CML-047 Post Hoc Analysis of Responses to Ponatinib in Patients With Chronic-Phase Chronic Myeloid Leukemia (CP-CML) by Baseline BCR::ABL1 Level and Baseline Mutation Status in the OPTIC Trial

Objectives: OPTIC (NCT02467270) is a Phase 2 trial evaluating the safety and efficacy of ponatinib in patients with CP-CML resistant to ≥2 TKIs or have a T315I mutation. We present a post hoc analysis of patient responses by baseline BCR::ABL1 level and mutation status. Methods: Patients with CP-CML resistant to ≥2 TKIs or with the T315I mutation were randomized to ponatinib starting doses of 45 mg, 30 mg, and 15 mg once daily. Doses were reduced to 15 mg after achievement of ≤1% BCR::ABL1^IS in the 45-mg and 30-mg cohorts. The primary endpoint is ≤1% BCR::ABL1^IS at 12 months. In this analysis, outcomes are analyzed by baseline T315I mutation status and baseline BCR::ABL1 level in the intent-to-treat (ITT) population. Results: 283 patients were randomized (45-mg/30-mg/15-mg cohorts: n=94/95/94). At baseline, 84.1% of patients had >10% BCR::ABL1^IS; 23.8% had T315I mutation. Subanalysis showed that patients with T315I mutations in the 45-mg cohort had the highest ≤1% BCR::ABL1^IS response rates (60%) by 3 years versus other cohorts. Across cohorts, 97 patients without T315I mutations achieved ≤1% BCR::ABL1^IS. Median duration of response (mDoR) for patients with a T315I mutation at baseline was 27 months in the 45-mg cohort (n=15) and 12 months in the 30-mg cohort (n=5). For patients without T315I mutations, the mDoR was not reached. Across cohorts, 79% of patients who achieved ≤1% BCR::ABL1^IS maintained this response during the study. The most common nonhematologic treatment-emergent adverse events (TEAEs) and hematological TEAEs in the ITT population for all cohorts combined were arterial hypertension (28%), headache (18%), lipase increase (17%), thrombocytopenia (40%), neutropenia (26%), and anemia (19%). Overall, 6.0% of patients experienced a treatment-emergent arterial occlusive event (TE-AOE); 4.6% experienced a Grade ≥3 TE-AOE. Conclusions: The OPTIC post hoc analysis showed clinical benefit across dosing regimens regardless of T315I mutation status at baseline; the 45-mg cohort showed the highest response rates regardless of baseline BCR::ABL1^IS levels. Regardless of T315I mutation status, most patients were able to maintain their response after dose reduction upon achieving BCR::ABL1^IS ≤1%. This abstract is an encore from the American Society of Hematology 2021 Annual Meeting.