Post-Hoc OPTIC Results Showcase Continued Safety in CP-CML


Ponatinib remains a safe treatment for patients with chronic-phase chronic myeloid leukemia.

Ponatinib remains a safe treatment for patients with chronic-phase chronic myeloid leukemia.

Ponatinib remains a safe treatment for patients with chronic-phase chronic myeloid leukemia.

The 4-year long-term results of the phase 2 OPTIC trial (NCT02467270) found ponatinib (Iclusig) continued to produce efficacy and manageable safety outcomes in patients with chronic-phase chronic myeloid leukemia (CP-CML) harboring a BCR::ABL1 T315I mutation, of which were presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.

The ≤1% BCR:ABL1IS (MR2) response rate by 48 months was highest in the patients who received ponatinib at a highest dose of 45 mg daily and who harbored a BCR::ABL1 T315I mutation. Specifically, in those with a BCR::ABL1 T315I mutation, the response rates were 64%, 25%, and 16% at highest doses of 45 mg (n = 25), 30 mg (n = 20), and 15 mg (n = 19).

In those with a BCR::ABL1 mutation other than T315I, the respective response rates with highest doses of 45 mg (n = 16), 30 mg (n = 15), and 15 mg (n = 18) were 56%, 40%, and 50%. In the group of patients who did not harbor a BCR::ABL1 mutation, the response rates were 60%, 47%, and 45% for highest doses of 45 mg (n = 50), 30 mg (n = 58), and 15 mg (n = 53), respectively.

“[Differences in ≤1% BCR:ABL1IS (MR2) response rates by dose were] less demonstrable in the patients without BCR::ABL1 mutations, and certainly not different in those patients with a mutation other than T315I,” Michael Deininger, MD, PhD, of Versiti Blood Research Institute, in Milwaukee, Wisconsin, said in a presentation of the data. “Bear in mind that the numbers are relatively small, but the signal is relatively clear [for the 45-mg dose] for those patients with the T315I mutation.”

Similar findings were observed with regard to the ≤0.1% BCR::ABLIS (MR3) response rate and the ≤0.0032% BCR::ABL1IS (MR4.5) response rate by 48 months. Superior responses were observed with the 45-mg dose of ponatinib in those who harbored a T315I mutation.

“These results from the post-hoc analysis of the 4-year follow-up of the OPTIC trial support ponatinib’s long-term efficacy and manageable safety profile in patients who are positive for the difficult-to-treat T315I mutation, Deininger said. “Although it’s a post-hoc analysis with small numbers of patients in the mutation and dosing cohorts, the results in patients with CP-CML with the T315I mutation appear consistent with previous analyses of the trial.”

A Closer Look at the Trial: Design, Objectives, and Prior Data

The ongoing, multicenter, randomized OPTIC trial enrolled a total of 283 adult patients with CP-CML who were resistant to 2 or more prior TKIs or who harbored BCR::ABL1 T315I mutations, and who had greater than 1 BCR::ABL1IS.

Study participants were randomly assigned 1:1:1 to receive ponatinib at 45 mg daily, 30 mg daily, or 15 mg daily. Those in the 45- and 30-mg cohorts reduced dosing to 15 mg daily upon achievement of ≤1% BCR::ABL1IS. Those in the 15-mg cohort reduced dosing to 10 mg daily if they experienced adverse effects (AEs). The primary end point of the study was ≤1% BCR::ABL1IS at 12 months.

Results from the primary analysis of the trial showed that ponatinib had “robust efficacy” in the overall population of patients with CP-CML and in the subset of patients who harbored the T315I mutation, according to Deininger.

Diving Into the Subanalysis: Objectives and Additional Findings

The key objectives of the post-hoc analysis were to evaluate BCR::ABL1IS response rates, progression-free survival (PFS), overall survival (OS), and safety at 4 years in the subset of patients with the T315I mutation. The data cutoff was May 8, 2023, and the median follow-up for the 45-, 30-, and 15-mg cohorts was 60.6, 63.5, and 60.7 months, respectively.

“The 3 groups were well balanced. You will also note that they are not super large. If you look at the T315I-positive patients, [they accounted for] roughly 25% throughout the 3 dosing cohorts,” Deininger said. No significant differences in other demographics and baseline disease characteristics were noted.

