Ponatinib after failure of second-generation tyrosine kinase inhibitor in resistant chronic-phase chronic myeloid leukemia

Am J Hematol. 2022 Nov;97(11):1419-1426. doi: 10.1002/ajh.26686. Epub 2022 Aug 30.


Ponatinib, the only third-generation pan-BCR::ABL1 inhibitor with activity against all known BCR::ABL1 mutations including T315I, has demonstrated deep and durable responses in patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to prior second-generation (2G) TKI treatment. We present efficacy and safety outcomes from the Ponatinib Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and CML Evaluation (PACE) and Optimizing Ponatinib Treatment in CP-CML (OPTIC) trials for this patient population. PACE (NCT01207440) evaluated ponatinib 45 mg/day in CML patients with resistance to prior TKI or T315I. In OPTIC (NCT02467270), patients with CP-CML and resistance to ≥2 prior TKIs or T315I receiving 45 or 30 mg/day reduced their doses to 15 mg/day upon achieving ≤1% BCR::ABL1IS or received 15 mg/day continuously. Efficacy and safety outcomes from patients with CP-CML treated with ≥1 2G TKI (PACE, n = 257) and OPTIC (n = 93), 45-mg starting dose cohort, were analyzed for BCR::ABL1IS response rates, overall survival (OS), progression-free survival (PFS), and safety. By 24 months, the percentages of patients with ≤1% BCR::ABL1IS response, PFS, and OS were 46%, 68%, and 85%, respectively, in PACE and 57%, 80%, and 91%, respectively, in OPTIC. Serious treatment-emergent adverse events and serious treatment-emergent arterial occlusive event rates were 63% and 18% in PACE and 34% and 4% in OPTIC. Ponatinib shows high response rates and robust survival outcomes in patients whose disease failed prior to 2G TKIs, including patients with T315I mutation. The response-based dosing in OPTIC led to improved safety and similar efficacy outcomes compared with PACE.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Clinical Trials as Topic
  • Drug Resistance, Neoplasm / genetics
  • Fusion Proteins, bcr-abl / genetics
  • Humans
  • Imidazoles* / adverse effects
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / genetics
  • Leukemia, Myeloid, Chronic-Phase* / drug therapy
  • Leukemia, Myeloid, Chronic-Phase* / genetics
  • Protein Kinase Inhibitors / adverse effects
  • Pyridazines* / adverse effects


  • Imidazoles
  • Protein Kinase Inhibitors
  • Pyridazines
  • ponatinib
  • Fusion Proteins, bcr-abl

Associated data

  • ClinicalTrials.gov/NCT02467270
  • ClinicalTrials.gov/NCT01207440