Iclusig (ponatinib) / Takeda, Otsuka 
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  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka, Erivedge (vismodegib) / Roche, Tavalisse (fostamatinib) / Rigel
    Journal:  Computer-Aided Identification and Design of Ligands for Multi-Targeting Inhibition of a Molecular Acute Myeloid Leukemia Network. (Pubmed Central) -  Nov 15, 2024   
    Overall, by integrating network and structural pharmacology with molecular modeling, we determined two complementary strategies with the potential to annihilate the AML network, one in the form of repurposable drug combinations and the other as a de novo synthesized triple-targeting agent. These target-drug interactions could be prioritized for preclinical and clinical testing toward precision medicine for AML.
  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka, buparlisib (AN2025) / Adlai Nortye
    Journal:  Buparlisib and ponatinib inhibit aggressiveness of cholangiocarcinoma cells via suppression of IRS1-related pathway by targeting oxidative stress resistance. (Pubmed Central) -  Nov 13, 2024   
    Additionally, the drug combination significantly diminished the expression of YAP1, the cell proliferation marker and an antioxidant regulator, and increased oxidative stress-responsive markers in the xenograft model. In conclusion, targeting oxidative stress resistance with combined buparlisib and ponatinib suppressed tumor growth and migration by repressing IRS1-related pathways and ultimately inducing oxidative damage, suggesting the potential for targeted therapy and clinical trials in CCA patients over the use of a single drug.
  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka
    Journal:  APMCG-1 attenuates ischemic stroke injury by reducing oxidative stress and apoptosis and promoting angiogenesis via activating PI3K/AKT pathway. (Pubmed Central) -  Nov 13, 2024   
    This study investigated APMCG-1's remedial mechanisms against IS injury using an H2O2-induced oxidative stress paradigm in human umbilical vein endothelial cells (HUVECs) emulating ischemic endothelial cells, in a ponatinib-induced zebrafish IS model, and in rat middle cerebral artery occlusion (MCAO) prototypes...In cells and animal models, APMCG-1 activated the PI3K/AKT signaling pathway, modulating factors such as Nrf2, Bcl-2, Caspase 3, eNOS, and VEGFA, thereby ameliorating cellular oxidative distress and catalyzing angiogenesis. Collectively, these results demonstrate the potential protective effects of APMCG-1 in IS pharmacotherapy and its prospective utility as an herbal-derived IS treatment modality.
  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka, aspirin / Generic mfg.
    Journal:  Aspirin reduces Ponatinib-induced cardiovascular toxic phenotypes and death in zebrafish. (Pubmed Central) -  Nov 13, 2024   
    Collectively, these results demonstrate the potential protective effects of APMCG-1 in IS pharmacotherapy and its prospective utility as an herbal-derived IS treatment modality. Our findings suggest that Aspirin exhibits the potential to reduce Ponatinib-induced cardiovascular toxicity.
  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka
    Journal:  Anti-thrombotic effect of protoparaxotriol saponins from Panax notoginseng using zebrafish model. (Pubmed Central) -  Nov 13, 2024   
    It reduced the ponatinib-induced cerebral thrombus area and decreased the intensity of erythrocyte staining. The qPCR data showed that the anti-thrombotic effect of PTS was mediated by suppression of genes related to coagulation, inflammation and apoptosis, and also involved inhibition of NF-?B and PI3K/Akt pathways.
  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka
    Ponatinib Safety Profile: An Analysis of 10 Years of Real-World Experience (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_6239;    
    Our study findings suggest the safety profile of ponatinib has improved since it first became commercially available, with improvements likely attributable to the implementation of risk management measures and increasing knowledge of ponatinib among clinicians. Despite the potential limitations of this analysis, such as underreporting of AEs, the Weber effect (ie, reporting bias associated with increased reporting of AEs during the initial period following a drug's regulatory approval), and the use of estimated patient exposure, our results show that the introduction of measures designed to minimize the risks related to ponatinib use was associated with improved safety among patients receiving ponatinib.
  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka
    The Impact of Ponatinib on Pregnancy Outcomes (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_6211;    
    However, definite conclusions are limited by the small number of reports, limited information, and retrospective review. In contrast, in pregnancies with maternal exposure, 2 pregnancies resulted in infants born with the rare congenital malformation of HD.
  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka, Blincyto (blinatumomab) / Astellas, Amgen, Besponsa (inotuzumab ozogamicin) / Pfizer, UCB
    Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Real-World Outcomes and Disparities in the Era of Novel Therapies, 2010-2021 (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_6050;    
    Subsequent new agents, including ponatinib, a 3rd generation TKI introduced in 2012 which retains activity against all imatinib resistant mutations, and blinatumomab (Blin) and inotuzumab ozogamicin (Ino), both approved in 2017, have rapidly changed the treatment landscape of Ph+ B-ALL...Kaplan-Meier and Cox regression methods compared OS by time period of dx, corresponding with approved therapies (dasatinib, 2010-2011, ponatinib 2012-2016, Blin and Ino 2017-2021), and by age group (18-39, 40-64, 65-74, 75+ yrs)...We found considerable survival disparities in underinsured pts and pts from low-income areas, signaling that access to care may be a significant barrier to optimal outcomes. Efforts to optimize treatment regimens, such as novel chemotherapy-free regimens in elderly and frail pts, and improved access to novel therapies, are critically needed in Ph+ B-ALL to replicate the success observed in clinical trials in a real-world population.
