Influence of KIR Genes and HLA Class I Ligands on Overall and Event-Free Survivals after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myelogenous Leukemia

Abstract

Acute myelogenous leukemia (AML) is the most sensitive to natural killer (NK)-cell reactivity among blood malignancies treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Function of NK cells is regulated by their inhibitory and activating surface receptors, including killer-cell immunoglobulin-like receptors (KIRs). KIRs with specificity to different HLA class I-encoded ligands seem to play a major role in allorecognition: HLA-C allotypes with asparagine at position 80 (HLA-C1ligands) are recognized by KIR2DL2/3, HLA-C allotypes with lysine at position 80 (HLA-C2 ligands) are recognized by KIR2DL1and KIR2DS1, and HLA-B allotypes with a polymorphic sequence motif at position 77-83 (Bw4 ligands) are recognized by KIR3DL1.There are numerous but sometimes contradictory data about the role of KIR genes and genes of their HLA ligands in outcomes after HLA-identical related and HLA-matched unrelated HCST in patients with AML.The goal of our prospective study was to evaluate the influence of KIR genes and HLA class Iligands on overall survival (OS) and event-free survival (EFS) after allo-HSCT in adult patients with AML.35 patients with AML (median age 36 years, range 19-60) treated with allogeneic HSCT in our transplant center from HLA-identical related (n=19) and HLA-matched (10/10) unrelated (n=16) donors were included in the study. Median follow-up was 18 months (range, 5-56). The pre-transplantation risk category included standard or high risk. Patients in complete remission 1 (CR1) were categorized as standard risk (n=22), whereas patients in > CR1 were considered as high risk (n=13). In case of HLA-identical related HSCT donor KIR genotyping was performed simultaneously with HLA-typing. In case of HLA-matched unrelated HSCT donor KIR genotyping was performed in time of confirmatory HLA-testing or in day of HSCT. KIR genotyping was done using a PCR-SSP kit (Olerup, Sweden). Overall survival (OS) and event-free survival (EFS) were calculated by Kaplan-Meier method, and compared with 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.The 3-year estimated OS and EFS in all patients were 66 and 43%, respectively. 10 patients died (29%), relapse (hematological and/or molecular) was diagnosed in 18 patients (51%). The pre-transplantation risk category was the main factor affecting OS and EFS after HSCT. The probability of the 3-year OS and EFS for standard-risk patients was 86 and 57%, respectively. Nobody of our patients with high risk lived more than18 months. Conditioning regimen, graft source and donor/patient gender combination had no significant effect on OS and EFS. The patients with unrelated HLA-matched donors had better (not significantly) EFS in comparison with recipients of related HLA-identical grafts (p=0.12).The influence of KIR and HLA- ligand genes on EFS after allo-HSCT was investigated in patients with standard risk. We did not find the immunogenetic factors (presence of B- haplotypes in donors, donor KIR B content, presence of centromeric or telomeric B- motifs in donors, presence of missing HLA ligand for any inhibitory KIR of donor), which significantly affected EFS, but we found two obvious tendencies. The patients with HLA-C1/C1 homozygosity had a tendency to improved EFS compared with patients having either HLA-C1/C2 or HLA-C2/C2 ligands (p=0.09). There was a tendency to better EFS in HLA-C1/x recipients of KIR2DS1 -positive allografts (p=0.09).Our data suggest that KIRs and their HLA class I ligands play role in the graft versus leukemia effect in AML. It seems that HLA-C1 homozygosity improves EFS in patients after allo-HSCT, and KIR2DS 1-positive donors are preferable for HLA-C1/x patients. DisclosuresNo relevant conflicts of interest to declare.