2021 ASCO prospective | Ponatinib third-generation TKI can benefit CP-CML patients

Related studies (PACE; NCT01207440) show that the third-generation tyrosine kinase inhibitor (TKI) Ponatinib (PON) can be resistant to or intolerable to the second-generation TKI in chronic phase chronic myeloid leukemia (CP-CML) The patients brought deep disease remission and sustained survival.
The post-mortem analysis of the study showed that the dose of PON was related to the occurrence of adverse reactions and disease remission.

The Phase II OPTIC study (NCT02467270) explored the efficacy of a PON treatment regimen that adjusts the dose according to treatment remission in patients with drug-resistant or refractory CP-CML.
The preliminary analysis results of this study will be held in the recent 2021 American Society of Clinical Oncology Announced at the annual meeting (ASCO).

The editor organizes the main content as follows for the reference of readers.

Research methods The study included CP-CML patients who were intolerable/resistant to ≥2 TKIs, or had BCR-ABL1 T315I mutations, and were randomly assigned to receive an initial dose of 45 mg per day (cohort A: 45 mg → 15 mg) and 30 mg per day (Cohort B: 30mg→15mg), 15mg per day (Cohort C) PON treatment.

The PON dose of patients with BCR-ABL1IS expression ≤ 1% in cohorts A and B was reduced to 15 mg.

The primary endpoint of the study was the expression of BCR-ABL1IS ≤ 1% at 12 months of treatment, and the secondary endpoints included cytogenetics and molecular biology remission and safety.

Research Results A total of 283 patients were included in the study for randomization (A/B/C: n=94/95/94).

The median age of patients was 48 years (range: 18-81 years), 98% of patients had received ≥2 TKI treatments, 55% of patients had received ≥3 TKI treatments; 99% of patients were resistant to TKI, and 40% Of patients had ≥1 mutation at baseline (23% were T315I mutations).

Preliminary analysis showed that at a median follow-up of 32 months, 134 patients (47%; n=50/41/43) were still receiving PON treatment, and 204 patients (72%) were exposed to PON for ≥12 months.

At 12 months of treatment, 44% of patients in cohort A, 29% of patients in cohort B, and 23% of patients in cohort C had BCR-ABL1IS expression ≤ 1%, and cohort A reached the study endpoint.

The PON dose of 48 patients (29%) in cohorts A and B was reduced to 15 mg.

 The most common treatment-related adverse events (TEAE) ≥ grade 3 were thrombocytopenia (27%), neutropenia (17%), and anemia (7%).

In cohorts A, B, and C, 10%, 5%, and 3% of patients had adverse events, respectively, and 4%, 4%, and 3% of patients had serious adverse events, respectively.

In cohorts A, B, and C, 46%, 35%, and 32% of patients had reduced PON dose due to TEAE, and 19%, 16%, and 14% of patients stopped PON due to TEAE, respectively.

Research conclusions The preliminary analysis of the OPTIC study showed that the PON treatment plan that adjusts the dose based on the treatment remission may benefit CP-CML patients, especially those without the T315I mutation.

For CP-CML patients who are resistant to second-generation TKIs, regardless of the presence of BCR-ABL1 mutations, BCR-ABL1IS expression ≤ 1% can bring better survival outcomes.

Reference source: Jorge E.
Cortes, et al.
OPTIC primaryanalysis: A dose-optimization study of 3 starting doses of ponatinib (PON).
2021ASCO Annual Meeting.
Abstract 7000.
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