KIR2DS1 genotype predicts for complete cytogenetic response and survival in newly diagnosed chronic myeloid leukemia patients treated with imatinib

Natural killer (NK) cells are expanded in chronic myeloid leukemia (CML) patients on tyrosine kinase inhibitors (TKI) and exert cytotoxicity. The inherited repertoire of killer immunoglobulin-like receptors (KIR) may influence response to TKI. We investigated the impact of KIR-genotype on outcome in 166 chronic phase CML patients on first-line imatinib treatment. We validated our findings in an independent patient group. On multivariate analysis, KIR2DS1 genotype (RR= 1.51, P=0.03) and Sokal risk score (low-risk RR=1, intermediate-risk RR=1.53, P= 0.04, high-risk RR=1.69, P= 0.034) were the only independent predictors for failure to achieve complete cytogenetic response (CCyR). Furthermore, KIR2DS1 was the only factor predicting shorter progression-free (PFS) (RR= 3.1, P=0.03) and overall survival (OS) (RR=2.6, P=0.04). The association between KIR2DS1 and CCyR, PFS and OS was validated by KIR genotyping in 174 CML patients on first-line imatinib in the UK multi-center SPIRIT-1 trial; in this cohort, KIR2DS1(+) patients had significantly lower 2-year probabilities of achieving CCyR (76.9 vs 87.9%, P= 0.003), PFS (85.3 vs 98.1%, P=0.007) and OS (94.4 vs 100%, P=0.015) than KIR2DS1(―) patients. The impact of KIR2DS1 on CCyR was greatest when the ligand for the corresponding inhibitory receptor, KIR2DL1, was absent (P= 0.00006). Our data suggest a novel role for KIR-HLA immunogenetics in CML patients on TKI.