Ponatinib starting dose may be linked to efficacy, safety in chronic-phase CML
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A trial of ponatinib for certain patients with chronic myeloid leukemia demonstrated a trend toward dose-dependent efficacy and safety, according to study results presented at Society of Hematologic Oncology Annual Meeting.
“[The results] may provide a refined understanding of the benefit-risk profile [of ponatinib] and its relation to dose,” Jorge Cortes, MD, professor of medicine and director of the Georgia Cancer Center at Augusta University, and colleagues wrote. “Data from longer follow-up may support an alternate dosing regimen for patients with [chronic-phase] CML.”
A previous trial demonstrated that heavily pretreated patients with chronic-phase CML can achieve deep, durable responses to ponatinib (Iclusig, Takeda Oncology), a multitargeted tyrosine kinase inhibitor. However, long-term follow-up revealed increasing rates of arterial occlusive events.
In the OPTIC trial, Cortes and colleagues sought to analyze efficacy and safety of ponatinib at a range of starting doses.
The trial included 283 patients with chronic-phase CML (median age, 48 years; range, 18-81) who were resistant or intolerant to at least two TKIs or who had a T315I mutation.
Researchers randomly assigned patients to ponatinib dosed at 45 mg (n = 94; group A), 30 mg (n = 95; group B) or 15 mg (n = 94; group C) daily. Investigators reduced the dose to 15 mg daily in the first two groups upon achievement of 1% or less BCR-ABL1 measured using the international standard (IS) ratio.
About one-quarter of all patients (26%) had a history of hypertension; 40% had one or more baseline mutations and 23% had a T315I mutation.
Achievement of 1% or less BCR-ABL1IS at 12 months served as the primary endpoint. Cytogenetic and molecular response, arterial occlusive events, venous thromboembolism and treatment-related adverse events served as secondary endpoints.
At data cutoff for the interim analysis, 162 patients (group A, n = 57; group B, n = 51; group C, n = 54) remained on treatment, with a median duration of exposure of approximately 1 year.
At 12 months, 39% (95% CI, 27.6-50.6) of patients in group A, 27% (95% CI, 17.6-39.1) of patients in group B, and 26% (95% CI, 16.5-38.6) in group C achieved 1% or less BCR-ABL1IS.
Researchers reported dose reductions due to efficacy among 35% of patients in group A and 21% of patients in group B.
All patients on the reduced dose for at least 90 days (n = 37) maintained molecular responses.
Common treatment-related adverse events included thrombocytopenia (39% any grade, 27% grade 3 or higher) and neutropenia (25% any grade, 17% grade 3 or higher).
Arterial occlusive events occurred among 5% of patients in group A, 4% of patients in group B and 1% of patients in group C.
Treatment-related adverse events led to ponatinib dose reductions for 44% of the patients in group A, 31% of patients in group B and 28% of patients in group C, and to treatment discontinuation for 18% of group A, 15% of group B and 14% of group C.
Researchers reported four on-study deaths, which included two sudden deaths in group A and two deaths of pneumonia in group C.
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Cortes J, et al. Abstract CML-114. Presented at: Society of Hematologic Oncology Annual Meeting (virtual meeting); Sept. 9-12, 2020.
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