According to results of the OPTIC study ( Identifier: NCT02467270), recently published in Blood, ponatinib showed benefit with 3 dosage regimens in a population of patients with resistant chronic-phase chronic myeloid leukemia (CP-CML). Optimal benefit/risk outcomes occurred with a starting dose of 45 mg that was decreased to 15 mg upon patient response.

The study follows up on findings from a phase 2 trial, PACE (Ponatinib Ph1 ALL and CML Evaluation; Identifier: NCT01207440), of ponatinib that demonstrated deep and durable responses in some patients with CP-CML resistant to multiple prior tyrosine kinase inhibitors (TKIs); notable adverse events included arterial occlusive events (AOEs); however, post hoc analyses revealed that AOEs were dose dependent.

“This global, multicenter, phase 2 study is the first to prospectively evaluate a response-based dose-reduction strategy to optimize the benefit/risk of a TKI in patients with CP-CML,” the authors wrote in their report.

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In the OPTIC study, the investigators assessed the benefit/risk ratio of 3 ponatinib starting doses to evaluate a novel, response-based, dose-reduction strategy for TKI treatment in adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation.

Between August 2015 and May 2019, patients were randomized (1:1:1) to receive ponatinib at 3 starting dosages, 45, 30, or 15 mg once daily. Upon response (BCR-ABL1IS transcript levels ≤1%), patients who received daily doses of 45 or 30 mg had their doses reduced to 15 mg. The primary end point was response at 12 months (data cutoff, May 31, 2020).

A total of 282 patients were assigned to the 3 cohorts (n=94 each) and received treatment. The median age was 46 years (range, 19-81) in the 45-mg cohort, 51 years (21-77) in the 30-mg cohort, and 49 years (18-81) in the 15-mg cohort. Males comprised 53% of the 45-mg cohort, 40% of the 30-mg cohort, and 56% of the 15-mg cohort. The median time since diagnosis was between 5 and 6 years in all cohorts and ranged from 1 to 29 years. The proportion of patients who had received ≥3 prior TKIs was 53% in the 45-mg cohort, 60% in the 30-mg cohort, and 51% in the 15-mg cohort.

All cohorts showed benefit with ponatinib, with the primary end point achieved in 44.1% (98.3% confidence interval, 31.7-57.0) of the 45-mg cohort, 29.0% (18.4-41.6) of the 30-mg cohort, and 23.1% (13.4-35.3) of the 15-mg cohort.

Grade 3 or above treatment-emergent AOEs (independently confirmed) occurred in 5 patients in the 45-mg cohort, 5 patients in the 30-mg cohort, and 3 patients in the 15-mg cohort.

Limitations of the study included the open-label design and the small sample size.

“[The] results of the OPTIC trial support a novel ponatinib treatment regimen of a 45-mg starting dose reduced to 15 mg upon reaching ≤1% BCR-ABL1IS, which maximizes response while minimizing toxicity and provides a rationale to explore response-based dose-modification strategies for other BCR-ABL1 TKIs,” the authors concluded.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Cortes J, Apperley J, Lomaia E, et al. Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial. Blood. 2021;138(21):2042-2050. doi:10.1182/blood.2021012082