title: Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy.
abstract: Although imatinib induces marked responses in patients with chronic myeloid leukemia (CML), resistance is increasingly problematic, and treatment options for imatinib-resistant or -intolerant CML are limited. Dasatinib, a novel, highly potent, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, induced cytogenetic responses in a phase 1 study in imatinib-resistant or -intolerant CML and was well tolerated. Initial results are presented from a phase 2 study of 186 patients with imatinib-resistant or -intolerant chronic-phase CML (CML-CP) designed to further establish the efficacy and safety of dasatinib (70 mg twice daily). At 8-months' follow-up, dasatinib induced notable responses, with 90% and 52% of patients achieving complete hematologic and major cytogenetic responses (MCyR), respectively. Responses were long lasting: only 2% of patients achieving MCyR progressed or died. Importantly, comparable responses were achieved by patients carrying BCR-ABL mutations conferring imatinib resistance. Dasatinib also induced molecular responses, reducing BCR-ABL/ABL transcript ratios from 66% at baseline to 2.6% at 9 months. Nonhematologic adverse events were generally mild to moderate, and most cytopenias were effectively managed with dose modifications. Cross-intolerance with imatinib was not evident. To conclude, dasatinib induces notable responses in imatinib-resistant or -intolerant CML-CP, is well tolerated, and represents a promising therapeutic option for these patients. This trial was registered at www.clinicaltrials.gov as CA180013.
authors.affiliation: III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. hochhaus@uni-hd.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Lipton
authors.forename: Jane F
authors.initials: JF
authors.lastname: Apperley
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Thierry
authors.initials: T
authors.lastname: Facon
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Goldberg
authors.forename: Francisco
authors.initials: F
authors.lastname: Cervantes
authors.forename: Dietger
authors.initials: D
authors.lastname: Niederwieser
authors.forename: Richard T
authors.initials: RT
authors.lastname: Silver
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hughes
authors.forename: Martin C
authors.initials: MC
authors.lastname: Muller
authors.forename: Rana
authors.initials: R
authors.lastname: Ezzeddine
authors.forename: Athena M
authors.initials: AM
authors.lastname: Countouriotis
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
mesh_terms: D000328:Adult; D000368:Aged; D001549:Benzamides; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006405:Hematology; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D013844:Thiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D017211:Treatment Failure
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib