Ponatinib Shows Clinical Benefit Over Imatinib in MRD-Positive Ph+ ALL Post Induction

Ponatinib extended EFS and PFS in patients with newly diagnosed, Ph-positive acute lymphoblastic leukemia who did not achieve MRD negativity after induction.

Ponatinib (Iclusig) was associated with higher rates of deep molecular responses and improved survival in patients with newly diagnosed, Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL) who were positive for minimal residual disease (MRD) after induction and continued treatment beyond cycle 3, according to findings from a post hoc analysis of the phase 3 PhALLCON trial (NCT03589326) shared at the 2025 EHA Congress.¹

Data showed that 56% of patients in the ponatinib arm did not achieve MRD negativity by the end of induction (n = 86/154) compared with 69% of patients in the imatinib (Gleevec) arm (n = 54/78). Seventy-three patients and 40 patients who were MRD-positive after induction continued treatment in the respective arms. MRD negativity was achieved at the end of treatment by 48% of patients in the ponatinib arm (n = 35/73) vs 33% for imatinib (n = 13/40).

In the ponatinib arm, MR4 MRD negativity was achieved by 38% of patients at the end of cycle 9, 41% of patients at the end of cycle 20, and 48% of patients at the end of treatment. These respective rates were 28%, 30%, and 33% in the imatinib arm. The rates of MR4.5 MRD negativity at these time points were 23%, 32%, and 37%, respectively, for ponatinib. These respective rates were 5%, 8%, and 10% for ponatinib.

Additionally, 29% of patients in the ponatinib arm who achieved MRD negativity after induction proceeded to hematopoietic stem cell transplant compared with 46% of patients in the imatinib arm.

“These results appear to support the clinical benefit and tolerability of continuing ponatinib beyond cycle 3 in patients with newly diagnosed, Ph-positive ALL who have not achieved MRD negativity by the end of induction,” lead study author Carlo Gambacorti-Passerini, MD, of the University of Milano-Bicocca in Monza, Italy, said in a presentation of the data. Gambacorti-Passerini did note that this post hoc analysis should be interpreted with caution “due to the small number of patients and the potential for selection bias.”

In March 2024, the FDA granted accelerated approval to ponatinib in combination with chemotherapy for the treatment of adult patients with newly diagnosed, Ph-positive ALL.² This regulatory decision was supported by prior data from PhALLCON, which showed that the MRD-negative complete remission (CR) rate was 30% at the end of induction for ponatinib vs 12% for imatinib (difference, 18%; 95% CI, 8%-28%; P =.0004).

PhALLCON Background

The global, randomized, open-label, multicenter trial enrolled adult patients with newly diagnosed, Ph-positive ALL or BCR::ABL1–positive ALL who had an ECOG performance status of 0 to 2 and did not have clinically significant or uncontrolled cardiovascular disease.¹

Patients were randomly assigned to receive ponatinib plus reduced-intensity chemotherapy or imatinib plus reduced-intensity chemotherapy. The starting dose was 30 mg once per day for ponatinib vs 600 mg per day for imatinib. Induction lasted for 3 cycles, where patients received the TKI plus vincristine and dexamethasone. In the 6 consolidation cycles, the TKI was administered with methotrexate and cytarabine, and in 11 maintenance cycles, the TKI was given with vincristine and prednisone. Single-agent ponatinib and imatinib were given at the end of maintenance.

The study’s primary end point was the MRD-negative CR rate at the end of induction. Event-free survival (EFS) was a key secondary end point, and others included molecular response rate, duration of MRD-negative CR, overall survival (OS), and safety.

Post Hoc Baseline Characteristics

Among patients who did not achieve MRD negativity at the end of induction, the median age was 53.5 years (range, 19-82) for the ponatinib arm vs 54.0 years (range, 19-75) in the imatinib arm. Most patients were female (ponatinib, 56%; imatinib, 54%), harbored a BCR::ABL1 p190 variant (66%; 65%), and did not have extramedullary disease (94%; 96%).

