The following article features coverage from the 2021 Annual Meeting of the Society of Hematologic Oncology (SOHO). Click here to read more of Hematology Advisor‘s conference coverage.

Primary analysis of the ongoing phase 2 trial OPTIC demonstrated that the optimal benefit/risk profile for ponatinib was achieved with a response-based dosing regimen starting with 45 mg per day followed by dose reduction to 15 mg per day in patients with resistant/intolerant chronic-phase chronic myeloid leukemia (CP-CML).

The findings were presented by Jorge Cortes, MD, of the Georgia Cancer Center at Augusta University, Augusta, GA, at the Annual Meeting of the Society of Hematologic Oncology (SOHO).

“This is an important study because it is the first study to prospectively evaluate a response-based dose reduction, not a toxicity-based dose reduction,” Dr Cortes explained.

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Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) with demonstrated deep, long-lasting responses in patients with CP-CML resistant/intolerant to second-generation TKI therapy.

The investigators of OPTIC ( Identifier: NCT02467270) aimed to evaluate safety and efficacy of ponatinib response-based dosing regimens in patients with resistant/intolerant CP-CML.

Patients with CP-CML (resistant/intolerant to ≥2 TKIs or with the BCR-ABL1 T315I mutation) were randomized to receive ponatinib once daily at 1 of 3 different starting doses: 45 mg, 30 mg, and 15 mg. When patients in the 45-mg and 30-mg cohorts achieved ≤1% Breakpoint Cluster Region-Abelson Transcript Level as measured by the International Scale (BCR-ABL1IS), the doses were reduced to 15 mg. The primary endpoint is <1% BCR-ABL1IS at 12 months, and key secondary endpoints include cytogenetic and molecular responses and safety outcomes.

The study has 283 participants (cohorts: 45-mg, n=94; 30-mg, n=95; 15-mg, n=94), with a median age of 48 years (range, 18-81 years). The majority (99%) had resistant disease; most (98%) had received ≥2 TKIs, and over half (55%) had received ≥3 TKIs. Baseline mutations (≥1) were present in 40% of patients, including 23% with T315I mutations.

At 32-month median follow-up, 47% of patients remained on treatment (n=134: 45-mg, n=50; 30-mg, n=41; 15-mg, n=43), and 72% of patients had ponatinib exposure ≥12 months. At 12 months, 44% of the 45-mg cohort, 29% of the 30-mg cohort, and 23% of the 15-mg cohort achieved ≤1% BCR-ABL1IS. The 45-mg cohort met the prespecified statistical primary endpoint (P <.017). Progression-free survival and overall survival at 36 months were 73% and 89% for the 45-mg cohort, 66% and 89% for the 30-mg cohort, and 70% and 92% for the 15-mg cohort.

When patients were grouped by T315I status at baseline, in the 45-mg cohort, 60% of those with T315I mutations, 56% of those with mutations other than T315I, and 46% with no mutations achieved ≤1% BCR-ABL1IS by 12 months. In the 30-mg and 15-mg cohorts, 25% and 11% of those with T315I mutations, 40% and 33% of those with other mutations, and 38% and 28% of those with no mutations achieved ≤1% BCR-ABL1IS by 12 months.

The most common grade ≥3 treatment-emergent adverse events (TEAEs) were thrombocytopenia (27%), neutropenia (17%), and anemia (7%). Arterial occlusive events (AOEs) and serious AOEs occurred in 10% and 4% in the 45-mg cohort; in 5% and 4% in the 30-mg cohort; and in 3% and 3% of the 15-mg cohort, respectively.

“By using the 3 different dosing regimens, we do see good responses with all three doses, but clearly 45 mg with a response-based dose reduction to 15 mg gives the best risk-benefit value for these patients, particularly among the patients with high-risk features,” said Dr Cortes.

Disclosure: This research was supported by ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, with additional funding from Incyte Corporation (Wilmington, DE). Please see the original reference for a full list of disclosures.

Read more of Hematology Advisor’s coverage of SOHO 2021 by visiting the conference page.


Cortes JE, Apperley JF, Lomaia E, et al. OPTIC primary analysis: A dose-optimization study of 3 starting doses of ponatinib (PON). Paper presented at: Annual Meeting of the Society of Hematologic Oncology (SOHO); September 8-11, 2021. Abstract CML-129.