Dr Deininger on Long-Term Outcomes With Ponatinib in T315I-Mutant CP-CML

Michael Deininger, MD, PhD, professor, medicine, Division of Hematology and Oncology, Medical College of Wisconsin; member, Cancer Center, Froedtert Hospital, discusses 4-year results from the phase 2 OPTIC trial (NCT02467270) investigating ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) harboring a T315I mutation.

In the OPTIC study, patients with CP-CML resistant to 2 or more TKIs, or those with the BCR::ABL1 T315I mutation, were randomly assigned to receive ponatinib at starting doses of 45 mg, 30 mg, or 15 mg per day, Deininger begins. Dose reduction to 15 mg was implemented upon achieving a BCR::ABL1IS level of 1% or lower in the 45 mg and 30 mg cohorts. The primary analysis demonstrated robust responses with ponatinib at 12 months in the overall patient population as well as in those with T315I mutations, he details. Accordingly, investigators conducted a post-hoc analysis to evaluate BCR::ABL1IS response rates, progression-free survival (PFS), overall survival (OS), and safety outcomes at 48 months in the T315I-mutant subgroup.

Findings presented at the 2024 ASCO Annual Meeting confirmed that patients with the BCR::ABL1 T315I mutation benefit most from a starting dose of 45 mg, in terms of achieving a molecular response (MR2), defined as a BCR::ABL1IS transcript level of 1% or less) or a complete molecular response (MR4.5), defined as a BCR::ABL1IS transcript level no greater than 0.0032%). In contrast, for patients without BCR::ABL1 mutations or with BCR::ABL1 mutations other than T315I, lower starting doses of ponatinib were more effective, Deininger reports.

A key design feature of the trial was the mandatory dose reduction upon achieving the primary response end point, Deininger continues. The post-hoc analysis explored whether patients who reduced their dose would maintain their response or experience a recurrence of their disease, and whether they could respond to another dose escalation if needed, he explains. Among the 16 patients who started on 45 mg of ponatinib, achieved a BCR::ABL1ISresponse at any time, and then reduced their dose to 15 mg, approximately half experienced a recurrence of more active leukemia and lost their primary response, Deininger states. However, most of these patients were able to re-attain their response upon dose re-escalation, he notes. The 14 remaining patients who received the 45 mg starting dose maintained a response following dose reduction to 15 mg.

This indicates that a substantial proportion of patients can safely maintain their response after dose reduction, and those who experience a recurrence can often regain their response with re-escalation, demonstrating the flexibility and efficacy of the dose adjustment strategy in managing CP-CML, Deininger concludes.