TY - JOUR
T1 - Dose modification dynamics of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) from the PACE and OPTIC trials
AU - Jabbour, Elias
AU - Apperley, Jane
AU - Cortes, Jorge
AU - Rea, Delphine
AU - Deininger, Michael
AU - Abruzzese, Elisabetta
AU - Chuah, Charles
AU - DeAngelo, Daniel J.
AU - Hochhaus, Andreas
AU - Lipton, Jeffrey H.
AU - Mauro, Michael
AU - Nicolini, Franck
AU - Pinilla-Ibarz, Javier
AU - Rosti, Gianantonio
AU - Rousselot, Philippe
AU - Shah, Neil P.
AU - Talpaz, Moshe
AU - Vorog, Alexander
AU - Ren, Xiaowei
AU - Kantarjian, Hagop
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/3
Y1 - 2024/3
N2 - 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.)
AB - 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.)
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U2 - 10.1038/s41375-024-02159-0
DO - 10.1038/s41375-024-02159-0
M3 - Article
C2 - 38287132
AN - SCOPUS:85184276236
SN - 0887-6924
VL - 38
SP - 475
EP - 481
JO - Leukemia
JF - Leukemia
IS - 3
ER -