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Type: Journal article
Title: Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations
Author: Muller, M.
Cortes, J.
Kim, D.
Druker, B.
Erben, P.
Pasquini, R.
Branford, S.
Hughes, T.
Radich, J.
Ploughman, L.
Mukhopadhyay, J.
Hochhaus, A.
Citation: Blood, 2009; 114(24):4944-4953
Publisher: Amer Soc Hematology
Issue Date: 2009
ISSN: 0006-4971
Statement of
Martin C. Müller, Jorge E. Cortes, Dong-Wook Kim, Brian J. Druker, Philipp Erben, Ricardo Pasquini, Susan Branford, Timothy P. Hughes, Jerald P. Radich, Lynn Ploughman, Jaydip Mukhopadhyay, and Andreas Hochhaus
Abstract: Dasatinib is a BCR-ABL inhibitor with 325-fold higher potency than imatinib against unmutated BCR-ABL in vitro. Imatinib failure is commonly caused by BCR-ABL mutations. Here, dasatinib efficacy was analyzed in patients recruited to phase 2/3 trials with chronic-phase chronic myeloid leukemia with or without BCR-ABL mutations after prior imatinib. Among 1043 patients, 39% had a preexisting BCR-ABL mutation, including 48% of 805 patients with imatinib resistance or suboptimal response. Sixty-threedifferent BCR-ABL mutations affecting 49 amino acids were detected at baseline, with G250, M351, M244, and F359 most frequently affected. After 2 years of follow-up, dasatinib treatment of imatinib-resistant patients with or without a mutation resulted in notable response rates (complete cytogenetic response: 43% vs 47%) and durable progression-free survival (70% vs 80%). High response rates were achieved with different mutations except T315I, including highly imatinib-resistant mutations in the P-loop region. Impaired responses were observed with some mutations with a dasatinib median inhibitory concentration (IC₅₀) greater than 3nM; among patients with mutations with lower or unknown IC₅₀, efficacy was comparable with those with no mutation. Overall, dasatinib has durable efficacy in patients with or without BCR-ABL mutations.
Keywords: Humans; Pyrimidines; Thiazoles; Fusion Proteins, bcr-abl; Protein Kinase Inhibitors; Treatment Outcome; DNA Mutational Analysis; Mutation; Adolescent; Adult; Aged; Aged, 80 and over; Middle Aged; Female; Male; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Randomized Controlled Trials as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Young Adult; Kaplan-Meier Estimate; Dasatinib
Rights: © 2009 by The American Society of Hematology
RMID: 0020094090
DOI: 10.1182/blood-2009-04-214221
Appears in Collections:Medicine publications

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