ECOG performance status in the ponatinib arm included 0 (49%), 1 (45%), and 2 (6%). These respective rates were 37%, 56%, and 7% in the imatinib arm. The median leukocyte count was 5.9 x 109/L (range, 0.4-197.3) in the ponatinib group vs 3.3 x 109/L (range, 0.2-81.2) in the imatinib group. Leukemic blast percentages at baseline were 82.0% (range, 0%-100%) and 75.0% (range, 0%-100%), respectively. Notably, prephase therapy was given to 44% of patients in the ponatinib arm vs 57% of patients in the imatinib arm.

Additional Post Hoc Findings

Among patients who did not achieve MRD negativity at the end of induction, the median EFS was not reached (NR; 95% CI, NR-NR) for ponatinib vs 24.8 months (95% CI, 21.3-NR) for imatinib (HR, 0.198; 95% CI, 0.075-0.527; P = .0004). The 2-year EFS rates were 87% (95% CI, 72%-94%) and 62% (95% CI, 36%-80%), respectively.

In patients who reached MRD negativity after induction and by the end of treatment, the median EFS was NR (95% CI, NR-NR) for ponatinib vs NR (95% CI, 21.3-NR) for imatinib (HR, 0.261; 95% CI, 0.034-2.008; P = .1709).

The median PFS for patients who were MRD positive after induction was 8.5 months (95% CI, 7.0-22.5) in the ponatinib arm vs 7.3 months (95% CI, 5.1-10.6) in the imatinib arm (HR, 0.569; 95% CI, 0.351-0.924; P = .0207). The respective 2-year PFS rates were 36% (95% CI, 24%-39%) and 13% (95% CI, 4%-28%).

Ponatinib produced a median PFS that was NR (95% CI, NR-NR) vs 16.0 months (95% CI, 8.3-NR) for imatinib in those who achieved MRD negativity after induction and by the end of treatment (HR, 0.257; 95% CI, 0.063-1.057; P = .0440).

Patients who were MRD positive after induction in the ponatinib arm achieved a median OS that was NR (95% CI, NR-NR) vs NR (95% CI, 25.9-NR) for those given imatinib (HR, 0.277; 95% CI, 0.073-1.053; P = .0468). The 2-year OS rates were 91% (95% CI, 78%-97%) and 87% (95% CI, 64%-96%), respectively.

The median OS was NR (95% CI, NR-NR) for ponatinib and NR (95% CI, 25.9-NR) for imatinib among patients who achieved MRD negativity after induction and before the end of treatment (HR, 0.354; 95% CI, 0.018-6.893; P = .4795).

Regarding safety in patients who did not achieve MRD negativity by the end of induction, treatment-emergent adverse effects (TEAEs) occurred in all patients in the ponatinib arm (n = 86) vs 98% of patients in the imatinib arm (n = 54). The rates of grade 3 or higher TEAEs were 91% and 94%, respectively. In the ponatinib arm, TEAEs led to dose interruptions in 66% of patients, dose reductions in 16% of patients, and treatment discontinuation in 15% of patients. These respective rates were 41%, 28%, and 9% for imatinib.

Treatment-emergent arterial occlusive effects (TE-AOEs) were reported at any grade in 3% of patients given ponatinib vs 2% treated with imatinib. The respective grade 3 or higher rates were 2% and 0%. TE-AOEs did not lead to any dose interruptions or reductions in either arm; 2% of patients in the ponatinib arm discontinued treatment due to TE-AOEs vs no patients in the imatinib arm.

References

1. Gambacorti-Passerini C, Jabbour E, Aldoss I, et al. Achievement of mrd negativity after end of induction with ponatinib and imatinib in the phase 3 PhALLCON trial: a post hoc analysis. Presented at: 2025 EHA Congress; June 12-15, 2025; Milan, Italy. Abstract S116.
2. FDA grants accelerated approval to ponatinib with chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. FDA. March 19, 2024. Accessed June 13, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-ponatinib-chemotherapy-newly-diagnosed-philadelphia-chromosome