Dose modification dynamics of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) from the PACE and OPTIC trials

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.

Clinical Insights into Structure, Regulation, and Targeting of ABL Kinases in Human Leukemia

“…At both 12-month and 36-month time points, the 45 mg QD dose strategy with a reduction to 15 mg QD upon reaching MR 2 displayed the most optimal benefit-to-risk ratio [98,100]. Overall, a comparison study found that patients from the OPTIC trial had lower incidences of adverse effects compared to patients from the PACE trial and highlighted the benefits of dose optimization strategies for TKIs [101] It has previously been reported that in a phase I/II clinical study, DA could be combined with the hypomethylating agent, decitabine, to effectively treat advanced phase CML (CML-AP, CML-BP) [102]. Furthermore, it has been shown that the anti-apoptotic BCL-2 family proteins are upregulated in CML blast crisis cells and LSCs via BCR::ABL1 signaling, and preclinical studies combining TKIs with the BCL-2 inhibitor venetoclax revealed synergistic anti-leukemic effects in BCR::ABL1 + myeloid leukemias [103,104].…”

“…At both 12-month and 36-month time points, the 45 mg QD dose strategy with a reduction to 15 mg QD upon reaching MR 2 displayed the most optimal benefit-to-risk ratio [ 98 , 100 ]. Overall, a comparison study found that patients from the OPTIC trial had lower incidences of adverse effects compared to patients from the PACE trial and highlighted the benefits of dose optimization strategies for TKIs [ 101 ].…”

Asciminib monotherapy in patients with chronic-phase chronic myeloid leukemia with the T315I mutation after ≥1 prior tyrosine kinase inhibitor: 2-year follow-up results

“…In the OPTIC trial, which assessed ponatinib starting doses of 45, 30, and 15 mg QD, 51.6%, 35.5%%, and 25.3%, respectively, of patients with T315I-mutated CML-CP achieved BCR::ABL1 on the International Scale (IS) ≤1% by 12 months (predictive of long-term survival) [ 1 , 16 , 19 , 20 ]. Safety concerns associated with ponatinib include the risk of cardiovascular (CV) adverse events (AEs), including arterial occlusive events (AOEs), in 14% to 31% of patients with CML-CP, although rates can be reduced by approximately 60% using response-based dose-reduction strategies [ 1 , 13 , 18 , 21 ].…”

PhALLCON Soars to New Heights—Faster, Stronger, but Better?

“…9,11 Subsequent studies of ponatinib in both chronic myeloid leukemia and Ph+ ALL used a response-based dose-reduction strategy to improve the risk-benefit ratio. 11,12 But whether these riskreduction strategies and increased tyrosine kinase inhibitor potency will translate to an improved outcome for ponatinib vs imatinib in Ph+ ALL is the question that PhALLCON aims to address.…”

“…However, ponatinib has also been associated with increased vascular toxicity, particularly in patients who received higher doses for longer periods. 12 These arterial occlusive events have plagued prior ponatinib trials, leading to temporary withdrawal of ponatinib from the market and a black box warning. Arterial occlusive events were the main reason for early termination of the frontline ponatinib vs imatinib phase 3 randomized trial in chronic myeloid leukemia, which treated patients with 45 mg once daily of ponatinib.…”