TY - JOUR
T1 - Dasatinib treatment of chronic-phase chronic myeloid leukemia
T2 - Analysis of responses according to preexisting BCR-ABL mutations
AU - Müller, Martin C.
AU - Cortes, Jorge E.
AU - Kim, Dong Wook
AU - Druker, Brian J.
AU - Erben, Philipp
AU - Pasquini, Ricardo
AU - Branford, Susan
AU - Hughes, Timothy P.
AU - Radich, Jerald P.
AU - Ploughman, Lynn
AU - Mukhopadhyay, Jaydip
AU - Hochhaus, Andreas
PY - 2009/12/3
Y1 - 2009/12/3
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2009-04-214221
DO - 10.1182/blood-2009-04-214221
M3 - Article
C2 - 19779040
AN - SCOPUS:73949105873
SN - 0006-4971
VL - 114
SP - 4944
EP - 4953
JO - Blood
JF - Blood
IS - 24
ER -