Dose optimisation of ponatinib in patients with resistant chronic-phase CML

January 2022 Clinical practice Andrea Enguita
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Patients with chronic-phase chronic myeloid leukaemia who are resistant to multiple prior tyrosine kinase inhibitors and are treated with ponatinib show deep and durable responses, but arterial occlusive events emerged as notable adverse events. The OPTIC study therefore assessed the benefit/risk ratio across three ponatinib starting doses, developing a novel, response-based, dose-reduction strategy.


“The results of the OPTIC study support a new ponatinib treatment regimen in which, in patients without T315I mutation, after starting dosage of 45 mg, dosage can be safely reduced to 15 mg upon reaching BCR-ABL ≤1%. Lower starting dosages also exhibit clear benefit, except in patients harbouring the T315I mutation, Patients with T315I at baseline have a higher probability of losing response after dose reduction and as such, the benefit/risk of dose reduction in such patients should be carefully assessed. With this new treatment regimen, a maximal response can be obtained while minimising toxicity.”

Most patients with chronic-phase chronic myeloid leukaemia (CP-CML) have good long-term outcomes when treated with tyrosine kinase inhibitors (TKIs). However, a significant percentage of patients experience lack of efficacy or adverse events (AEs). Only 21-35% of these patients have a complete cytogenetic response (CCyR) after being treated with a different second-generation TKI. Ponatinib is a third-generation TKI that inhibits BCR-ABL1, with or without kinase domain mutations, including T315I. In the phase II PACE trial, ponatinib (45 mg daily) showed durable responses in CML patients resistant to prior TKIs. However, arterial occlusive events (AOEs) emerged as notable AEs and appeared to be dose-dependent. To further understand the impact of the dose on safety and efficacy, the phase II OPTIC (Optimizing Ponatinib Treatment in CP-CML) trial explored a novel, response-based, dose-reduction strategy of ponatinib in this setting.

Study design

The OPTIC study is a multicentre, global,  phase II trial that enrolled adult patients (aged ≥18 years) with CP-CML resistant or intolerant to ≥2 prior TKIs or who had a T315I mutation. BCR-ABL1 transcript levels had to measure >1% on the International Scale (BCR-ABL1IS). Patients were randomised (1:1:1) to receive a once-daily starting dose of ponatinib 45, 30, or 15 mg. Patients in the 45- and 30-mg cohorts were required to have the dose reduced to 15 mg once daily upon achieving  ≤1% BCR-ABL1IS (grossly equivalent to CCyR). Patients in the 15 mg cohort had no response-based dose changes. The primary endpoint was ≤1% BCR-ABL1IS at twelve months.


In total, 283 patients were enrolled between August 2015 and May 2019, of whom 282 received at least one dose of study treatment. Most patients (55%) had received at least three prior TKIs, and 99% were resistant to at least one prior TKI therapy. The rate of ≤1% BCR-ABL1IS at twelve months was 44.1%, 29.0% and 23.1% in the 45-, 30-, and 15-mg cohorts, respectively. The prespecified statistical endpoint was met in the 45-mg cohort (p< 0.017). Patients with or without the T315I mutation at baseline had high ≤1% BCR-ABL1ISrates by 12 months (60.0% and 48.5%, respectively) in the 45-mg cohort. A lower proportion of patients with the T315I mutation had ≤1% BCR-ABL1IS rate compared with those without T315I in both the 30-mg (25.0% vs. 38.4%) and 15-mg cohort (10.5% vs. 29.6%). 

Median time to dose reduction was shortest in the 45-mg cohort, 3.4 months, compared with the 30-and 15-mg cohorts, 7.1 months and 11.4 months, respectively. In the 30- and 45-mg cohorts, 73 patients had a dose reduction to 15 mg after achieving ≤ 1% BCR-ABL1IS. Of those, 75% maintained a response for any period of time. Of the eighteen patients who did not maintain the response, eleven presented the T315I mutation at baseline. Thirteen and five patients re-escalated to 45 and 30 mg, respectively; of those, 8 (61.5%) and 4 (80.0%) regained the response by the data cut-off. Median PFS was not reached (NR) in the 45- and 30-mg cohorts and was 45.6 months in the 15-mg cohort. Median OS was NR in all cohorts; the estimated probability of 24-month OS was more than 90% in all three cohorts.

The most common non-haematologic treatment-emergent AEs (TEAEs) were arterial hypertension (28%), headache (18%), and lipase increase (17%) in all cohorts combined; the majority were grade 1 or 2. The most common haematologic AEs were thrombocytopenia (40%), neutropenia (26%), and anaemia (19%). There were four deaths related to AEs (two in the 45-mg cohort and two in the 15-mg cohort). Six percent of the patients experienced any AOE (9, 5, and 3 patients in the 45-, 30- and 15-mg cohort, respectively). Grade 3 to 5 treatment-emergent AOEs were reported in thirteen patients (5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively). A starting dose of 45 mg compared with 15 mg was associated with a 6.4 percentage-point increase in the AOE rate (9.6% to 3.2%), but with a 26.3 percentage-point improvement in the response rate (51.6% to 25.3%).


This is the first study prospectively evaluating a response-based dose-reduction strategy to optimise the benefit/risk of a TKI in patients with resistant CP-CML. 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 (optimal benefit/risk dosage). With lower dosage (15 or 30 mg), benefit was seen mainly for those without the T315I mutation or less resistant disease, indicating that molecular characteristics may be useful in further refinement of risk-adapted therapy strategies.


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):2042-50.