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https://hdl.handle.net/2440/58773
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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 1528-0020 |
Statement of Responsibility: | 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 |
DOI: | 10.1182/blood-2009-04-214221 |
Published version: | http://dx.doi.org/10.1182/blood-2009-04-214221 |
Appears in Collections: | Aurora harvest Medicine publications |
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