| Abstract: |
Ponatinib, the only approved all known-BCR::ABL1 inhibitor, is a third-generation tyrosine-kinase inhibitor (TKI) designed to inhibit BCR::ABL1 with or without any single resistance mutation, including T315I, and induced robust and durable responses at 45 mg/day in patients with CP-CML resistant to second-generation TKIs in the PACE trial. However, cardiovascular toxicities, including arterial occlusive events (AOEs), have emerged as treatment-related AEs within this class of TKIs. The OPTIC trial evaluated the efficacy and safety of ponatinib using a novel, response-based, dose-reduction strategy in patients with CP-CML whose disease is resistant to ≥2 TKIs or who harbor T315I. To assess the dose-response relationship and the effect on the safety of ponatinib, we examined the outcomes of patients with CP-CML enrolled in PACE and OPTIC who received 45 mg/day of ponatinib. A propensity score analysis was used to evaluate AOEs across both trials. Survival rates and median time to achieve ≤1% BCR::ABL1IS in OPTIC were similar or better than in PACE. The outcomes of patients with T315I mutations were robust in both trials. Patients in OPTIC had a lower exposure-adjusted incidence of AOEs compared with those in PACE. This analysis demonstrates that response-based dosing for ponatinib improves treatment tolerance and mitigates cardiovascular risk. (Figure presented.) © The Author(s) 2024. |
| Keywords: |
adult; controlled study; treatment response; middle aged; survival rate; gene mutation; major clinical study; genetics; drug dose reduction; drug efficacy; drug safety; treatment duration; antineoplastic agents; outcome assessment; antineoplastic agent; progression free survival; protein kinase inhibitor; incidence; cohort analysis; drug resistance; drug resistance, neoplasm; chronic myeloid leukemia; risk factor; risk assessment; protein kinase inhibitors; cardiovascular risk; bcr abl protein; hypercholesterolemia; leukemia, myelogenous, chronic, bcr-abl positive; fusion proteins, bcr-abl; imidazoles; vascular disease; imidazole derivative; myeloid leukemia; clinical outcome; leukemia, myeloid, chronic-phase; ponatinib; humans; human; article; pyridazine derivative; pyridazines
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