imatinib

In this updated exploratory analysis from INTRIGUE, OS was longer for ripretinib vs sunitinib for pts with KIT exon 11 + 17/18 mutations identified by baseline ctDNA. The safety profile was consistent and more favorable for ripretinib vs sunitinib in these pts. Previously presented at the 2024 ESMO Sarcoma and Rare Cancers Congress.

Meanwhile, MBZ directly targeted the colchicine-binding site of β-tubulin protein, hampered microtubule polymerization and induced mitosis arrest and mitotic catastrophe. This work discovered that anthelmintic MBZ exerts remarkable anticancer effects in both imatinib-sensitive and imatinib-resistant CML cells in vitro and revealed mechanisms underlying. From the perspective of drug repositioning and multi-target therapeutic strategy, this study provides a promising option for CML treatment, especially in TKI-resistant or intolerant individuals.

We validated the expression levels of these four genes using clinical samples and confirmed through cell experiments that targeted inhibition of IGFBP2 effectively suppressed proliferation of resistant CML cells, promoted apoptosis, and enhanced therapeutic sensitivity to imatinib...The identification of molecular subtypes provides valuable insights into assessing individual patients' biological characteristics for guiding clinical treatment decisions. Additionally, IGFBP2 has emerged as a promising therapeutic target for therapy-resistant cases of CML.

In conclusion, this study provides a novel, real-world reference for survival outcomes in patients with metastatic GIST.

Additionally, overexpression of LPAR1 restrained the biological function of miR-429 on imatinib chemoresistance. MiR-429 partly sensitized glioma cells to imatinib via downregulation LPAR1, which might provide an approach to overcome imatinib chemoresistance during glioma treatment.

P=N/A, N=61, Completed, CStone Pharmaceuticals | Active, not recruiting --> Completed | Trial completion date: Oct 2025 --> Sep 2024 | Trial primary completion date: May 2025 --> Sep 2024

P3, N=182, Not yet recruiting, Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

Univariate and multivariate analyses showed heightened ARG1 levels and a transition from PD1/PDL1 dominance at 3 months to TIM3/GAL9 at 12 months in non-optimal responders (BCR::ABL1 ≥ 0.1%). Our longitudinal design offers a deeper exploration of immune gene expression dynamics in CML patients on imatinib, highlighting its potential implications for therapy outcomes.

Samples derived from cases from both the experimental and the control arm, based respectively on ponatinib followed by blinatumomab and on a combination of imatinib and conventional chemotherapy. While some groups reported a higher predictive prognostic power of IG/TR monitoring, our findings do not confirm these data, also in view of the very low rate of relapses so far observed. Nevertheless, a double-hit strategy may be informative for MRD monitoring and possibly for the distinction between typical/lymphoid Ph+ ALL vs multilineage/CML-like Ph+ ALL.

Their conjugation with the drugs Irinotecan, Imatinib, and Methotrexate was also confirmed using UV-Vis, FTIR, and Dynamic light scattering (DLS). The result of the methylthiazol tetrazolium (MTT) assay showed that conjugated AgNPs and AuNPs with Irinotecan had a higher toxic effect on the A549 cancer cell line than AgNPs and AuNPs conjugated with Imatinib. This study provides a promising avenue for further investigation and development of nanoparticle-drug conjugates as a potential cancer immunotherapy strategy.

In addition to BCR-ABLIS level, HT of BCR-ABLIS can be used as another important predictor of treatment efficacy in CML patients. The combination of BCR-ABLIS level and HT has a more accurate predictive value for long-term molecular response of CML patients after TKI treatment.

He was found to be positive for BCR-ABL by reverse transcription polymerase chain reaction (RT-PCR), thus confirming the diagnosis of CML. He received imatinib 400 mg/day and subsequently experienced resolution of symptoms and complete hematological response by the 12th week of therapy.

For example, imatinib acts by targeting cell surface receptors, and these inhibitors have shown potential for the control and treatment of tumor growth, angiogenesis, and metastasis. Imatinib, for example acts by targeting cell surface receptors, and these inhibitors have shown the future direction toward the control and treatment of tumor growth, angiogenesis, and metastasis.

