Ph+ ALL: 1L ponatinib ups MRD-negative CR at end of induction vs imatinib

Minimal residual disease (MRD)–negative complete remission (CR) rate at end of induction is significantly higher in adult patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukaemia (ALL) treated with ponatinib vs imatinib combined with reduced-intensity chemotherapy, results of the phase III PhALLCON trial have shown.

The positive findings, together with ponatinib’s manageable safety profile in the trial, support the US FDA’s recent accelerated approval of ponatinib in combination with chemotherapy for adult patients with newly diagnosed Ph+ ALL. [JAMA 2024;331:1814-1823; https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-ponatinib-chemotherapy-newly-diagnosed-philadelphia-chromosome]

In the PhALLCON trial, the primary endpoint of MRD-negative CR at end of induction, defined as BCR::ABL^IS ≤0.01 percent (ie, molecular response with 4-log reduction [MR4]) centrally assessed by reverse transcriptase–quantitative polymerase chain reaction at end of cycle 3 with investigator-reported CR maintained for ≥4 weeks, was achieved in 34.4 percent of patients in the ponatinib group vs 16.7 percent of those in the imatinib group (relative risk [RR], 2.06) (risk difference, 0.18; 95 percent confidence interval [CI], 0.06–0.29; p=0.002). Median duration of MRD-negative CR was not reached (NR) in the ponatinib group vs 18.0 months in the imatinib group.

“Benefit [in the primary endpoint] was observed for ponatinib vs imatinib across all subgroups analyzed, including in patients ≥60 years of age [40.0 vs 10.3 percent; RR, 3.87] [risk difference, 0.30; 95 percent CI, 0.13–0.46; p<0.001], which represents a challenging-to-treat population with suboptimal response to limited treatment options,” the investigators pointed out.

At end of induction, rates of MR4 and MR4.5 (BCR::ABL1^IS ≤0.0043 percent) were higher with ponatinib vs imatinib (MR4, 43.0 vs 22.1 percent; RR, 1.94; 95 percent CI, 1.19–3.17; p=0.002) (MR4.5, 26.8 vs 14.7 percent). Cumulative rates of MR4 and MR4.5 consistently increased over time, with MR4 rates reaching 62.1 vs 44.9 percent by cycle 9.

Median time to loss of MRD negativity, defined as increase to BCR::ABL1^IS >0.01 percent, was NR with ponatinib vs 20.9 months with imatinib. Median time to treatment failure, defined as discontinuation due to lack of efficacy or toxicity, was NR vs 21.9 months.

Median event-free survival after a median follow-up of 20.1 months was NR with ponatinib vs 29.0 months with imatinib (hazard ratio [HR], 0.65; 95 percent CI, 0.39–1.10).

Median progression-free survival in post hoc analyses was 12 months longer with ponatinib vs imatinib (20.0 vs 7.9 months; HR, 0.58; 95 percent CI, 0.41–0.83), despite 37.0 percent of patients in the imatinib group discontinuing study drug to receive a second- or third-generation tyrosine kinase inhibitor and/or immunotherapy, including 16.0 percent of patients who received subsequent ponatinib-based therapy. Median overall survival was NR in either group.

In terms of safety, comparable rates were reported with ponatinib vs imatinib for grade 3/4 treatment-emergent adverse events (AEs) (85.3 vs 87.7 percent) and treatment-related AEs (65.6 vs 59.3 percent). “The most common AEs were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups [2.5 vs 1.2 percent],” the investigators noted.