In a head-to-head comparison, ponatinib appears to be more effective than imatinib along with reduced-intensity chemotherapy in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).
The Phase III open-label PhALLCON trial met its primary endpoint with ponatinib resulting in a twofold higher minimal residual disease (MRD)-negative complete remission rate at the end of induction-34.4 percent for ponatinib versus 16.7 percent for imatinib. The MRD negativity rate, regardless of the outcome identified in induction, was higher with ponatinib (41.6%) compared to imatinib (20.5%). MRD negativity duration and time to treatment failure also both favored ponatinib.
"The efficacy and safety results demonstrate a favorable benefit-risk assessment for ponatinib that should be considered as standard of care for frontline therapy in patients with newly diagnosed Ph+ ALL," said Elias Jabbour, MD, Professor of Medicine in the Department of Leukemia at the University of Texas MD Anderson Cancer Center. He presented the study data at the February 2023 American Society of Clinical Oncology (ASCO) Plenary Series.
Study Details
The combination of a tyrosine kinase inhibitor (TKI) and chemotherapy or steroid is the standard of care in Ph+ALL. Cross-trial comparison of low-dose chemotherapy with first- or second-generation TKIs shows a 12-week complete molecular remission rate of 14-40 percent.
"Despite the high rate of initial response, resistance is often observed and frequently driven by the acquisition of T315I kinase domain mutation," Jabbour said. Ponatinib is a potent third-generation BCR-ABL inhibitor with activity against wild-type and mutated BCR-ABL, including the T315I mutation.
The PhALLCON trial was designed as a comparison between ponatinib and the first-generation TKI imatinib in combination with reduced-intensity chemotherapy in adults with a newly diagnosed Ph+ALL. The study randomized 245 patients, median age 54 years, to receive ponatinib (164 patients) 30 mg once daily or imatinib (81 patients) 600 mg once daily with reduced-intensity chemotherapy through the end of induction (Cycles 1-3), consolidation (Cycles 4-9), and post-consolidation (Cycles 10-20). After Cycle 20, patients received single-agent ponatinib or imatinib until disease progression or unacceptable toxicity. The composite primary endpoint was MRD-negativity complete remission for 4 weeks at end of induction.
Patients had ECOG performance status of 0-2 with no history of chronic myeloid leukemia and did not have any uncontrolled cardiovascular disease. Baseline demographics were balanced between the two arms, although the baseline blast count was slightly higher in the ponatinib than the imatinib arm.
After a median follow-up of 20 months for ponatinib and 18 months for imatinib, 41 percent of patients in the ponatinib arm continued study treatment versus only 12 percent in imatinib arm. More patients discontinued treatment for lack of efficacy with imatinib (26%) compared to ponatinib (7%). Discontinuation due to adverse events was similar in both arms. Following study drug discontinuation, patients in the imatinib arm received subsequent transplants at a higher rate than in the ponatinib arm.
"Ponatinib was associated with a higher MRD-negativity rate at any time compared with imatinib. Additionally, substantially higher deep molecular responses, for example MR4.5, were also observed for ponatinib compared with imatinib at the end of induction and over time," Jabbour explained.
Ponatinib provided more durable responses than imatinib, with a small proportion of patients in the ponatinib arm experiencing relapse after the shift of MRD-negativity. "Patients who received ponatinib remain on therapy longer than imatinib without treatment failure defined as treatment discontinuation due to either adverse event of loss of response already obtained. The median was already reached in the imatinib arm, but not in the ponatinib arm," he said. Among those who discontinued treatment, the ponatinib arm had fewer patients receiving subsequent anti-cancer therapy (35%) compared to imatinib (57%).
Survival endpoints were not mature yet, but there was a favorable trend toward ponatinib in event-free survival. This positive trend was observed in spite of patients in the imatinib arm discontinuing the study drug to receive potentially more effective therapies, Jabbour noted. There was a favorable trend towards progression-free survival for ponatinib compared to imatinib, and there appears to be a trend in overall survival (OS) as well.
Safety events were similar, and the rate and severity of treatment-emergent adverse events were comparable between arms. There was more hypertension in the ponatinib arm; other adverse events, such as hyperkalemia and nausea, were observed more often in the imatinib arm. Importantly, arterial occlusive events and venous thromboembolic events were infrequent and comparable between the two arms.
Research Discussion
ASCO discussant Anjali Advani, MD, Director of the Inpatient Leukemia Program in the Taussig Cancer Institute at Cleveland Clinic, noted some caveats. "This was a relatively young patient population with a median age of 54 years and Ph+ALL is typically a disease of the elderly. This population also had a low incidence of cardiovascular risk factors, so the question is whether we can generalize these results to the larger population who may be older and have comorbidities," she said. "There was a trend toward improved EFS with ponatinib. However, with the new treatments we have, such as antibody-based therapies or CAR-T cells, we are now able to salvage these patients. There was no difference in OS between the two arms, although follow-up is short and the results are not mature yet."
Most U.S. clinicians use the second-generation TKI dasatinib, not imatinib, for these patients, Advani noted. "The landscape is changing with the use of blinatumomab plus TKIs of either dasatinib or ponatinib in the upfront setting, and there are data now published from various groups showing excellent results, although longer follow-up is needed on all of these studies."
Mark L. Fuerst is a contributing writer.