title: Ponatinib: A new tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.
abstract: OBJECTIVE
  To review the pharmacology, pharmacokinetics, clinical trials, adverse effects, and formulary considerations of ponatinib, a pan-tyrosine kinase inhibitor (TKI).
  
  
  METHODS
  A literature search of articles published between January 1966 and June 2013 was performed using PubMed with the following search terms: ponatinib, AP24534, and Iclusig. ARIAD Pharmaceuticals, Inc, was contacted for unpublished information. Other sources included American Society of Hematology abstracts, the Food and Drug Administration Center for Drug Evaluation and Research Web site, and clinicaltrials.gov.
  
  
  METHODS
  Included articles and abstracts were published in English and contain information about ponatinib, particularly in the treatment of chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
  
  
  RESULTS
  Following the phase II PACE trial, ponatinib was approved for the treatment of patients with chronic-phase (CP), accelerated-phase (AP), or blast-phase (BP) CML or Ph+ ALL who have become intolerant or resistant to previous therapy. Unlike other BCR-ABL TKIs, ponatinib was designed to overcome the T315I mutation. At 15.3 months, 46% of patients with CP-CML achieved a complete cytogenetic response, and 34% achieved a major molecular response. Complete hematologic responses occurred in 47% of patients with AP-CML, 21% with BP-CML, and 34% with Ph+ ALL after 1 year. Severe toxicities included myelosuppression, hepatotoxicity, pancreatitis, and arterial thrombosis.
  
  
  CONCLUSIONS
  Ponatinib is a potent TKI that can overcome several resistance mechanisms in previously treated patients with CML and Ph+ ALL. Ponatinib should be reserved for patients who have failed first-line therapy, have the T315I mutation, or have progressed.
authors.affiliation: Louisiana State University Health, Shreveport, LA, USA.
authors.forename: Caitlin L
authors.initials: CL
authors.lastname: Shamroe
authors.forename: Jill M
authors.initials: JM
authors.lastname: Comeau
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C545373:ponatinib; D011505:Protein-Tyrosine Kinases
keywords: ALL; AP24534; BCR-ABL tyrosine kinase inhibitors; CML; Iclusig; acute lymphoblastic leukemia; chronic myeloid leukemia; ponatinib