1. Dose modification dynamics of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) from the PACE and OPTIC trials.
- Author
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Jabbour, Elias, Apperley, Jane, Cortes, Jorge, Rea, Delphine, Deininger, Michael, Abruzzese, Elisabetta, Chuah, Charles, DeAngelo, Daniel, Hochhaus, Andreas, Lipton, Jeffrey, Mauro, Michael, Nicolini, Franck, Pinilla-Ibarz, Javier, Rosti, Gianantonio, Rousselot, Philippe, Talpaz, Moshe, Vorog, Alexander, Ren, Xiaowei, Kantarjian, Hagop, and Shah, Neil Pravin
- Subjects
Humans ,Drug Resistance ,Neoplasm ,Leukemia ,Myeloid ,Chronic-Phase ,Leukemia ,Myelogenous ,Chronic ,BCR-ABL Positive ,Imidazoles ,Pyridazines ,Fusion Proteins ,bcr-abl ,Protein Kinase Inhibitors ,Antineoplastic Agents - 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.
- Published
- 2024