Dr Lai Discusses Results From the OPTIC Trial in Chronic Myeloid Leukemia
Presenter
Catherine Lai, MD, MPH, University of Pennsylvania
Conference
2024 ASCO Direct Philadelphia
The Bottom Line
The OPTIC trial focused on assessing long-term outcomes using ponatinib, a tyrosine kinase inhibitor drug, in chronic phase chronic myeloid leukemia (CP-CML) patients with resistance to multiple treatments or the high-risk T315I mutation. The study showed that higher initial doses of ponatinib, with subsequent dose reductions, led to the best response rates in patients with the T315I mutation while also reducing their risk for toxicity. Dr Catherine Lai emphasized the promising results in her presentation at the 2024 ASCO Direct Philadelphia conference, suggesting that this dosing strategy may enhance management and outcomes for those CML patients who have limited treatment options.
Background
Chronic phase chronic myeloid leukemia (CP-CML) is primarily treated with tyrosine kinase inhibitor type therapies (TKIs), but treatment can be challenging for patients with mutations such as T315I, which confer resistance to most TKIs, except ponatinib. Ponatinib, a third-generation TKI, was shown to be effective against CML with the T315I mutation. Ponatinib’s dose-dependent impact on the heart and cardiovascular system, however, make it essential to determine the optimal dosing strategy that balances efficacy and safety for patients.
Trial Design and Patients
The OPTIC trial was a phase II, randomized, dose-optimization study that included nearly 300 patients with CP-CML who had either the T315I mutation or who had resistance to at least two previous lines of TKI therapy. Patients were randomly assigned to one of three dosing regimens of ponatinib:
45 mg daily, with a reduction to 15 mg upon achieving a response
30 mg daily, also reduced to 15 mg with a response
15 mg daily throughout the trial
The primary endpoint was achieving a BCR-ABL1 (Philadelphia chromosome-positive) response of less than 1% at 12 months, with secondary endpoints of four-year progression-free survival (PFS), overall survival (OS), and safety assessments.
Main Trial Results
Response Rates: For patients with the T315I mutation, the 45 mg starting dose, followed by a reduction to 15 mg upon achieving response, provided the highest rates of molecular response. At 48 months, this group achieved the most favorable responses compared to the 30 mg and 15 mg groups.
Progression-Free Survival (PFS): Among T315I-positive patients, the median PFS was not reached in the 45 mg group, indicating sustained disease control. In contrast, median PFS was significantly shorter in the 30 mg and 15 mg groups.
Overall Survival (OS): Median OS was also not reached across any dose groups at the four-year follow-up. This suggests long-term survival benefits for patients on all dosing strategies, though response and disease control were superior in the 45 mg cohort.
Dose Reduction Findings: Patients whose doses were reduced from 45 mg or 30 mg to 15 mg maintained their responses. Additionally, patients who experienced disease progression after dose reduction often regained response upon re-escalating to a higher dose, particularly in the 45 mg cohort.
Adverse Events and Toxicities
While ponatinib shows a high degree of effectiveness in CP-CML, it carries a risk of cardiovascular events. The OPTIC trial’s dose-reduction strategy helped to reduce some of these risks by limiting high-dose exposure after achieving disease control. As such, the 45 mg group, while yielding the best response rates, also had a slightly higher incidence of cardiovascular side effects. A dose reduction to 15 mg after the initial response was helpful in reducing these risks, while maintaining control of the disease.
Conclusions and Faculty Insights
Dr. Lai highlighted the significance of OPTIC’s findings for CML treatment, especially for those with the challenging T315I mutation. She noted that the trial’s dose-optimization strategy allowed clinicians to initiate treatment at a potent 45 mg dose and reduce it once disease control is achieved, thus balancing efficacy with safety. Dr. Lai emphasized that ponatinib remains an essential option for T315I-positive patients, as other TKIs typically lack effectiveness against this mutation. She noted the strategy of starting at a higher dose and transitioning to a lower maintenance dose of ponatinib appears effective in minimizing side effects without compromising outcomes. Results from the trial may also influence future CML treatment guidelines by offering a flexible, data-backed dosing regimen that improves outcomes in a high-risk patient subset. Dr. Lai underscored that, while T315I mutation is rare, ponatinib’s dose-adaptive approach may provide a viable, long-term treatment path, especially for patients with multiple TKI resistance.
Speaker Disclosure Information: Dr Lai reported the following disclosures for this presentation: Consultant/Advisory Board: Servier, Daiichi, BMS, AbbVie, Genentech, Syndax, Rigel, Astellas. Research Funding: Jazz Pharma, BMS.