ABL1 T315I

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.

There were acceptable treatment-related adverse events. We conclude olverembatinib is effective and tolerable in subjects in accelerated phase CML failing prior TKI therapy.

Combination therapies with ponatinib or other agents, as well as newer TKIs like olverembatinib, have demonstrated potential in overcoming resistance in preclinical and clinical models. Understanding these diverse resistance mechanisms is critical for optimizing asciminib-based treatment strategies and guiding the development of effective combination therapies for patients with resistant CML.

This study introduces a microfluidic cell culture array for the comparative analysis of six BCR::ABL1 TKIs, namely imatinib, nilotinib, bosutinib, ponatinib, dasatinib, and asciminib, using CML-related cell lines. We further validated the device with a CML patient-derived bone marrow sample, requiring only minimal adjustments to the experimental conditions. The proposed microfluidic single-cell-based screening array could refine treatment regimens and advance personalized medicine in CML.