title: A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.
abstract: BACKGROUND
  Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL).
  
  
  METHODS
  We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months.
  
  
  RESULTS
  Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event.
  
  
  CONCLUSIONS
  Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).
authors.affiliation: The authors' full names, degrees, and affiliations are listed in the Appendix.
authors.forename: J E
authors.initials: JE
authors.lastname: Cortes
authors.forename: D-W
authors.initials: DW
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Pinilla-Ibarz
authors.forename: P
authors.initials: P
authors.lastname: le Coutre
authors.forename: R
authors.initials: R
authors.lastname: Paquette
authors.forename: C
authors.initials: C
authors.lastname: Chuah
authors.forename: F E
authors.initials: FE
authors.lastname: Nicolini
authors.forename: J F
authors.initials: JF
authors.lastname: Apperley
authors.forename: H J
authors.initials: HJ
authors.lastname: Khoury
authors.forename: M
authors.initials: M
authors.lastname: Talpaz
authors.forename: J
authors.initials: J
authors.lastname: DiPersio
authors.forename: D J
authors.initials: DJ
authors.lastname: DeAngelo
authors.forename: E
authors.initials: E
authors.lastname: Abruzzese
authors.forename: D
authors.initials: D
authors.lastname: Rea
authors.forename: M
authors.initials: M
authors.lastname: Baccarani
authors.forename: M C
authors.initials: MC
authors.lastname: Müller
authors.forename: C
authors.initials: C
authors.lastname: Gambacorti-Passerini
authors.forename: S
authors.initials: S
authors.lastname: Wong
authors.forename: S
authors.initials: S
authors.lastname: Lustgarten
authors.forename: V M
authors.initials: VM
authors.lastname: Rivera
authors.forename: T
authors.initials: T
authors.lastname: Clackson
authors.forename: C D
authors.initials: CD
authors.lastname: Turner
authors.forename: F G
authors.initials: FG
authors.lastname: Haluska
authors.forename: F
authors.initials: F
authors.lastname: Guilhot
authors.forename: M W
authors.initials: MW
authors.lastname: Deininger
authors.forename: A
authors.initials: A
authors.lastname: Hochhaus
authors.forename: T
authors.initials: T
authors.lastname: Hughes
authors.forename: J M
authors.initials: JM
authors.lastname: Goldman
authors.forename: N P
authors.initials: NP
authors.lastname: Shah
authors.forename: H
authors.initials: H
authors.lastname: Kantarjian
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011724:Pyridazines / Q000009:adverse effects / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced; D013927:Thrombosis / Q000139:chemically induced*; D055815:Young Adult
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C545373:ponatinib