Lack of Predictive Value of KIR-HLA Genotypes for Autologous Transplant Outcome for Multiple Myeloma.

Abstract

In allogeneic hematopoietic cell transplantation (HCT), donor alloreactive natural killer (NK) cells can prevent leukemia relapse and prolong survival. Donor NK alloreactivity has been shown to be influenced by the killer Ig-like receptor (KIR) repertoire of the donor and the HLA class I KIR ligand phenotype of the recipient. In T-cell depleted HLA-identical sibling HCT, it has been shown that lack of recipient class I ligand for donor inhibitory KIR is associated with improved outcome in acute myelogenous leukemia. In the normal population, more than 60% of individuals lack class I ligand for one or more of their inhibitory KIR. Because autoreactive NK cells are known to occur in normal individuals with low frequency, we sought to determine if these same NK clones driven by autologous KIR-HLA interactions might expand and play a role following treatment involving autologous stem cell infusion for hematologic malignancy. 233 patients with multiple myeloma who underwent high-dose chemotherapy with autologous stem cell infusion were evaluated with HLA and KIR genotyping. KIR-HLA genotype combinations were then correlated with event-free survival (EFS) and overall survival (OS) following autologous HCT. Cox regression models were fit to examine the association of KIR-HLA combinations with the hazards of mortality and relapse. We found that there was no association between lack of KIR ligand for inhibitory KIR and improved EFS (p=0.69) or OS (p=0.36), nor was there any association between presence of specific activating KIRs and transplant outcome. Furthermore, the cumulative effect of more than one activating KIR did not affect outcome, including the specific combination of KIR2DS1 and KIR2DS2 (EFS p=0.86 and OS p=0.67), which have been previously reported to be associated with lower leukemia relapse in allogeneic HLA-identical HCT. The combination of activating KIR with their known or putative HLA ligands was also not associated with improvement in transplant outcome. Patients were also evaluated for KIR haplotype (AA versus AB and BB). There was no association between KIR haplotype and DFS (p=0.59) or OS (p=0.96). These data suggest that KIR genotypes and KIR-HLA genotype combinations are not associated with improved outcome in multiple myeloma patients undergoing autologous HCT. This implies that NK cells in autologous HCT do not significantly impact outcome, either because they are not expanded in the post-HCT period or because they have no activity against autologous multiple myeloma cells.