Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations

• Published in: Blood Vol. 114; no. 24; pp. 4944 - 4953
• Main Authors: Müller, Martin C., Cortes, Jorge E., Kim, Dong-Wook, Druker, Brian J., Erben, Philipp, Pasquini, Ricardo, Branford, Susan, Hughes, Timothy P., Radich, Jerald P., Ploughman, Lynn, Mukhopadhyay, Jaydip, Hochhaus, Andreas
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 03.12.2009; Americain Society of Hematology; American Society of Hematology
• Series: Clinical Trials and Observations
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Biological and medical sciences; Chromosome aberrations; Clinical Trials and Observations; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dasatinib; DNA Mutational Analysis; Female; Fusion Proteins, bcr-abl - genetics; Hematologic and hematopoietic diseases; Humans; Kaplan-Meier Estimate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - mortality; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical genetics; Medical sciences; Middle Aged; Mutation; Protein Kinase Inhibitors - therapeutic use; Pyrimidines - therapeutic use; Randomized Controlled Trials as Topic; Thiazoles - therapeutic use; Treatment Outcome; Young Adult; Chromosomal aberration; Antineoplastic agent; Dasatinib; Hematology; Enzyme; Tyrosine kinase inhibitor; Transferases; Non-specific serine/threonine protein kinase; Chronic myelogenous leukemia; Malignant hemopathy; Philadelphia chromosome; Myeloproliferative syndrome; Abnormal chromosome C9; Treatment; bcr gene; C-Onc gene; Abnormal chromosome G22; Abnormal chromosome; Genetics; Multikinase inhibitor; Mutation; Hybrid gene; Cancer; Chromosome translocation
• DOI: 10.1182/blood-2009-04-214221
• ISSN: 0006-4971; 1528-0020

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. All trials were registered at http://www.clinicaltrials.gov as NCT00123474, NCT00101660, and NCT00103844.