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Type: Journal article
Title: Impact of baseline BCR-ABL mutations on response to Nilotinib in patients with chronic myeloid leukemia in chronic phase
Author: Hughes, T.
Saglio, G.
Branford, S.
Soverini, S.
Kim, J.
Muller, M.
Martinelli, G.
Cortes, J.
Beppu, L.
Gottardi, E.
Dongho, K.
Erben, P.
Shou, Y.
Haque, A.
Gallagher, N.
Radich, J.
Hochhaus, A.
Citation: Journal of Clinical Oncology, 2009; 27(25):4204-4210
Publisher: Amer Soc Clinical Oncology
Issue Date: 2009
ISSN: 0732-183X
Statement of
Timothy Hughes, Giuseppe Saglio, Susan Branford, Simona Soverini, Dong-Wook Kim, Martin C. Müller, Giovanni Martinelli, Jorge Cortes, Lan Beppu, Enrico Gottardi, Dongho Kim, Philipp Erben, Yaping Shou, Ariful Haque, Neil Gallagher, Jerald Radich, and Andreas Hochhaus
Abstract: Nilotinib is a second-generation tyrosine kinase inhibitor indicated for the treatment of patients with chronic myeloid leukemia (CML) in chronic phase (CP; CML-CP) and accelerated phase (AP; CML-AP) who are resistant to or intolerant of prior imatinib therapy. In this subanalysis of a phase II study of nilotinib in patients with imatinib-resistant or imatinib-intolerant CML-CP, the occurrence and impact of baseline and newly detectable BCR-ABL mutations were assessed.Baseline mutation data were assessed in 281 (88%) of 321 patients with CML-CP in the phase II nilotinib registration trial.Among imatinib-resistant patients, the frequency of mutations at baseline was 55%. After 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 29% of patients without baseline mutations versus 49% (P = .145), 32% (P = .285), and 22% (P = .366), respectively, of patients with mutations. Responses in patients who harbored mutations with high in vitro sensitivity to nilotinib (50% inhibitory concentration [IC(50)] <or= 150 nM) or mutations with unknown nilotinib sensitivity were equivalent to those responses for patients without mutations (not significant). Patients with mutations that were less sensitive to nilotinib in vitro (IC(50) > 150 nM; Y253H, E255V/K, F359V/C) had less favorable responses, as 13%, 43%, and 9% of patients with each of these mutations, respectively, achieved MCyR; none achieved CCyR.For most patients with imatinib resistance and with mutations, nilotinib offers a substantial probability of response. However, mutational status at baseline may influence response. Less sensitive mutations that occurred at three residues defined in this study, as well as the T315I mutation, may be associated with less favorable responses to nilotinib.
Keywords: Humans; Benzamides; Piperazines; Pyrimidines; Fusion Proteins, bcr-abl; Antineoplastic Agents; Protein Kinase Inhibitors; Treatment Outcome; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Leukemic; Drug Resistance, Neoplasm; Mutation; Time Factors; United States; Korea; Australia; Europe; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Imatinib Mesylate
Rights: © 2009 by American Society of Clinical Oncology
RMID: 0020092348
DOI: 10.1200/JCO.2009.21.8230
Appears in Collections:Medicine publications

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