Ponatinib appears to be a more effective tyrosine kinase inhibitor than imatinib in newly diagnosed, Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) when combined with reduced-intensity chemotherapy, according to data presented during the ASCO Plenary Series: February 2023 Session.¹

Results of the phase III PhALLCON study showed that the addition of ponatinib to reduced-intensity chemotherapy was associated with twice the rate of measurable residual disease (MRD)-negative complete remission at the end of induction vs imatinib (34.4% vs 16.7%, respectively; P = .0021). Rates of MRD negativity at the completion of therapy were also doubled in the ponatinib arm compared with imatinib (41.6% vs 20.5%, respectively). The safety profile of ponatinib was comparable with imatinib, authors of the study reported.

“The efficacy and safety results demonstrate a favorable benefit-risk profile for ponatinib that should be considered a standard of care for front-line therapy in patients with newly diagnosed, Ph-positive ALL,” said lead study author Elias Jabbour, MD, Professor of Medicine, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.

The efficacy and safety results demonstrate a favorable benefit-risk profile for ponatinib that should be considered a standard of care for front-line therapy in patients with newly diagnosed, Ph-positive ALL.

— Elias Jabbour, MD

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As Dr. Jabbour explained, the standard of care in patients with newly diagnosed, Ph-positive ALL is BCR-ABL1 tyrosine kinase inhibitors in combination with chemotherapy or steroids. A cross-trial comparison of low-dose chemotherapy and first- and second-generation BCR-ABL1 tyrosine kinase inhibitors reported a 12-week complete molecular remission rate of approximately 14% to 39%, and resistance was frequently driven by acquisition of a T315I kinase domain mutation.^2,3

According to Dr. Jabbour, ponatinib is the only pan-inhibitory BCR-ABL1 tyrosine kinase inhibitor with activity against BCR-ABL1 wild-type and single mutation variants, including T315I. Ponatinib in combination with chemotherapy or immunotherapy has been shown to improve long-term outcomes in Ph-positive lymphoblastic leukemia.^4,5

Study Methods

In the phase III PhALLCON study, newly diagnosed adults with Ph-positive ALL were randomly assigned to receive either ponatinib or imatinib. Patients received a reduced-intensity chemotherapy regimen during 3 cycles of induction, 6 cycles of consolidation, and 11 cycles after consolidation. After cycle 20, patients were given either single-agent ponatinib or imatinib until disease progression or unacceptable toxicity. The primary endpoint of the study was achievement of complete remission for at least 4 weeks at the end of induction with MRD negativity. The key secondary endpoint was event-free survival.

Ponatinib Doubles Complete Remission Rate vs Imatinib

As Dr. Jabbour reported, a total of 245 patients were randomly assigned to receive ponatinib (n = 164) or imatinib (n = 81). The median age of patients on study was 54 years, with 37% aged 60 or older.

At data cutoff in August 2022, more patients in the ponatinib arm continued to receive study treatment compared with the imatinib arm (41% vs 12%). The primary reasons for discontinuation of therapy were hematopoietic stem cell transplantation (34% vs 48%), adverse events (12% vs 12%), and lack of efficacy (7% vs 26%). 

The median follow-up was 20 months for ponatinib and 18 months for imatinib. The primary endpoint of the study was met, with a significantly higher rate of MRD-negative complete remission for ponatinib compared with imatinib (34.4% vs 16.7%, respectively; P = .0021). The rate of MRD negativity at the end of induction was also twice as high with ponatinib (41.6%) vs imatinib (20.5%).

Although survival data were not mature, there was a trend toward improvement in event-free survival with ponatinib. The median event-free survival had not yet been reached in the ponatinib arm at data cutoff compared with 29 months for patients randomly assigned to receive imatinib, Dr. Jabbour reported. More patients assigned to the imatinib arm received a subsequent second- or third-generation tyrosine kinase inhibitor with or without immunotherapy (37% vs 19%). The median progression-free survival was 20 months and 7.9 months, respectively.

Finally, the rate of treatment-emergent adverse events was comparable between the two treatment arms. Arterial occlusive events were infrequent and similar between the two groups. 

DISCLOSURE: Dr. Jabbour reported financial relationships with AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Astellas Pharma, Bristol Myers Squibb, Genentech, Incyte, Pfizer, and Takeda. 

REFERENCES

1. Jabbour E, Kantarjian H, Aldoss I, et al: First report of PhALLCON: A phase 3 study comparing ponatinib vs imatinib in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. ASCO Plenary Series: February 2023 Session. Abstract 398868. Presented February 15, 2023.

2. Pfeifer H, Raum K, Markovic S, et al: Genomic CDKN2A/2B deletions in adult Ph⁺ ALL are adverse despite allogeneic stem cell transplantation. Blood 131:1464-1475, 2018.

3. Ribera JM, García O, Fernández-Abellán P, et al: Lack of negative impact of Philadelphia chromosome in older patients with acute lymphoblastic leukaemia in the tyrosine kinase inhibitor era: Comparison of two prospective parallel protocols. Br J Haematol 159:485-488, 2012.

4. Jabbour E, Short NJ, Ravandi F, et al: Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome–positive acute lymphoblastic leukaemia: Long-term follow-up of a single-centre, phase 2 study. Lancet Haematol 5:e618-e627, 2018.

5. Martinelli G, Papayannidis C, Piciocchi A, et al: INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph⁺ acute lymphoblastic leukemia. Blood Adv 6:1742-1753, 2022.