Ponatinib regimen improves outcomes in Ph+ acute lymphoblastic leukemia
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Ponatinib improved outcomes compared with imatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia, according to study results presented at Society of Hematologic Oncology Annual Meeting.
The findings suggest ponatinib (Iclusig, Takeda) plus reduced-intensity chemotherapy could be a standard of care for this population, researchers concluded.
Standard first-line therapy for patients with Philadelphia chromosome-positive ALL (Ph+ALL) includes BCR::ABL1 tyrosine kinase inhibitors plus chemotherapy or steroids.
Ponatinib — the only pan-BCR::ABL1 TKI approved in the United States — is a third-generation TKI developed to inhibit BCR::ABL1 with or without any single resistance mutation. Prior studies showed ponatinib in combination with immunotherapy or chemotherapy improved long-term outcomes, according to study background.
Imatinib is a first-generation inhibitor of the ABL1 kinase.
Elias Jabbour, MD, professor of medicine in the department of leukemia at The University of Texas MD Anderson Cancer Center, and colleagues conducted the randomized phase 3 PhALLCON trial to evaluate the efficacy and safety of reduced-intensity chemotherapy plus either ponatinib or imatinib as a front-line therapy for adults with newly diagnosed Ph+ALL.
The study included 245 adults (median age, 54 years; 37% aged 60 years or older) with newly diagnosed Ph+ALL.
Researchers randomly assigned patients 2:1 to 30 mg daily ponatinib — reduced to 15 mg upon achievement of minimal residual disease (MRD)-negative complete response — or 600 mg daily imatinib with reduced-intensity chemotherapy through the end of induction, consolidation and post-consolidation.
After post-consolidation, patients continued to receive ponatinib or imatinib monotherapy, with treatment continuing until unacceptable toxicity or disease progression.
Investigator-assessed MRD-negative complete remission for at least 4 weeks at the end of induction and centrally reported MRD negativity — defined as BCR::ABL1 of 0.01% or less — served as a composite primary endpoint. EFS served as a key secondary endpoint.
Median follow-up was 20 months (range, 18-24) in the ponatinib group and 18 months (range, 14-24) in the imatinib group.
At data cutoff, a higher percentage of patients assigned ponatinib remained on treatment (41% vs. 12%). A higher percentage of patients assigned imatinib discontinued due to lack of efficacy (26% vs. 7%); 12% in each group discontinued due to adverse events.
The study met its primary endpoint, showing a higher MRD-negative complete remission rate at the end of induction in the ponatinib group (34.4% vs. 16.7%; relative risk = 2.06; 95% CI, 1.19-3.56).
A higher percentage of ponatinib-treated patients achieved MRD negativity at the end of induction regardless of complete remission assessment (41.6% vs. 20.5%; relative risk = 1.94; 95% CI, 1.19-3.17).
Although survival data had not matured, researchers reported trends toward improvements in the ponatinib group for EFS (median, not reached vs. 29 months; HR = 0.65; 95% CI, 0.39-1.1) and PFS (median, 20 months vs. 7.9 months; HR = 0.58; 95% CI, 0.41-0.83). Median OS had not been reached in the ponatinib or imatinib groups (HR = 0.76; 95% CI, 0.38-1.52).
The most common grade 3 or grade 4 nonhematologic treatment-emergent adverse events included increased alanine transaminase (19% for ponatinib vs. 9% for imatinib), increased lipase (13% vs. 19%), hypokalemia (6% vs. 19%) and hypertension (12% vs. 6%).
The most common grade 3 or grade 4 hematologic treatment-emergent adverse events included decreased platelet count (63% for ponatinib vs. 58% for imatinib), decreased white blood cell count (53% vs. 49%), decreased neutrophil count (49% vs. 46%) and decreased lymphocyte count (38% vs. 47%).
Four patients (2%) assigned ponatinib and one patient (1%) assigned imatinib experienced treatment-emergent arterial occlusive events. Nineteen patients (12%) assigned ponatinib and 10 (12%) assigned imatinib developed treatment-emergent venous thromboembolism.
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Jabbour E, et al. Abstract ALL-300. Presented at: Society of Hematologic Oncology Annual Meeting; Sept. 6-9, 2023; Houston.
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