Ponatinib ‘should be considered a standard of care’ for newly diagnosed Ph+ALL
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Ponatinib conferred deeper and more durable responses than imatinib in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia who received either agent in combination with reduced-intensity chemotherapy.
Results of the randomized, prospective phase 3 PhALLCON study, presented during an ASCO Plenary Series session, also showed a trend toward longer EFS with ponatinib and similar rates of adverse events with each tyrosine kinase inhibitor (TKI).
Rationale
PH+ALL is a common ALL subtype among adults and has been observed in more than 50% of cases in those aged older than 50 years, according to Marlise Rachel Luskin, MD, MSCE, assistant professor of medicine at Harvard Medical School and senior physician at Dana-Farber Cancer Institute. PH+ALL responds poorly to conventional chemotherapy, and allogeneic hematopoietic stem cell transplant is seldom feasible for these patients and rarely results in cure, she said in a “State of the Science” presentation.
Imatinib, a first-generation, potent inhibitor of the ABL1 kinase, has improved outcomes for these patients but is not the “magic bullet” for ALL, she said. Challenges include insufficient depth of complete remission, systemic or central nervous system relapse and toxicity of post-remission chemotherapy or transplantation regimens.
More potent second- and third-generation TKIs have been pursued as successors to imatinib for this patient population. They include ponatinib (Iclusig, Takeda), a third-generation TKI that has been shown to be active against the T315I mutation.
“This is important because the majority of relapses in imatinib-treated patients and in second-generation-TKI-treated patients occur via acquisition of this mutation,” she said.
In previous studies, ponatinib has conferred promising rates of minimal residual disease (MRD) negativity and survival outcomes, with or without chemotherapy, according to study background. However, it has also been associated with arterial thrombotic events, which have been ameliorated through dose reductions, Luskin said.
Methodology
The PhALLCON study is the first randomized study to compare TKIs among patients with PH+ALL, according to researchers.
The study included 245 adults (median age, 54 years; 37% aged 60 years or older) with newly diagnosed PH+ALL. Researchers randomly assigned patients in a 2:1 ratio to 30 mg ponatinib, reduced to 15 mg upon achievement of MRD-negative complete response after induction (n = 164), or imatinib at a starting dose of 600 mg (n = 81) once daily plus reduced-intensity chemotherapy.
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 the composite primary endpoint, with EFS as a key secondary endpoint.
Median follow-up was 20 months for the ponatinib group and 18 months for the imatinib group.
Results
Seventy-eight patients remained on study treatment at the data cutoff date of Aug. 12, 2022, including 41% of the ponatinib group and 12% of the imatinib group. The most common reasons for discontinuation included HSCT (30% ponatinib vs. 37% imatinib), adverse events (12% vs. 12%) and lack of efficacy (7% vs 26%). A higher proportion of patients in the imatinib group received HSCT at any time (48% vs. 34%).
Results showed the ponatinib group had significantly higher rates of MRD-negative complete remission (34.4% vs. 16.7%; RR = 2.06; 95% CI, 1.19-3.56) and MRD negativity (41.6% vs. 20.5%; RR = 1.94; 95% CI, 1.19-3.17) at the end of induction than the imatinib group. The ponatinib group also had a longer duration of MRD negativity (not estimable vs. 20.9 months) and time to treatment failure (not estimable vs. 21.9 months).
Survival data remained immature, although researchers noted a trend toward improved EFS (median, not estimable vs. 29 months; HR = 0.65; 95% CI, 0.38-1.1), PFS (median, 20 months vs. 7.9 months; HR = 0.58; 95% CI, 0.41-0.83) and OS (median not estimable in either group; HR = 0.76; 95% CI, 0.38-1.52) with ponatinib.
The ponatinib and imatinib groups had similar rates of treatment-emergent adverse events, including grade 3 to grade 4 (90% vs. 93%) and grade 5 (5% each) events. One patient in the imatinib group experienced a grade 5 treatment-related adverse event.
Four patients in the ponatinib group (2%) and one in the imatinib group (1%) experienced arterial occlusive events, and 12% of patients in each group had venous thrombolic events.
“Taken together, for this patient population, the efficacy and safety results demonstrate a favorable benefit-risk assessment for ponatinib that should be considered a standard of care for front-line therapy in patients with newly diagnosed PH+ALL,” lead study author Elias Jabbour, MD, of the department of leukemia in the division of cancer medicine at The University of Texas MD Anderson Cancer Center, said during the abstract presentation.
Implications
Discussant Anjali S. Advani, MD, professor of medicine at Cleveland Clinic Lerner College of Medicine and director of the inpatient leukemia unit at Taussig Cancer Institute, pointed out the trial’s strengths, including the large number of patients for a relatively rare disease subtype and the encouraging results, as well as its caveats, such as lack of a comparison with the potent BCR-ABL inhibitor dasatinib (Sprycel, Bristol Myers Squibb) and low incidence of cardiovascular risk factors among the study population.
“Particularly in a younger patient with relatively few or no cardiovascular comorbidities, this treatment represents a really exciting option,” Advani added. “What’s hard is the landscape of treatment is changing quickly in this field, and so is the standard of care. So, the questions I think we struggle with are whether we should be using the antibody-based therapies plus TKIs or looking at an approach such as this, and further studies are going to be needed to answer that question.”
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