title: Ponatinib in refractory Philadelphia chromosome-positive leukemias.
abstract: BACKGROUND
  Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors.
  
  
  METHODS
  In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140).
  
  
  RESULTS
  Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response.
  
  
  CONCLUSIONS
  Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.).
authors.affiliation: Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. jcortes@mdanderson.org
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
authors.forename: Dale
authors.initials: D
authors.lastname: Bixby
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mauro
authors.forename: Ian
authors.initials: I
authors.lastname: Flinn
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Hare
authors.forename: Simin
authors.initials: S
authors.lastname: Hu
authors.forename: Narayana I
authors.initials: NI
authors.lastname: Narasimhan
authors.forename: Victor M
authors.initials: VM
authors.lastname: Rivera
authors.forename: Tim
authors.initials: T
authors.lastname: Clackson
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Turner
authors.forename: Frank G
authors.initials: FG
authors.lastname: Haluska
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Michael W N
authors.initials: MW
authors.lastname: Deininger
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000681:Amylases / Q000097:blood; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D008049:Lipase / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010195:Pancreatitis / Q000139:chemically induced; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011724:Pyridazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D011724:Pyridazines; C545373:ponatinib; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D008049:Lipase; D000681:Amylases