title: Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis.
abstract: The prognosis for patients with chronic myeloid leukemia (CML) in myeloid blast crisis (MBC) or lymphoid blast crisis (LBC) remains poor. Although imatinib can induce responses in a subset of these patients, resistance to the drug develops rapidly. Dasatinib is a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases. After promising phase 1 results, we report the results of phase 2 clinical trials of dasatinib in patients with imatinib-resistant or -intolerant blast crisis CML (MBC, n = 74; LBC, n = 42). At the 8-month follow-up, dasatinib induced major hematologic responses (MaHRs) in 34% and 31% of MBC- and LBC-CML patients and major cytogenetic responses (MCyRs) in 31% and 50% of these patients, respectively. Most (86%) of these MCyRs were complete cytogenetic responses (CCyRs). Responses were rapid and durable: 88% and 46%, respectively, of MBC- and LBC-CML patients achieving MaHR had not experienced disease progression at the 8-month follow-up. Response rates were similar in patients with and without BCR-ABL mutations known to confer resistance to imatinib. Dasatinib was well tolerated. Nonhematologic adverse events were mild to moderate. Cytopenias were common and could be managed by dose modification. Dasatinib is highly active and produces hematologic and cytogenetic responses in a significant number of patients with imatinib-resistant or -intolerant MBC- and LBC-CML. These trials were registered at www.clinicaltrials.gov as #CA180006 and #CA180015.
authors.affiliation: M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. jcortes@mdanderson.org
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Philippe
authors.initials: P
authors.lastname: Rousselot
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Ellen
authors.initials: E
authors.lastname: Ritchie
authors.forename: Nelson
authors.initials: N
authors.lastname: Hamerschlak
authors.forename: Steven
authors.initials: S
authors.lastname: Coutre
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Francois
authors.initials: F
authors.lastname: Guilhot
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.forename: Jane
authors.initials: J
authors.lastname: Apperley
authors.forename: Oliver
authors.initials: O
authors.lastname: Ottmann
authors.forename: Neil
authors.initials: N
authors.lastname: Shah
authors.forename: Philipp
authors.initials: P
authors.lastname: Erben
authors.forename: Susan
authors.initials: S
authors.lastname: Branford
authors.forename: Prasheen
authors.initials: P
authors.lastname: Agarwal
authors.forename: Ashwin
authors.initials: A
authors.lastname: Gollerkeri
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001549:Benzamides; D001752:Blast Crisis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D020127:Recovery of Function / Q000187:drug effects*; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D019061:src-Family Kinases; D000069439:Dasatinib