Response dynamics to nilotinib depend on the type of BCR-ABL mutations in patients with chronic myelogenous leukemia (CML) after imatinib failure

Abstract

7024 Background: Nilotinib (AMN107) is an oral, aminopyrimidine-derivative, selective inhibitor of the BCR-ABL tyrosine kinase with improved potency and specificity compared with imatinib. In preclinical models, activity of nilotinib was also demonstrated in 32/33 imatinib- resistant mutant cell lines. We sought to explore the efficacy of nilotinib in vivo according to the type of preexisting BCR-ABL mutations associated with imatinib resistance. Methods: We have investigated peripheral blood samples from 101 chronic phase (CP) and 41 accelerated phase (AP) CML patients (pts) who had been enrolled in a phase II study investigating the efficacy and safety of 400mg nilotinib bid after imatinib failure. Screening for BCR-ABL mutations was performed by D-HPLC combined with DNA sequencing. The analysis covered amino acids 207–517 of the BCR-ABL tyrosine kinase domain. Results: Prior to nilotinib, 24 different BCR-ABL mutations involving 20 amino acids were detected affecting 44% CP and 61% AP pts. After 6 mo of therapy, complete hematologic response was achieved in 59%, major cytogenetic response (MCR) in 25% being complete (CCR) in 16% of pts with mutations vs 81%, 51% and 33% of pts without mutations, respectively. Response dynamics were associated with preclinical activity of nilotinib: MCR was reached in 10/18 pts with mutations associated with preclinical IC50 to nilotinib of <100nM, 2/9 pts with IC50 of 100–1,000 nM, and 0/4 pts with mutation T315I demonstrating virtual resistance to imatinib and nilotinib. In AP pts, hematologic response was achieved in 56% and 31%, MCR in 24% vs 19%, and CCR in 24% vs 13% of pts with or without mutations, respectively. Conclusions: Nilotinib is efficacious in pts with BCR-ABL mutations, except T315I, as well as in patients with BCR-ABL-independent resistance. Time to response may depend on the individual type of the mutation and correlates with the IC50 to nilotinib. Thus, nilotinib may have an important therapeutic role in imatinib resistance as well as in frontline CML therapy to prevent emergence of resistant clones. [Table: see text]