PhALLCON: Third-generation TKI superior to first-generation TKI in Ph+ ALL

Ponatinib outperformed imatinib in participants with previously untreated Ph+ acute lymphoblastic leukaemia (ALL) in progression-free survival (PFS) and measurable residual disease (MRD) negativity rates. These findings were consistent across age and BCR::ABL1 variant subgroups.

The phase 3 PhALLCON trial (NCT03589326) compared the third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) ponatinib to the first-generation variant imatinib in participants with newly diagnosed Ph+ ALL. Enrolled participants (n=245) were randomised 2:1 to ponatinib or imatinib plus reduced-intensity chemotherapy. A previous analysis demonstrated that the primary endpoint, MRD-negative clinical remission rate at the end of induction, favoured the ponatinib arm (34.4% vs 16.7%) [1]. In the current analysis, Prof. Jose Maria Ribera (Josep Carreras Leukaemia Research Institute, Spain) shared additional efficacy data, outcomes in subgroups, and results from participants who proceeded to stem cell transplantation [2].

After a median follow-up of 19.4 months, the median PFS was significantly longer for participants receiving ponatinib than for imatinib controls (20.2 months vs 7.5 months; HR 0.52; 95% CI 0.36–0.73). This result was consistent with the higher rates of participants who were MRD negative at any time in the ponatinib group, even when subdivided per age (younger or older than 65 years), and BCR::ABL1 subgroups (p190 or p210; see Figure). Fewer participants in the ponatinib arm proceeded to stem cell transplantation at any time (36% vs 47%). This finding was consistent in the MRD-negative subgroup of participants (32% vs 56%).

Figure: MRD negativity at all time rates for participants receiving ponatinib vs imatinib [2]



CI, confidence interval; MRD, measurable residual disease; RR, relative risk; y, years of age.

The safety profiles of the 2 agents were very comparable, although more participants in the ponatinib arm had dose interruptions due to unspecified reasons (73% vs 41%). “Of note, the exposure time was more than 2-fold longer in the ponatinib arm than in the imatinib arm among participants who did not proceed to stem cell transplantation, whereas the adverse event rates remained similar,” emphasised Prof. Ribera.

Additional data from the PhALLCON trial confirmed the superior efficacy of ponatinib over imatinib plus chemotherapy in participants with newly diagnosed Ph+ ALL. Also, the exposure-adjusted safety profile of ponatinib appears to be more acceptable than the imatinib profile.

1. Jabbour E, et al. JAMA. 2024;331(21):1814–1823.
2. Ribera J-M, et al. Ponatinib versus imatinib in patients with newly diagnosed Ph+ acute lymphoblastic leukemia in the phase 3 PhALLCON trial: in-depth responder analysis. S115, EHA congress 2024, 13–16 June, Madrid, Spain.

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Posted on 12 August 202412 August 2024