Objective: In the PACE trial (NCT01207440), patients with resistant/intolerant chronic-phase chronic myeloid leukemia (CP-CML) demonstrated lasting responses to ponatinib 45 mg once daily (QD). The OPTIC trial (NCT02467270) prospectively evaluated a response-based dose-reduction strategy to optimize the dosing schedule of ponatinib in patients with CP-CML resistant to second-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) therapy or with a T315I mutation. Our objective was to analyze dosing dynamics between the 2 trials and compare efficacy and safety outcomes. Methods: In PACE, patients received an initial dose of ponatinib 45 mg QD. In OPTIC, patients were randomly assigned (1:1:1) to an initial oral dose of ponatinib 45 mg, 30 mg, or 15 mg QD. In PACE, proactive dose reductions were mandated as arterial occlusive events (AOEs) emerged as notable adverse events (AEs). In OPTIC, patients in the 45-mg and 30-mg cohorts in OPTIC achieving ≤1% BCR::ABL1IS had their doses reduced to 15 mg QD; doses were also reduced to manage AEs. Data from patients with CP-CML in PACE and from the 45-mg starting dose cohort in OPTIC were analyzed. Efficacy outcomes include ≤1% BCR::ABL1IS, progression-free survival (PFS), and overall survival (OS). Safety outcomes include treatment-emergent (TE) AEs and TE-AOE rates. Results: A total of 364 CP-CML patients had ≥1 prior second-generation TKI or a T315I mutation and received a starting dose of ponatinib 45 mg (PACE, n=270; OPTIC, n=94). The percentages of patients with vascular disorders were 44% in PACE and 32% in OPTIC. The median follow-ups were 57 months (PACE) and 32 months (OPTIC). The ≤1% BCR::ABL1IS responses by 24 months were 52% (PACE) and 56% (OPTIC), 2-year PFS was 68% (PACE) and 80% (OPTIC), and 2-year OS was 86% (PACE) and 91% (OPTIC). Dose reductions due to AEs occurred in 82% (PACE) and 46% (OPTIC) of patients. Per 100 patient-years, exposure-adjusted TE-AOEs were 15.8 (PACE) and 7.6 (OPTIC) at 0 to <1 year. Conclusions: The response-based dose-reduction strategy in OPTIC resulted in comparable or better efficacy outcomes and fewer AE-related dose reductions and exposure-adjusted TE-AOEs, further demonstrating the benefit of the response-based dosing regimen used in OPTIC. This abstract is an encore from the European Hematology Association 2022 Annual Meeting.