In-depth analysis of responders in the phase 3 PhALLCON trial of ponatinib vs imatinib in newly diagnosed Ph+ ALL.

6533 Background: Ponatinib, a third-generation BCR::ABL TKI, has potent activity against all clinically relevant BCR::ABL1 variants, including T315I. PhALLCON (NCT03589326), a phase 3 trial comparing frontline TKIs in adults with Ph+ ALL, met its primary endpoint with a higher rate of minimum residual disease–negative (MRD-neg) complete remission (CR) at end of induction (EOI) with ponatinib vs imatinib (34.4%/16.7%; P=0.002). Here, we report response rates of MRD-neg at any time and PFS by age and BCR::ABL1 variant subgroups. Methods: Adults with newly diagnosed Ph+ ALL were randomized 2:1 to ponatinib (30 mg QD reduced to 15 mg QD upon MRD-neg CR at or after EOI) or imatinib (600 mg QD) plus 20 cycles of reduced-intensity chemotherapy (induction: 3 cycles; consolidation: 6 cycles; maintenance: 11 cycles), followed by single-agent ponatinib or imatinib until disease progression or unacceptable toxicity. Hematopoietic stem cell transplant (HSCT) was per investigator’s discretion. Post hoc analyses compared MRD-neg ( BCR:: ABL1 IS ≤0.01%; MR4) at any time and PFS (any-cause death, failure to achieve CR by EOI, relapse from CR, or failure to achieve/loss of MRD-neg) by age (2-fold longer in the ponatinib vs imatinib arms (median 12.8/5.1 mo) with comparable rates of arterial occlusive (3%/2%) and venous thromboembolic events (11%/12%), and discontinuations due to TEAEs (13%/14%). Conclusions: Ponatinib was superior to imatinib in combination with reduced-intensity chemotherapy for frontline treatment of Ph+ ALL, with higher rates of MRD-neg at any time, substantially longer PFS across age and BCR::ABL1 variant subgroups, and a safety profile comparable to imatinib. Clinical trial information: NCT03589326 . Table: see text