| Abstract: |
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. © 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC. |
| Keywords: |
adult; treatment outcome; treatment response; treatment failure; young adult; human cell; major clinical study; overall survival; genetics; drug efficacy; drug safety; antineoplastic agents; antineoplastic agent; gene; progression free survival; phase 2 clinical trial; protein kinase inhibitor; cohort analysis; drug resistance; drug resistance, neoplasm; dasatinib; chronic myeloid leukemia; acute lymphoblastic leukemia; protein tyrosine kinase inhibitor; protein kinase inhibitors; gene fusion; therapy effect; bcr abl protein; nilotinib; leukemia, myelogenous, chronic, bcr-abl positive; fusion proteins, bcr-abl; imidazoles; imidazole derivative; myeloid leukemia; artery occlusion; leukemia, myeloid, chronic-phase; bosutinib; philadelphia chromosome positive cell; ponatinib; humans; human; article; pyridazine derivative; pyridazines; bcr abl1 gene; t315i gene
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