Both primary patient and Ba/F3 cells carrying TPR::ABL2 exhibited kinase activation and sensitivity to tyrosine kinase inhibitors (TKIs). This study expands the repertoire of ABL2 fusions identified in ALL and supports the incorporation of TKIs into T-ALL treatment regimens to improve outcomes for this subtype.

For resistance, assessment of BCR::ABL1 mutations is essential, and second-line agents should be chosen according to the initial TKI and mutation sensitivity. This article summarizes the criteria and timing for switching to second-line therapy and key considerations for selecting and managing second-line TKIs, and briefly reviews the evidence for asciminib and ponatinib in second-line and later settings.

The effectiveness of asciminib, combined with its capacity to overcome resistance through combination strategies with adenosine triphosphate-binding site tyrosine kinase inhibitors, establishes it as a focal point in emerging chronic myeloid leukemia treatment approaches. It remains essential to continue research and clinical trials to enhance the therapeutic efficacy of asciminib and manage its associated side effects.

A model-informed drug development (MIDD) approach was applied to predict 2L efficacy and supported global regulatory approval of asciminib across treatment lines, despite limited clinical data in 2L.

P1/2, N=50, Not yet recruiting, Novartis Pharmaceuticals

P4, N=200, Recruiting, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; Union Hospital, Tongji Medical College, Huazhong University o

P=N/A, N=200, Not yet recruiting, Novartis Pharmaceuticals

P2, N=50, Not yet recruiting, Novartis Pharmaceuticals

Overall, our findings showed that an adjustment of the initial asciminib dose may be needed based on genotyping information for the NR1I2 -25385C > T polymorphism and the body weight of the patient; however, further prospective studies are necessary.

P2, N=55, Enrolling by invitation, SWOG Cancer Research Network | Not yet recruiting --> Enrolling by invitation

Particular attention is paid to how STAMP inhibition differs from ATP-competitive TKIs in terms of selectivity, toxicity profile, and resistance patterns, and how asciminib can be positioned relative to ponatinib in later-line settings.Asciminib has established itself as an effective and generally well-tolerated option for patients with TKI-resistant or -intolerant CML and is poised to expand into earlier lines of therapy. Its ability to induce rapid and deep molecular responses with reduced off-target toxicity may have important implications for long-term disease control and future treatment-free remission (TFR) strategies. Ongoing studies will clarify its optimal sequencing, combination potential, and role in facilitating durable TFR.