ABL1 T315I

The introduction of imatinib established proof of principle for oncogene-targeted therapy, leading to sustained survival improvements...More recently, the development of the allosteric inhibitor asciminib introduced a novel mechanism of action and expanded therapeutic options for pretreated patients...Thus, CML represents a unique model of translational oncology, demonstrating how mechanistic insight can drive therapeutic innovation. Future strategies will focus on increasing TFR rates, overcoming resistance, targeting leukemic stem cells, and improving global access to therapy and monitoring, with the ultimate aim of achieving functional cure in the majority of patients.

The ADAPT 2.0 survey highlights potential areas of improvement in current CML-CP management in the UK.

P1/2, N=50, Not yet recruiting, Friedrich-Schiller-Universitaet Jena

Blinatumomab achieved high short-term MRD response rates in high-risk B-ALL. Inferior outcomes appeared to be associated with the presence of BCR::ABL1 T315I mutations and E2A::PBX1 rearrangements.

P1, N=30, Recruiting, City of Hope Medical Center | Not yet recruiting --> Recruiting

P=N/A, N=37, Completed, Novartis Pharmaceuticals

The patient had a history of CML treated with imatinib for 4 years, with loss of complete hematological response for 3 months before being diagnosed with RCC and lung metastases. Due to a T315I mutation in the BCR-ABL1 gene, the treatment regimen included a novel combination of Axitinib, Dasatinib, and low-dose nivolumab. The patient showed a remarkable therapeutic response with a complete metabolic response accompanied by a highly significant reduction in the size of the tumor and complete resolution of the metastatic lung lesions, as well as a major molecular response in terms of CML disease control.

P1/2, N=50, Not yet recruiting, Novartis Pharmaceuticals | Trial completion date: Dec 2035 --> Jun 2036 | Trial primary completion date: Jan 2033 --> Jul 2033

P1/2, N=50, Not yet recruiting, Novartis Pharmaceuticals | Initiation date: Mar 2026 --> Jul 2026

BCR::ABL1 e6a3 demonstrated enhanced sensitivity to active-state selective inhibitors dasatinib and bosutinib, whereas BCR::ABL1 e6a3/T315I remained resistant. These data show that treatment with asciminib and ponatinib can select for mutations with notably elevated enzymatic activity, effectively targeted by an axitinib-based triple combination. These data highlight the remarkable mutability of the BCR::ABL1 kinase, including through novel isoforms and provides a strong rationale for the clinical assessment of a triple inhibitor combination as a strategy to overcome resistance to dual ponatinib and asciminib therapy.

P1/2, N=14, Not yet recruiting, Novartis Pharma AG

Its greatest clinical value appears to lie in rational combination regimens, maintenance strategies, and bridging to definitive therapies rather than single-agent salvage. Emerging structural biomarkers and ongoing clinical trials are expected to further refine patient selection, sequencing, and optimal integration of asciminib, particularly in CNS-involved disease and post-CAR-T cell relapse.