Management included observation in 6 (46.3%), hydroxyurea in 3 (23.1%), imatinib in 3 (23.1%) and Interferon-α (IFN-α) in 1 (7.7%) patients. Effective management of newly diagnosed CML-CP during pregnancy is contingent on the trimester of presentation. Further research and collaboration are warranted to develop standardised guidelines for managing pregnancy-associated CML, particularly in LMICs.

Our findings reveal a significantly higher proportion of Tregs and PD-1 + CD8 T-cells in patients with CML-CP compared to healthy controls, notably diminished following imatinib treatment. These observations suggest the potential for immunotherapy as a promising approach to managing immune exhaustion in CML patients.

Thirty five (92%) patients were treated with imatinib at diagnosis...On multivariate analysis, none of these factors were found to be significant. This retrospective study suggests that for CML CP patients achieving deep molecular response, discontinuing TKI therapy in real-world settings may be feasible while potentially achieving comparable outcomes.

P3, N=173, Recruiting, Il-Yang Pharm. Co., Ltd. | Trial completion date: Apr 2025 --> Dec 2027 | Trial primary completion date: Jan 2025 --> Jun 2026

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).

We report the case of a 63-year-old woman with a history of CML with poor response to imatinib who progressed to myeloid BP-CML, driven by the acquisition of t(8;21)(q22;q22)/RUNX1::RUNX1T1. The patient received intensive chemotherapy and dasatinib, followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT)...Ponatinib and azacitidine were started as salvage treatment, allowing for the achievement of complete remission with deep molecular response after five cycles. Advances in the knowledge of disease biology and clonal evolution are crucial for optimal treatment selection, which ultimately translates into better patient outcomes.

We also found that NK-128 inhibits colony formation by CD34+ CML cells isolated from the bone marrow of untreated CML patients. Taken together, these findings suggest that targeting OXPHOS is a beneficial approach to eliminating CML-LSCs, and may improve the treatment of CML.

Then we detected 6 repurposable drug molecules (Entrectinib, Imatinib, Ponatinib, Sorafenib, Retevmo, and Pazopanib) by molecular docking with KGs-mediated receptor proteins, ADME/T analysis, and cross-validation with the independent receptors. Therefore, these findings might be useful resources for wet lab researchers and clinicians to consider an effective treatment strategy against THCA.

The results showed lower expression of HOTAIR and PTGS2 in CML patients. The HOTAIR expression is inversely associated with BCR::ABL1 expression in imatinib-treated CML patients, and to PTGS2 showing that CML patients with high BCR::ABL1 expression showed reduced PTGS2 expression.

In 3 cases, this increase reflected the occurrence or worsening of imatinib side effects. This case-series highlights the clinical impact of SARS-CoV-2 infection on the management of patients with GIST treated with imatinib.

Despite the significant improvement in treatment outcomes with adjuvant imatinib therapy for patients, drug resistance remains a major challenge for GIST therapy...The OXPHOS pathway is a promising therapeutic target in combination with TKI against sensitive KIT/PDGFRA mutants. Comprehensive understanding of the above resistance mechanisms, experimental drugs/strategies and metabolic changes is critical to implement the proper therapy strategy and improve the clinical therapy outcomes for GIST.

This case underscores the necessity of total gastrectomy with lymph node dissection due to the high incidence of metastasis in GISTs associated with Carney's triad. Further research is required to determine the optimal extent of lymph node dissection in such cases.

Overall, our findings indicate the prevalence and impact of new ABL1 KD mutations in BCR::ABL1-positive ALL patients, highlighting the necessity for effective therapies targetingthese mutations.

The study concluded that dasatinib treatment improved response in CML patients with decreased Treg cells. Dasatinib reduces Treg-mediated immunological suppression, reducing CTLA-4 and TGF-β1 levels.

P1, N=157, Not yet recruiting, Kura Oncology, Inc.

The BDP conferred almost complete resistance to cell death induced by imatinib in CML stem and progenitor cells (LSPCs). Using BH3 profiling, we identified a novel therapeutic vulnerability of BDP LSPCs to MCL-1 antagonists, which we confirmed in primary human LSPCs, and in vivo. Our findings demonstrate the impact of human polymorphisms on the survival of LSPCs and highlight their potential as companion diagnostics for tailored therapies.

