ABL1 T315I

P=N/A, N=1480, Completed, Novartis Pharmaceuticals

The detection of ASXL1 variants correlated strongly with the presence of ABL1 mutations (P = 3.51E-04). These methodologies are directly applicable to all assays used for the diagnosis, prognosis, and monitoring of CML and have important implications in bringing state-of-the-art genetic analysis to CML patients in LMICs.

Asciminib has shown efficacy in heavily pretreated patients and in the first-line setting, but resistance and limited benefit after ponatinib highlight the need for new therapeutic options...TGRX-678 exhibits potent activity against wild-type and mutant ABL1, including T315I, synergism with orthosteric tyrosine kinase inhibitors (TKIs), central nervous system (CNS) penetration, and encouraging phase Ia/Ib clinical activity in heavily pretreated CML. Early but promising data are also emerging for TERN-701 from the CARDINAL trial...Key questions regarding durability, long-term safety, and optimal integration with ATP-competitive TKIs remain open. Ongoing trials will define the clinical role of these STAMPi and their potential to advance cure-directed strategies, including treatment-free remission.

Individualized dosing strategies are essential to balance efficacy and cardiovascular safety. Ponatinib remains a valuable bridging therapy for patients requiring allogeneic transplantation.

Low-dose dasatinib is effective and tolerable in imatinib-resistant CML-CP, with nearly two-thirds achieving DMRs. Predictive biomarkers (T315I mutation, high ELTS risk, high baseline BCR-ABL1) can guide dose optimization.

SiRNA-mediated FN1 knockdown reduced the cell's susceptibility to all generations of TKIs employed in treatment of CML, including asciminib...Clinically, deregulation of FN1 was also observed in peripheral blood cells derived from CML patients. Our data indicate that FN1 may serve as a potential therapeutic target to address TKI resistance or as a suitable biomarker for the treatment.

Our findings indicate that CAPE could serve as an adjunctive therapy for CML against drug resistance caused by the T315I mutation through a mechanism that does not directly inhibit BCR-ABL1. This study underscores the promise of targeting mitochondrial metabolism as a novel approach for overcoming therapeutic resistance in CML.

A personalized approach that takes into account the BCR::ABL1mutation profile is key to optimizing therapeutic strategies for CML. Further research is needed to more clearly define the mechanisms of resistance and the optimal sequence of use of available TKIs in clinical practice.

Our findings support the recommendation for BCR::ABL1 mutation screening in CML patients with an inadequate initial response or evidence of loss of response. Screening is also advised at progression to the accelerated or blast phase, and in patients with high-risk ELTS scores, and mutation profiles may serve as important prognostic indicators.

One of the mutations that is still an on-going challenge in clinical and scientific field is the T315I mutation, since it gives patients a poor prognosis attributable to acquired resistance to therapy. In the following narrative review, we will discuss the current knowledge on the T315I mutation, explore the most suitable treatment options, examine the role of third-generation tyrosine kinase inhibitors, and outline potential future therapeutic strategies.

P1, N=242, Recruiting, Ascentage Pharma Group Inc. | N=62 --> 242 | Trial completion date: Jan 2024 --> Mar 2030 | Trial primary completion date: Jan 2024 --> Dec 2029

The proportions of the patients with white blood cell count [14.1 (4.3, 48.9)×10⁹/L vs 50.1 (11.5, 149.0)×10⁹/L], serum lactate dehydrogenase level [510 (297, 930) vs 900 (535, 1 898) U/L], and treatment with imatinib following blast phase [8.4% (9/107) vs 20.5% (7/34)] were all lower than those in the monotherapy group (all P<0.05)...While patients receiving TKI combination therapy demonstrate higher rates of MMR, their overall survival remains poorer. Isolated extramedullary acute myeloid blast phase, and the achievement of MHR and/or DMR through treatment are beneficial for the survival of patients with CML-MBP.