BCR-ABL1 T315I

P1/2, N=11, Terminated, Takeda | Completed --> Terminated; Phase 1 enrollment was terminated due to dose-limiting toxicities, thus the study was terminated by Sponsor.

The primary treatment for chronic myeloid leukemia (CML) involves first- and second-generation tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, bosutinib, and dasatinib. It includes in silico calculations, such as the octanol/water partition coefficient (cLogP) via SwissAdme, and 2D maps of intermolecular interactions through molecular docking. This approach enhances understanding for both specialists and those interested in medicinal chemistry and pharmacology, while also contextualizing future directions for further optimizations of ponatinib, facilitating the development of new analogs of this crucial inhibitor for the treatment of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

Five (10.4%) patients experienced AEs leading to discontinuation, including 2 who discontinued asciminib and died due to COVID-19; these were the only deaths reported. These results show asciminib's effectiveness, including in almost 50% of ponatinib pretreated patients, and confirm its risk-benefit profile, supporting its use as a treatment option for T315I-mutated CML-CP.

We identified six genes that were consistently upregulated in the fly CML model and validated in adult and pediatric CML patients and in a mouse cell line expressing BCR::ABL1T315I. This study provides a comprehensive analysis of gene signatures in BCR::ABL1p210 and BCR::ABL1T315I, laying the groundwork for targeted investigations into the role of these genes in CML pathogenesis.

P1/2, N=68, Active, not recruiting, Takeda | Trial completion date: Aug 2027 --> Jan 2027 | Recruiting --> Active, not recruiting

2% at week 24) and a favorable safety profile compared with bosutinib 500 mg once daily (qd) in adult patients with Ph+ CML-CP in the phase 3 ASCEMBL study (NCT03106779). The study is still recruiting. This study will determine a pediatric dose for asciminib and support a strategy of full extrapolation from adult data to use in the pediatric patients with CML-CP.

Furthermore, regarding AOE, no expression levels exceeding the results of the clinical trial were confirmed. However, patients with advanced age and who have predisposing factors for AOEs should be closely monitored for possible adverse vascular events.

Background: In patients (pts) with CML, the BCR::ABL1 T315I gatekeeper mutation confers treatment resistance to all approved ATP-competitive tyrosine kinase inhibitors (TKIs) except ponatinib and olverembatinib; thus pts harboring this mutation have limited treatment options. Asciminib demonstrated effectiveness in pts with CML and the T315I mutation in routine medical practice, including ponatinib pre-treated pts, a population with limited available treatment options. Effectiveness estimates were consistent with those observed in clinical trials. Although the number of pts was small, this global study reports on one of the largest cohorts of pts with CML and the T315I mutation.

Introduction This was a multicenter, randomized, registrational phase 2 study to assess the efficacy and safety of olverembatinib compared with BAT in pts with CML-CP who were resistant and/or intolerant to 3 TKIs (imatinib [I], dasatinib [D], nilotinib [N]) in China...Pts were randomized 2:1 to investigational olverembatinib (40 mg QOD) or the BAT arm, which could be one of the following per investigator choice: TKIs (I, D, or N), interferon (IFN), hydroxyurea (HU), and homoharringtonine (HHT)...Olverembatinib was observed to be better tolerated and more effective than BAT in treating these pts. Internal study (CT.gov) numbers: HQP1351CC203 (NCT04126681).

ABL1 is subject to auto-inhibition mediated by myristoylation-triggered conformational change, which can be exploited to overcome resistance, as validated by allosteric inhibitors such as GNF2, GNF5 and asciminib. Furthermore, TGRX-678 and ponatinib synergize to overcome the clinically challenging resistance conferred by T315M or T315I-inclusive compound mutations. This data warrant further clinical investigation of TGRX-678 for the treatment of resistant or refractory CML patients.