title: Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase.
abstract: Treatment options are limited for patients with imatinib-resistant or -intolerant accelerated phase chronic myeloid leukemia (CML-AP). Dasatinib is a novel, potent, oral, multitargeted kinase inhibitor of BCR-ABL and SRC-family kinases that showed marked efficacy in a phase 1 trial of patients with imatinib-resistant CML. Results are presented for 107 patients with CML-AP with imatinib-resistance or -intolerance from a phase 2, open-label study further evaluating dasatinib efficacy and safety. At 8 months' minimum follow-up, 81%, 64%, and 39% of patients achieved overall, major (MaHR), and complete hematologic responses, respectively, whereas 33% and 24% attained major and complete cytogenetic remission. Of 69 patients who achieved MaHR, 7 progressed. Seventy-six percent of patients are estimated to be alive and progression-free at 10 months. Response rates for the 60% of patients with baseline BCR-ABL mutations did not differ from the total population. Dasatinib was well tolerated: most nonhematologic adverse events (AEs) were mild to moderate; no imatinib-intolerant patients discontinued dasatinib because of AEs. Although common (76% of patients with severe neutropenia), cytopenias were manageable through dose modification. In summary, dasatinib induced significant hematologic and cytogenetic responses in patients with imatinib resistance or intolerance, was well tolerated, and may represent a potent new therapeutic option for CML-AP. Further follow-up is warranted. This trial was registered at www.clinicaltrials.gov as #CA180005.
authors.affiliation: Clinical Research Centre, Centre Hospitalier et Universitaire La Miletrie, Poitiers, France. f.guilhot@chu-poitiers.fr
authors.forename: Francois
authors.initials: F
authors.lastname: Guilhot
authors.forename: Jane
authors.initials: J
authors.lastname: Apperley
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Eduardo O
authors.initials: EO
authors.lastname: Bullorsky
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Roboz
authors.forename: Sergio
authors.initials: S
authors.lastname: Amadori
authors.forename: Carmino A
authors.initials: CA
authors.lastname: de Souza
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Lipton
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Dominik
authors.initials: D
authors.lastname: Heim
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Susan
authors.initials: S
authors.lastname: Branford
authors.forename: Martin C
authors.initials: MC
authors.lastname: Muller
authors.forename: Prasheen
authors.initials: P
authors.lastname: Agarwal
authors.forename: Ashwin
authors.initials: A
authors.lastname: Gollerkeri
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001549:Benzamides; D001772:Blood Cell Count; D020732:Cytogenetic Analysis; D000069439:Dasatinib; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D013844:Thiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib