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

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, Andreas Hochhaus

Research output: Contribution to journalArticle

228 Scopus citations

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% hada preexisting BCR-ABLmutation, including 48% of 805 patients with imatinib resistance or suboptimal response. Sixty-three different 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.

Original languageEnglish (US)
Pages (from-to)4944-4953
Number of pages10
JournalBlood
Volume114
Issue number24
DOIs
StatePublished - Dec 3 2009

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Müller, M. C., Cortes, J. E., Kim, D. W., Druker, B. J., Erben, P., Pasquini, R., Branford, S., Hughes, T. P., Radich, J. P., Ploughman, L., Mukhopadhyay, J., & Hochhaus, A. (2009). Dasatinib treatment of chronic-phase chronic myeloid leukemia: Analysis of responses according to preexisting BCR-ABL mutations. Blood, 114(24), 4944-4953. https://doi.org/10.1182/blood-2009-04-214221