title: Ponatinib as first-line treatment for patients with chronic myeloid leukaemia in chronic phase: a phase 2 study.
abstract: BACKGROUND
  Ponatinib has shown efficacy in patients with refractory chronic myeloid leukaemia (CML) and in those with CML with a Thr315Ile mutation. We aimed to investigate the activity and safety of ponatinib as first-line treatment for patients with chronic-phase CML.
  
  
  METHODS
  We did a single-arm, phase 2 trial at MD Anderson Cancer Center in Houston, TX, USA. Between May 3, 2012, and Sept 24, 2013, we enrolled patients with early (<6 months) chronic-phase CML and treated them with oral ponatinib once a day. Patients enrolled before July 25, 2013, were given a starting dose of 45 mg per day; we lowered this due to tolerability issues and patients enrolled after this date were given a starting dose of 30 mg per day. After a warning by the US Food and Drug Administration (FDA) in Oct 6, 2013, for vascular complications with ponatinib, we started all patients on aspirin 81 mg daily and reduced the dose of ponatinib to 30 mg or 15 mg per day for all patients. The primary endpoint was the proportion of patients who achieved complete cytogenetic response by 6 months in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01570868.
  
  
  RESULTS
  We enrolled 51 patients. Median follow-up was 20·9 months (IQR 14·9–25·2). 43 patients were started on 45 mg ponatinib every day; eight patients were started on 30 mg per day. 43 (94%) of 46 evaluable patients achieved complete cytogenetic response at 6 months. Most frequent toxicities included skin-related effects (n=35; 69%) and elevated lipase (n=32; 63%). Cardiovascular events (mainly hypertension) occurred in 25 (49%) patients. Grade 3–4 myelosuppression occurred in 15 (29%) patients. Five (10%) patients developed cerebrovascular or vaso-occlusive disease. 43 (85%) patients needed treatment interruptions at some time and 45 (88%) needed dose reductions. The study was terminated June 18, 2014, at the recommendation of the FDA due to concern about the increased risk of thromboembolism with ponatinib.
  
  
  CONCLUSIONS
  Patients with newly diagnosed CML in chronic phase respond well to treatment with ponatinib, with most achieving a complete cytogenetic response. Dose adjustment, extensive monitoring, and counselling of the patients for thromboembolic events is needed for patients on ponatinib therapy. However, due to the risk of vascular thrombotic events and the availability of alternative options for these patients, other drugs should be considered first in the frontline setting.
  
  
  BACKGROUND
  MD Anderson Cancer Center, National Cancer Institute, ARIAD Pharmaceutical.
authors.forename: Preetesh
authors.initials: P
authors.lastname: Jain
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.forename: Graciela Nogueras
authors.initials: GN
authors.lastname: Gonzalez
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.forename: Naveen
authors.initials: N
authors.lastname: Pemmaraju
authors.forename: Naval
authors.initials: N
authors.lastname: Daver
authors.forename: Evguenia
authors.initials: E
authors.lastname: Gachimova
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferrajoli
authors.forename: Steven
authors.initials: S
authors.lastname: Kornblau
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D011724:Pyridazines / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D011724:Pyridazines; C545373:ponatinib