title: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias.
abstract: BACKGROUND
  The BCR-ABL tyrosine kinase inhibitor imatinib is effective in Philadelphia chromosome-positive (Ph-positive) leukemias, but relapse occurs, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations. We evaluated dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL).
  
  
  METHODS
  Patients with various phases of CML or with Ph-positive ALL who could not tolerate or were resistant to imatinib were enrolled in a phase 1 dose-escalation study. Dasatinib (15 to 240 mg per day) was administered orally in four-week treatment cycles, once or twice daily.
  
  
  RESULTS
  A complete hematologic response was achieved in 37 of 40 patients with chronic-phase CML, and major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML with blast crisis, or Ph-positive ALL. In these two phases, the rates of major cytogenetic response were 45 percent and 25 percent, respectively. Responses were maintained in 95 percent of patients with chronic-phase disease and in 82 percent of patients with accelerated-phase disease, with a median follow-up more than 12 months and 5 months, respectively. Nearly all patients with lymphoid blast crisis and Ph-positive ALL had a relapse within six months. Responses occurred among all BCR-ABL genotypes, with the exception of the T315I mutation, which confers resistance to both dasatinib and imatinib in vitro. Myelosuppression was common but not dose-limiting.
  
  
  CONCLUSIONS
  Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib. (ClinicalTrials.gov number, NCT00064233 [ClinicalTrials.gov].).
authors.affiliation: Department of Leukemia, M.D. Anderson Cancer Center, Houston, USA.
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Nicholas
authors.initials: N
authors.lastname: Donato
authors.forename: John
authors.initials: J
authors.lastname: Nicoll
authors.forename: Ron
authors.initials: R
authors.lastname: Paquette
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Claude
authors.initials: C
authors.lastname: Nicaise
authors.forename: Eric
authors.initials: E
authors.lastname: Bleickardt
authors.forename: M Anne
authors.initials: MA
authors.lastname: Blackwood-Chirchir
authors.forename: Vishwanath
authors.initials: V
authors.lastname: Iyer
authors.forename: Tai-Tsang
authors.initials: TT
authors.lastname: Chen
authors.forename: Fei
authors.initials: F
authors.lastname: Huang
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Decillis
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001549:Benzamides; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009503:Neutropenia / Q000139:chemically induced; D010879:Piperazines; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; C406060:abl-bcr fusion protein, human; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib