Ponatinib Demonstrates Deep and Durable Responses vs Imatinib in Ph+ ALL


The phase 3 PhALLCON trial showed a trend toward event-free survival in patients with Philadelphia chromosome positive acute lymphoblastic leukemia when treated with ponatinib compared with imatinib.

Elias Jabbour, MD

Elias Jabbour, MD

Treatment with ponatinib (Iclusig) led to significantly higher minimal residual disease (MRD)-negativity complete response (CR) rates in patients newly diagnosed Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) compared with imatinib (Gleevec) in the phase 3 PhALLCON trial (NCT03589326).

In the study, ponatinib led to more deep and durable responses, and showed a trend toward improved event-free survival in this patient population. The primary end point of MRD-negative CR rate at the end of induction was 34% vs 17% (P = .0021), and there was an MRD-negativity rate of 42% vs 21% for the ponatinib vs imatinib arms.

Additionally, there was comparable safety data between arms. These findings show that the combination of ponatinib and reduced-intensity chemotherapy may be more effective compared with imatinib in this patient population.

“The PhALLCON trial is showing superior efficacy with ponatinib compared with imatinib in combination with low-dose chemotherapy in patients with newly diagnosed Ph+ ALL with a significantly higher rate and clinically meaningful MRD-negativity complete remission rate at the end of induction,” stated Elias Jabbour, MD, professor of medicine at The University of Texas MD Anderson Cancer Center, in a presentation of findings from the PhALLCON trial during the February 2023 ASCO Plenary Session.

The current standard of care for patients with newly diagnosed Philadelphia chromosome

Ph+ ALL is BCR-ABL1 tyrosine kinase inhibitor (TKIs) in combination with chemotherapy or steroids. Now, the phase 3, open-label, randomized, PhALLCON trial (NCT03589326) is the first randomized study comparing TKIs in patients with Ph+ALL. In the trial, investigators are evaluating ponatinib vs imatinib in combination with reduced-intensity chemo in this newly diagnosed patient population.

The study randomized patients 2:1 to receive ponatinib at 30 mg once daily or imatinib at 600 mg once a day with reduced-intensity chemo through the end of induction, consolidation, and post-consolidation. After cycle 20, patients were given single-agent ponatinib or imatinib until disease progression or unacceptable toxicity.

Investigators evaluated the primary end point was MRD-negativity CR for 4 weeks, and the secondary end point of EFS.

A total of 245 patients were randomized to receive either ponatinib (n = 164) or imatinib (n = 81). The median age of those enrolled was 54 years in the ponatinib arm (range, 19-82) and 52 years in the imatinib arm (range, 19-75). Male patients made up 45% and 47% of patients and 96% and 94% had an ECOG performance status of 0 or 1 in the ponatinib vs imatinib arms. The median range of leukocyte count was 4.4 (range, 0.4-198) and 3.2 (range, 0.2-81). Ninety-two and 52 patients had greater than 1 CV comorbidities, and 45 and 27 patients had 2 or greater CV comorbidities between arms.

At the data cutoff date of August 2022, 78 patients were administered the study treatment, including 42% given ponatinib and 12% given imatinib. Discontinuation on the trial was attributed to hematopoietic stem cell transplantation in 31% of patients given ponatinib vs 37% given imatinib, adverse events (AEs; 12% vs 12%), and lack of efficacy (7% vs 26%).

A total of 37% of the 81 patients who discontinued treatment with imatinib received a second- or third-line generation TKI and/or immunotherapy. Sixteen percent of the 81 patients who received ponatinib then discontinued. In the ponatinib arm, 35% of patients received any subsequent anticancer therapy compared with 57% in the imatinib arm.

The median follow-up for the ponatinib vs imatinib arms were 20 months vs 18 months. Findings revealed that the primary end point was met with a significantly higher MRD-neg CR rate for ponatinib vs imatinib (34.4% vs 16.7%; P = .0021).

While the survival data were not mature, the median EFS was reached in the imatinib arm while it was not reached in the ponatinib arm, and there was a trend toward improvement (HR, 0.652, 95% CI, 0.385-1.104). The PFS in the ponatinib arm was 20.0 (95% CI, 11.8-NE) and was 7.9 (95% CI, 6.2-12.4) in the imatinib arm. OS was also nor reached in either arm at the data cutoff date.

For safety, treatment-emergent AEs (TEAEs) were comparable between arms. Serious TEAEs occurred in 60% vs 56%, grade 3-4 TEAEs were seen in 90% and 93%, and grade 5 TEAEs were observed in 5% in both the ponatinib and imatinib arms. Rates of arterial occlusive events were infrequent and similar between the arms with them being observed in 4 patients in the ponatinib arm vs 1 in the imatinib arm.

“Ponatinib had a safety profile that was comparable with imatinib, which is known to be a very well-tolerated tyrosine kinase inhibitor. The safety profile included similar and lower rates of adverse events. Taken together for this patient population, the efficacy and safety results demonstrate a favorable benefit/risk assessment for ponatinib and should be considered a standard of care for frontline therapy in patients who are newly diagnosed with ALL,” added Jabbour.

Jabbour E, Kantarjian HM, Aldoss I, et al. First report of PhALLCON: A phase 3 study comparing ponatinib (pon) vs imatinib (im) in newly diagnosed patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Presented at: 2023 February ASCO Plenary Series. Abstract 398868.

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