Dr Kantarjian on Long-Term Data for Dose-Optimized Ponatinib in CML

“[The OPTIC trial] also showed, which was very important, an improvement in the survival in patients with [a BCR::ABL1] T315I mutation. The 5-year survival was [86.3%], which is high and amazing.”

Hagop M. Kantarjian, MD, a professor in the Department of Leukemia and the Samsung Distinguished Leukemia Chair in Cancer Medicine at The University of Texas MD Anderson Cancer Center; as well as a non-resident fellow in health policy at the Rice University Baker Institute, discussed 5-year follow-up data from the phase 2 OPTIC trial (NCT02467270) evaluating a response-based dose-optimization strategy for ponatinib (Iclusig) in patients with chronic myeloid leukemia in chronic phase (CP-CML).

Ponatinib is among the most potent BCR::ABL1 TKIs available, but it produced significant toxicities at its original 45-mg daily dose, Kantarjian said. The OPTIC trial was designed to determine whether a safer dosing schedule could preserve that efficacy and mitigate toxicity, he explained. In the study, patients with CP-CML who had a BCR::ABL1 T315I mutation or were resistant to at least 2 prior TKIs were randomly assigned to ponatinib at an initial dose of 45 mg, 30 mg, or 15 mg daily; once patients achieved a complete molecular response, defined as BCR::ABL1 transcript levels below 1%, their dose was reduced to 15 mg, Kantarjian noted.

The dose-adjusted schedule made ponatinib considerably safer, with lower rates of arterial and venous occlusive adverse effects, hypertension, and skin rash than had been seen with continuous 45-mg dosing, according to Kantarjian. Among patients with a baseline T315I mutation, BCR::ABL1 responses below 1% occurred in 64%, 25%, and 16% of those starting at 45 mg, 30 mg, and 15 mg, respectively, he said. Starting at the higher 45-mg dose in this subgroup also translated into a 5-year overall survival rate of 86.3% (95% CI, 63.2%-95.4%), compared with 61.7% (95% CI, 37.7%-78.7%) and 31% (95% CI, 44.1%-85%) for the 30-mg and 15-mg starting doses, Kantarjian reported.

Kantarjian said these findings support starting patients with T315I-mutated CP-CML at 45 mg before reducing to 15 mg upon response, while patients with other mutations or no detectable mutation can begin at 30 mg. He noted that the same dose-optimization approach—starting at 30 mg and reducing to 15 mg after a complete molecular response—is now also used in Philadelphia chromosome–positive acute lymphoblastic leukemia. Kantarjian concluded that optimizing the ponatinib dose schedule preserved its potency while substantially improving its tolerability.