ABL1 T315I

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.

P4, N=85, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed | Trial completion date: Nov 2026 --> Mar 2026 | Trial primary completion date: Nov 2026 --> Mar 2026

We investigated the cytotoxic effects of ASC, alone or with imatinib (IM) or nilotinib (NIL), on committed progenitors and LSCs from CML patients expressing high or low BCR::ABL1 at diagnosis. When combined with IM or NIL, ASC restored TKI activity against LTC-ICs expressing high BCR::ABL1 transcripts, with the association of ASC and NIL reducing both LTC-IC division rates and LTC-IC-derived CFUs. These findings suggest that ASC, alone or with NIL, may target LSCs and improve outcomes in patients with high BCR::ABL1 expression at diagnosis.

P1, N=250, Recruiting, Enliven Therapeutics | Trial completion date: Dec 2026 --> Dec 2027 | Trial primary completion date: Dec 2026 --> Dec 2027

P3, N=348, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

The introduction of imatinib in the early 2000s revolutionized CML treatment, transforming a fatal disease into a chronic condition with near-normal life expectancy for most patients...Emerging therapies such as vamotinib, KF1601, and combination regimens are being explored. Furthermore, new insights into non-kinase functions of BCR::ABL1 and the role of microRNAs in resistance open additional therapeutic avenues. This review provides a concise overview of CML from a historical and molecular perspective, highlighting diagnostic advances, evolving response criteria, and future directions in treatment.

TFR patients exhibited distinct enrichment in complement and coagulation cascades (C3, C4B, F9, F11) and metabolic pathways. Plasma EV proteomes reflect CML clinical status, revealing immune and cytoskeletal alterations associated with treatment response, remission, and resistance, suggesting potential biomarkers for disease monitoring.