Ponatinib + reduced-intensity chemotherapy outperformed imatinib for the treatment of newly diagnosed Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL)

The data were presented during the 2023 American Society of Clinical Oncology (ASCO) Plenary Session.

Minimal residual disease (MRD)-negative complete remission (CR) at the end of induction was achieved in 34.4% of patients who received ponatinib (n = 154) vs 16.7% of patients who received imatinib (n = 78; RR, 2.06; 95% CI, 1.19-3.56; P = .0021). This end point was described as having a hematologic CR for at least 4 weeks plus MRD negativity defined as no greater than 0.01% BCR::ABL1 (MR4). Median follow-up was 20.4 months (range, 18.4-23.9) in the ponatinib arm and 18.1 months (range, 13.9-24.3) in the imatinib arm.

Overall, the MRD negativity rate at the end of induction was 41.6% with ponatinib vs 20.5% with imatinib (RR, 1.94; 95% CI, 1.19-3.17; P = .0017). The median duration of MRD negativity—defined as time from first documented MRD negativity to first documented loss of MRD negativity—was not estimable (NE; 95% CI, 17.0-NE) in the ponatinib arm compared with 20.9 months (95% CI, 10.9-NE) in the imatinib arm. The median time to treatment failure was not estimable with ponatinib vs 21.9 months with imatinib.

Ponatinib is a very potent BCR::ABL1 inhibitor with activity against wild-type and BCR::ABL1 [mutated disease] including T315I mutations,” Elias J. Jabbour, MD, said during a presentation of the data. “The combination of ponatinib with steroid, chemotherapy, or immunotherapy has [been shown] very promising [and] with propensity score matching was thought to be superior to dasatinib [Sprycel] and imatinib,” added Jabbour, who is a professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston. “The PhALLCON trial shows the superior efficacy of ponatinib compared with imatinib in combination with low-dose chemotherapy in patients Ph-positive ALL with a significantly higher and clinically meaningful MRD-negativity CR rate at the end of induction.”

The combination of [tyrosine kinase inhibitor] TKI and chemotherapy or steroids is the SOC for patients with Ph-positive ALL [and] cross-trial comparison of low-chemotherapy with first- or second-generation TKIs reported a 12-week CMR rate of approximately 14% to 40%, [but] despite the high rate of initial response, resistance is often observed and frequently driven by the acquisition of the T315I kinase domain mutation.”

The secondary end point of the study was event-free survival (EFS), which was assessed among the intention-to-treat population of 164 patients who received ponatinib and 81 patients who received imatinib. The median was NE with ponatinib vs 29.0 months with imatinib (HR, 0.65; 95% CI, 0.39-1.10). Events for this analysis included death from any cause, failure to achieve CR at the end of induction, or relapse from CR.

Progression-free and overall survival (PFS, OS) were also reported. The median PFS was 20.0 months (95% CI, 11.8-NE) vs 7.9 months (95% CI, 6.2-12.4) with ponatinib and imatinib, respectively (HR, 0.58; 95% CI, 0.41-0.83). The median OS was NE is both arms but showed a trend toward a benefit with ponatinib vs imatinib (HR, 0.76; 95% CI, 0.38-1.52.

In a discussion of the data, Anjali Advani, MD, provided perspective on how these data would impact clinical practice in the United States. “The strength of this trial [is that] this is the only prospective randomized trial comparing TKIs in this patient population in combination with chemotherapy,” she said. “This is a large number of patients in a relatively rare population, this was an international study, and finally, results were encouraging with no increased risk of TEAEs.”

Advani, who is a staff physician in the Department of Hematologic Oncology and Blood Disorders and director of the Inpatient Leukemia Program at Taussig Cancer Institute in Cleveland, Ohio, noted that the trial did have some caveats. “This was a relatively young patient population, with a median age of 54 years and Ph-positive ALL is typically a disease of the elderly. This population also had a low incidence of cardiovascular risk factors and so the question is whether we can generalize these results to the larger population who may be older and have comorbidities,” Advani said. “There was a trend toward improved EFS with ponatinib; however, with the new treatments we have such as antibody-based therapies, [or chimeric antigen receptor] CAR T cells, we are now able to salvage these patients,” Advani added. “There was no difference in OS between the 2 arms, although follow-up is short, and the results are not mature yet.”

“Although imatinib was a reasonable comparison to ponatinib in the United States, typically most clinicians are using dasatinib and so it would have been nice to have this comparison,” continued Advani.

Advani said. “The landscape is changing with the use of blinatumomab [Blincyto] plus TKIs 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.”