Hematologic and Cytogenetic Response Dynamics to Nilotinib (AMN107) Depend on the Type of BCR-ABL Mutations in Patients with Chronic Myelogeneous Leukemia (CML) after Imatinib Failure. (2006)

Abstract Nilotinib (AMN107) is a novel, orally active aminopyrimidine-derivative, which selectively inhibits the BCR-ABL tyrosine kinase with greater potency compared with imatinib (Im). In preclinical models, nilotinib was 20–50 times more potent than imatinib in Im-sensitive CML cell lines, and 3–7 times more potent in Im-resistant cell lines. Activity of nilotinib was also demonstrated in 32/33 Im-resistant mutant cell lines. We sought to investigate the efficacy of nilotinib in vivo according to the type of preexisting BCR-ABL mutations. We have investigated peripheral blood samples from 101 CML patients (pts, 63m, 38 f) with a median age of 61 yrs (range, 23–85) who had been enrolled in an international phase II study investigating the efficacy and safety of 400mg nilotinib bid after Im failure (chronic phase, CP, n=64; accelerated phase, AP, n=22; blast crisis, BC, n=15). 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. The proportion of the mutated clone was estimated from sequencing plots by comparison to plots from serial standard dilutions of Ba/F3 cell lines harboring various concentrations of mutated BCR-ABL. Hematologic and cytogenetic response data are available for a median of 4 mo (range, 1–10) after start of nilotinib therapy. Prior to nilotinib, 28 different BCR-ABL mutations involving 22 amino acids were detected in 61/101 pts (60%). Nine pts showed two, three pts three, and one patient four mutations. Mutations were observed in 37 pts in CP (49%), 15 pts in AP (68%), and 9 pts in BC (60%). In pts with mutations, the overall rate of hematologic response was 70% (78% in CP, 75% in AP, 25% in BC) compared with 88% in pts without mutations. In CP CML, complete cytogenetic response was achieved within 3–6 mo in pts with mutations with high in vitro sensitivity to nilotinib according to O’Hare et al., Cancer Res 2005 and Weisberg et al., Br J Cancer 2006 (M244V, 38nM, n=2; M351T, 15nM; H396R, 41nM; D276G+M351T, 69 and 15nM; E355G+L387F, 47 and 46nM). 4 pts with mutations resulting in relatively higher cellular IC50 to nilotinib had progressed (Y253F+E255K, 125 and 200nM; L248V, 102nM; Y253H, 450nM; F359V, 175nM). 2 pts with small clones (ratio mutated BCR-ABL/ABL 0.14% and 8.6%) harboring the BCR-ABL mutation T315I being highly resistant to Im and nilotinib in vitro did not show signs of relapse after one and 11 mo of nilotinib therapy, respectively. During therapy, novel BCR-ABL mutations (Y253F, E255V, T315I, and F359V) appeared in 4 pts. In conclusion, preliminary data suggest that nilotinib may overcome most of the mutation-associated resistance to Im, and may have an important therapeutic role in Im resistance and in frontline CML therapy to prevent emergence of resistant clones. Response dynamics depend on the individual type of the mutation which may be the basis for individualized dosage of nilotinib according to the mutation pattern. The molecular analysis of the total phase II study population will be reported at the meeting.