The presence of KIR2DL5B was associated with lower rates of major molecular response (MMR), transformation-free survival, and event-free survival (but not overall survival) in patients with chronic phase–chronic myeloid leukemia (CP-CML) treated with sequential imatinib/nilotinib, according to researchers.
Univariate analysis demonstrated a significant association between KIR2DL5B and achievement of a major molecular response, with hazard ratio 0.423 (95% CI, 0.262-0.682; P less than .001). Other KIR genotypes, KIR2DL2pos and KIR2DS3pos, were also associated with inferior achievement of MMR, probably because of their association with KIR2DL5B due to linkage disequilibrium among KIR genes, according to the investigators.
“Our findings suggest that even with the potent second-generation TKI [tyrosine kinase inhibitor] nilotinib, KIR genotypes, a predetermined genetic host factor, may still be one of the most discriminatory prognostic markers available at baseline,” wrote Dr. David T. Yeung of the department of genetics and molecular pathology, Centre for Cancer Biology and the University of Adelaide, South Australia, and colleagues (Blood 2015 Dec 17. doi:10.1182/blood-2015-07-655589).
Killer immunoglobulin-like receptors (KIRs) contribute to natural killer (NK) cell–mediated killing of tumor cells, in both activating and inhibitory roles. Normal cells are spared through actions of inhibitory KIRs. Although the mechanism underlying the association between KIR2DL5B and CP-CML treatment outcomes is still unclear, the gene encodes an inhibitory KIR receptor, the absence of which may increase efficiency of NK-mediated killing of leukemic stem cells, researchers suggested.
The Therapeutic Intensification in De Novo Leukaemia (TIDEL-II) study included 210 patients with CP-CML who were treated with imatinib initially, and nilotinib subsequently if predetermined molecular targets were not met. The KIR substudy included 148 patients with samples available for genotyping.
KIR genotype frequencies observed in this study were similar to other white populations reported in the Allele Frequency Database.
Early molecular response was also significantly associated with treatment outcomes, independent of KIR prognostic significance, and may add additional prognostic information, available 3 months after treatment commences.
“In contrast, KIR2DL5B can identify, at baseline, the 20% of patients with a transformation risk of [about] 10% over 2 years versus the 80% of patients with a transformation risk of less than 3%,” the authors wrote. They suggest that KIR2DL5B, combined with other predictive markers, may enable targeted early interventions to improve outcomes.