Additional efficacy data showed that in the 45-mg cohort, the median PFS was not yet reached (NE) in those who harbored a T315I mutation (95% CI, 55.2-NE) or those without a BCR::ABL1 mutation (95% CI, NE-NE). “This translates into survival differences as far as PFS is concerned,” Deininger said. “Those patients with a 45-mg starting dose do significantly better than the other 2 groups.”

He added, “Does this translate into OS? The answer is no. It doesn’t look like that; it’s very clear from the graphs. But again, let’s bear in mind that the numbers are relatively small. [They do] suggest that maybe unlike what we’ve always thought in the past, a lot of patients who become resistant have effective salvage options or maybe the post-ponatinib TKIs such as asciminib [Scemblix] play a role in this setting.”

Of those who achieved response at any time but subsequently lost response, the majority of patients regained ≤1% BCR::ABLIS after dose re-escalation. Specifically, in the 45-mg cohort, 64% of patients (n = 16/25) achieved ≤1% BCR::ABLIS at any time; 60% of patients (n = 9) lost that response, 89% (n = 8) dose re-escalated after loss of response, and 75% (n = 6) regained response. In the 30-mg cohort, 25% (n = 5/20) achieved ≤1% BCR::ABLIS at any time, 60% (n = 3) lost response, 67% (n = 2) dose re-escalated, and 50% (n = 1) regained response.

“All in all, that suggests that this dosing reduction that is built in is safe and effective,” Deininger noted.

Additional Safety Insights

Deininger noted that the incidence of treatment-emergent AEs (TEAEs) was comparable across the dosing cohorts and irrespective of mutation status.

Specifically, for patients harboring T315I mutations, any-grade TEAEs occurred in all evaluable patients in the 45-mg cohort (n = 25), 95% of those in the 30-mg cohort (n = 21), and 95% of those in the 15-mg cohort (n = 21); these effects were grade 3 or 4 for 52%, 33%, and 29% of patients, respectively. Serious AEs occurred in 36%, 33%, and 29% of patients, respectively, and grade 5 AEs occurred in 8%, 5%, and 10% of patients, respectively.

In the 45-mg cohort, 48% of patients harboring T315I mutations required dose reduction due to TEAEs, 64% required dose interruption, and 8% required discontinuation. These respective rates in the 30-mg cohort were 24%, 48%, and 14%; in the 15-mg cohort, these respective rates were 5%, 38%, and 5%.

The most common hematologic grade 3 or higher TEAEs across the dosing cohorts of patients with T315I mutations were thrombocytopenia, neutropenia, and anemia, he added. Thrombocytopenia occurred in 20%, 14%, and 5% of patients in the 45-, 30-, and 15-mg cohorts, respectively; neutropenia occurred in 16%, 5%, and 5% of patients, respectively; and anemia was reported in 4%, 5%, and 0% of patients, respectively.

An AE of special interest was treatment-emergent arterial occlusive events (TE-AOEs). Notably, rates of TE-AOEs were generally low across the cohorts and irrespective of mutation status.

In patients with T315I mutations, any-grade TEAOEs were reported in 8% of those in the 45-mg cohort, 14% of those in the 30-mg cohort, and 5% of those in the 15-mg cohort; these effects were grade 3 or 4 for 4%, 14%, and 5% of patients, respectively. No grade 5 TE-AOEs were reported.

“In particular, the 45-mg initial dosing seems to be safe in terms of cardiovascular toxicity. Now, this is different from what we have seen in the past or what was published a number of years ago in the initial [phase 2] PACE study [NCT01207440],” Deininger said.

Exposure-adjusted AOEs were 2.37 (95% CI, 0.00-5.74), 7.32 (95% CI, 0.00-15.64), and 2.83 (95% CI, 0.00-7.99) in the 45-, 30-, and 15-mg cohorts, respectively.


“This is a study that used a very novel design of inbuilt dose reduction, that in my mind, should be considered in other TKI [trials,] as well,” Deininger concluded.


Deininger M, Apperley J, Arthur CK, et al. Ponatinib (PON) in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) and the T315I mutation (mut): 4-year results from OPTIC. J Clin Oncol. 2024;42(suppl 16):6501. doi:10.1200/JCO.2024.42.16_suppl.6501

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