Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is a type of blood cancer caused by a genetic alteration that forms the abnormal Philadelphia chromosome. This chromosome results from a fusion of the BCR and ABL1 genes, creating the BCR-ABL1 protein, which drives excessive production of immature white blood cells (lymphoblasts) in the bone marrow, leading to leukemia. Tyrosine kinases are enzymes that are a part of many cell functions including cell signaling, growth, and division. These enzymes may become too active in patients 

ICLUSIG (ponatinib) is approved for use in newly diagnosed Ph+ ALL in combination with chemotherapy, and as monotherapy in patients who are T315I-positive or unable to tolerate other TKIs. 

At the 2025 EHA Congress, data revealed that 56% of patients treated with ponatinib did not reach MRD (minimal residual disease) negativity after induction therapy (86 out of 154), compared to 69% in the imatinib group (54 out of 78). Of those who remained MRD-positive, 73 patients in the ponatinib arm and 40 in the imatinib arm continued treatment. By the end of treatment, 48% of these ponatinib-treated patients (35/73) achieved MRD negativity, compared to 33% (13/40) in the imatinib arm.

For MR4 MRD negativity, the ponatinib group showed increasing rates over time—38% by the end of cycle 9, 41% by cycle 20, and 48% at treatment completion. In contrast, the imatinib group had lower rates: 28%, 30%, and 33% at the same time points. Similarly, MR4.5 MRD negativity was achieved in 23%, 32%, and 37% of patients receiving ponatinib across these intervals, whereas imatinib patients showed much lower rates—5%, 8%, and 10%, respectively. Furthermore, only 29% of MRD-negative ponatinib patients went on to receive stem cell transplants, compared to 46% of those in the imatinib group. 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 for imatinib. The 2-year EFS rates were 87% and 62% , respectively. In patients who reached MRD negativity after induction and by the end of treatment, the median EFS was NR for ponatinib vs. NR for imatinib. The median PFS for patients who were MRD positive after induction was 8.5 months in the ponatinib arm vs. 7.3 months in the imatinib arm. The respective 2-year PFS rates were 36% and 13%.

Ponatinib produced a median PFS that was NR vs. 16.0 months for imatinib in those who achieved MRD negativity after induction and by the end of treatment. Patients who were MRD positive after induction in the ponatinib arm achieved a median OS that was NR (NR-NR) vs. NR (25.9-NR) for those given imatinib. The 2-year OS rates were 91% and 87%, respectively. The median OS was NR (NR-NR) for ponatinib and NR (25.9-NR) for imatinib among patients who achieved MRD negativity after induction and before the end of treatment.

In patients not achieving MRD negativity, TEAEs occurred in nearly all patients in both arms (100% ponatinib vs. 98% imatinib), with similar rates of Grade ≥3 TEAEs (91% vs. 94%). Ponatinib led to more dose interruptions (66% vs. 41%) and discontinuations (15% vs. 9%), while imatinib had more dose reductions (28% vs. 16%). TE-AOEs were slightly higher with ponatinib (3% any grade, 2% Grade ≥3) vs. imatinib (2% any grade, 0% Grade ≥3), with minimal impact on treatment continuity.

KOL insights

“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. This post hoc analysis should be interpreted with caution “due to the small number of patients and the potential for selection bias.” – Expert Opinion

Conclusion

In 2024, the American Cancer Society projects approximately 6,550 new cases of ALL in the United States, with 3,590 cases expected in males and 2,960 cases in females. About 25% of adults with ALL have a subtype called “Ph-positive ALL.” TKIs are typically not used as standalone treatments for ALL; they are most effective when combined with other therapies, such as combination chemotherapy regimens. Commonly used TKIs in the treatment of Ph+ ALL include GLEEVEC (imatinib), SPRYCEL (dasatinib), ICLUSIG (ponatinib), BOSULIF (bosutinib), and TASIGNA (nilotinib).

Using attenuated chemotherapy alongside TKIs allows patients to maintain a better quality of life and arrive at transplantation in relatively good condition. However, transplantation still carries inherent risks, with transplant-related mortality in 10% to 15% of cases and notable morbidity. In contrast, newer non-chemotherapy approaches—such as third-generation TKIs or immunotherapy—offer improved tolerability and quality of life, often eliminating the need for transplantation altogether. Notably, these modern therapies are suitable for a broader patient population. Currently, clinical trials are incorporating third-generation TKIs and immunotherapy, leading to a significant shift in the treatment landscape. These approaches are producing remarkable responses, including strong and deep MRD negativity. As a result, the role of transplantation in these trials has become limited. 

In March 2024, the FDA granted accelerated approval to ponatinib a third generation TKI, marking it as the first targeted therapy approved in the US for newly diagnosed Ph+ ALL. What sets ponatinib apart is its unique ability to inhibit the T315I mutation in the BCR-ABL kinase—a mutation known to cause resistance to other TKIs. While agents like imatinib, dasatinib, nilotinib, and bosutinib are effective against the native BCR-ABL and several of its variants, they lack activity against T315I, a mutation that commonly emerges during treatment and contributes to therapeutic failure.