=0.15).

Conclusions. Our small one single-center prospective study supports the hypothesis about the specific, genetically determined role of NK cell in the graft versus leukemia effect in myeloid malignancies. We suggest that donors having KIR Tel-B haplotypes are preferable for patients with myelogenous leukemias, and selection of the donors with KIR Tel-B haplotypes can improve outcome after allo-HSCT for myelogenous leukemias.