P=N/A, N=787, Enrolling by invitation, Poitiers University Hospital

These findings demonstrate the role of BCAA/BCAT1 signaling in cancer development and suggest that targeting BCAA/BCAT1 signaling is a potential strategy for interfering with TKI-resistant CML.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm (MPN characterized by reciprocal translocation in the ABL1 and BCR region of chromosomes 9 and 22 respectively. We report a case of CML who presented to us with acute ischemic stroke and subsequently was diagnosed as CML transformed to the promyelocytic blast phase. She was successfully treated with dasatinib along with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO).

55% (42/77) of liquid samples with a KIT -driver mutation had a co-occurring imatinib-resistant alteration, and a minority of cases harbored non- KIT mechanisms of resistance such as FGFR2 fusion, BRAF or EGFR alterations... Known driver and TKI-resistant mutations are identified in liquid biopsies of patients with GIST, with high concordance to tissue in the presence of elevated TF. Liquid biopsy may be valuable in the molecular classification of GIST during the medical management of advanced disease.

In this updated exploratory analysis from INTRIGUE, OS was longer for ripretinib vs sunitinib for pts with KIT exon 11 + 17/18 mutations identified by baseline ctDNA. The safety profile was favorable for pts with KIT exon 11 + 17/18 mutations in the ripretinib arm.

Analysis of annexin V labelling demonstrated that combination of IMA with betulinic acid enhances the inhibition on cell proliferation via apoptosis pathway, with caspases 3/7 activation after 24 hours of treatment, and inhibition of the STAT5/Survivin pathway, decreasing cell viability. The combination of natural products and IMA on a multidrug-resistant leukemia cell line is a promising strategy for CML treatment.

The patient was treated with pegylated interferon and imatinib, which resulted in stable disease after three months...Analysis of ligand-receptor interactions showed significant communication between neoplastic cells and macrophages mediated by CSF1 and CSF1R. Our findings emphasize the importance of comprehensive molecular analysis in diagnosing and treating rare malignancies like TGCT.

Interestingly, the other prominent TKIs Nilotinib and Imatinib did not exert similar effects on muscle cell physiology. Collectively, we identified an unanticipated transcriptional mechanism underlying Sorafenib-induced cachexia. Our findings hold the potential to strategize therapy regimens to minimize chemotherapy-induced cachexia.

This literature review, along with clinical expertise and opinion, was used to develop this concise and clinically relevant consensus paper to harmonize the knowledge and clinical practice on GIST management across Canada. The content presented here will help guide healthcare providers, especially in Canada, in terms of approaching and managing GIST.

P3; Initiation date: Jul 2024 --> Feb 2025

In this longitudinal study, we analyzed the capacity of ponatinib to induce an antiviral response against HIV-1 infection in peripheral blood mononuclear cells (PBMCs) obtained from people with CML previously treated with imatinib for a median of 10 years who changed to ponatinib for 12 months to boost the anticancer response before discontinuing any TKI as part of the clinical trial NCT04043676. This cytotoxic immunity was mostly based on higher levels of Natural Killer and Tγδ cells seemingly boosted by ponatinib. In conclusion, transient treatment with immunomodulators like ponatinib along with ART could be explored to boost the antiviral activity of cytotoxic cells and contribute to the elimination of HIV-1 reservoir.

As tyrosine kinases serve pivotal roles in platelet hemostatic function, we investigated the potential impact of both established and emerging ABL TKIs on human platelet activities ex vivo Our study included standard-of-care agents (e.g., imatinib and nilotinib), and second-generation ABL inhibitors including ponatinib and bosutinib designed to mitigate drug resistance. Significance Statement This study examines the effects of clinically relevant small molecule BCR-ABL tyrosine kinase inhibitors (TKIs) on platelet activity. This analysis includes first-time assessments of agents such as asciminib and ELVN-919 on human platelet function ex vivo, alongside established therapies (e.g., imatinib, ponatinib) with well-characterized effects on platelet function, to discern potential anti-platelet and other effects of BCR-ABL TKIs and inform clinical safety.

P=N/A, N=168, Completed, First Affiliated Hospital, Sun Yat-Sen University