Iclusig (ponatinib)

ISR activation and RIPK3-mediated necroptosis converge to drive epithelial injury and barrier dysfunction in CD. Repurposing pazopanib and ponatinib offers a potentially translatable approach to restore barrier integrity in CD.

P1/2, N=67, Completed, Fondazione Gimema Franco Mandelli Onlus | Active, not recruiting --> Completed

P1, N=56, Recruiting, Sun Pharmaceutical Industries Limited | Not yet recruiting --> Recruiting

P2, N=25, Recruiting, University of Chicago | Suspended --> Recruiting | Trial completion date: Mar 2027 --> Mar 2028 | Trial primary completion date: Mar 2027 --> Mar 2028

P2, N=20, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Nov 2026 --> Jun 2026 | Trial primary completion date: Nov 2026 --> Jun 2026

P1/2, N=30, Not yet recruiting, Grupo Espanol De Leucemia Mieloide Cronica (GELMC)

P1, N=26, Not yet recruiting, Wake Forest University Health Sciences

In patients experiencing failure of frontline therapy due to resistance or intolerance, multiple second- and third-line options are available, including second-generation TKIs, ponatinib, and asciminib, as well as novel investigational agents, including the ABL1 kinase domain inhibitors olverembatinib and ELVN-001 and the STAMP inhibitors TGRX-678 and TERN-701. In this review, we discuss the recent advances in the treatment of CML-CP and challenge some established management practices.

In contrast, imatinib showed no overlap with these 81 genes under the same cross-dataset analysis framework. Cardiotoxicity-relevant functions were represented by directionally consistent genes linked to cardiac repolarization-associated ion handling (KCNN3), insulin-responsive metabolic regulation (FOXO1, HK2), cyclic adenosine monophosphate (cAMP)-responsive stress signaling (RAPGEF3), and mitochondrial homeostasis and redox regulation (MCL1, GCH1). Collectively, these results define a ponatinib-associated transcriptomic signature and nominate cross-dataset transcript-level candidates for subsequent mechanistic and experimental validation in ponatinib-associated cardiotoxicity.

These findings identify inflammation-induced pyroptosis as a central driver of the pathological changes in PON-induced cardiotoxicity. Notably, our work highlights BMP-7's capacity to inhibit these disease-related alterations. Collectively, these results expand on the current knowledge of the mechanistic framework of PON-induced cardiotoxicity, while also emphasizing BMP-7 as a promising therapeutic candidate with potential translational relevance.

Second-generation and third-generation TKIs further improved outcomes by targeting most imatinib-resistant mutations, with ponatinib-based regimens achieving deep molecular responses and long-term survival in most patients. Concurrently, immunotherapies like blinatumomab and CAR-T cells have enabled potent chemotherapy-free strategies, yielding high molecular response rates and challenging the necessity of allo-HSCT for all patients. Current evidence supports reserving allo-HSCT for high-risk patients, while those with sustained minimal residual disease (MRD) negativity may be cured with TKI and immunotherapy alone. Future progress hinges on optimizing combinations, integrating novel agents like asciminib and venetoclax, and leveraging MRD and genomic profiling for precision medicine.

There was no evidence of systemic toxicity or organ dysfunction after treatment. These findings demonstrated that PEG-pRAPA is an effective polymeric drug and drug delivery platform and support the hypothesis that nanoparticle-based pharmacotherapy can be an effective treatment strategy for VMs.