  • ||||||||||  Nailike (olverembatinib) / Takeda
    A Phase 2 Study of Olverembatinib for the Treatment of Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_5920;    
    Pemigatinib, a selective inhibitor of FGFR1-FGFR3, has shown remarkable complete remission (CR) rates and complete cytogenetic remission (CCyR) in patients with chronic-phase (CP) disease but poorer responses in those with blast-phase (BP) disease...Beyond its use in Philadephia-chromosome positive leukemia, olverembatinib has demonstrated antitumor activity in FGFR1-mutated cells in parallel to ponatinib...All patients (100%) achieved CR, among whom one achieved CCyR (Pt 04 who received olverembatinib alone) and one achieved CMR (Pt 08 who received olverembatinib combined with inotuzumab ozogamicin) at 2 months' evaluation...Olverembatinib was well tolerated, with reduced platelet counts (grade 3) in one patients, as well as elevated ?-glutamyl transpeptidase (grade 2), fatigue (grade 1), myalgia (grade 1) and rash in one patient each among the five patients who were treated with olverembatinib alone. Conclusions Olverembatinib showed a favorable CR rate and good tolerance in the treatment MLN-FGFR1, potentially enabling allo-HSCT in greater numbers of eligible patients.
  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka, Nailike (olverembatinib) / Takeda
    Immune-Related Signatures Predict Prognosis in Chronic Myeloid Leukemia (CML) Patients Receiving the 3rd-Generation Tyrosine-Kinase Inhibitors (3G-TKIs) (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_5897;    
    Methods RNA sequencing was performed on blood samples from CML-CP/AP patients who were resistant to prior imatinib and/or 2G-TKI therapy and subsequently received 3G-TKI therapy...Results 151 patients with available blood samples receiving olverembatinib (n = 120, 80%) or ponatinib (n = 31, 20%) therapy were enrolled in the study...Sensitive analyses were performed in patients receiving olverembatinib therapy, and the same results were obtained. Conclusions We revealed the characteristics and dynamic changes of immune cell subsets under the heterogeneous treatment response patterns of 3G-TKI, and identified a subgroup (C1) with the unique immune-related signature associated with worse outcomes in CML patients receiving 3G-TKI therapy, which is a promising biomarker to distinguish the prognosis, the molecular and immune characteristics.
  • ||||||||||  In Vitro Drug Profiling to Guide Treatment for Relapse/Refractory AML (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_4284;    
    Importantly, in vitro drug sensitivities of AML samples were correlated with in vivo anti-leukaemia effect in respective patient-derived xenogarafts e.g. entrectinib, venetoclax, alectinib and ponatinib in combination with azacitidine...Conclusions A biologically meaningful and clinically relevant in vitro drug screening platform with high throughput capacity and short turnover time showed potential of clinical application to guide treatment in relapse/refractory AML at real-time. It also provided insights to the development of novel therapeutic targets in certain AML subtypes.
  • ||||||||||  Assessment of Transitioning from High-Potency to Low-Potency Inhibitors in Chronic Myeloid Leukemia (CML) Patients: The Downgrading-Impact Project, a CML Campus Study (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_4027;    
    Recently, the allosteric inhibitor Asciminib (ASC) has been introduced...TKIs before downgrading: Imatinib (IMA) 800 mg (n=8; 5.8%), Bosutinib (BOS)(n=4; 2.9%), Nilotinib (NIL) (n=58; 42.3%), Dasatinib (DAS) (n=52; 38%), Ponatinib (PON) (n=14; 10.2%), ASC (n=1; 0.7%), in first 77 (56.2%), second 40 (29.9%), third 13 (9.5%), 4th-6th 7 (5.1%) line...Envisaging a broader context to the years to come, the introduction of generic drugs and new therapies, emphasizes the need for sustainable pharmaceutical spending. Documenting the transition from potent inhibitors to lower-impact, lower-cost options could improve resource management, ensuring access to necessary treatments without compromising care.
  • ||||||||||  Tyrosine Kinase Inhibitors Discontinuation in Chronic Myeloid Leukemia: Observational Study of 673 Patients in Italy (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_4018;    
    Respect to our previous study on 283 pts, we confirm the importance of treatment duration and of the type of TKI as prognostic factors for TFR maintenance. For the first time 2 pts progressed, suggesting that we need to explore other alerts aimed at early detection of those who, despite meeting the criteria for TFR, have an increased risk of resuming treatment.
  • ||||||||||  Characteristics of Pediatric and Adolescents and Young Adults (AYA) with Chronic Myeloid Leukemia: Data from the Canarian Registry of CML (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_4015;    
    55% of young patients received imatinib as first-line TKI, followed by nilotinib (27.5%) and dasatinib (17.5%)...Third line TKI was received by 9/22 (22.5%): 3 asciminib, 1 bosutinib, 4 ponatinib, 1 dasatinib...There was no difference in the TFR rates or duration of TFR for young patients who discontinued TKI. This is an important result as young patients would benefit from discontinuing therapy to limit the potential side effects of TKI treatment on development, and reduce the toxicity and adverse effects due to the prolonged exposure to TKIs from an early age.
  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka
    Treatment-Free Remission in CML Patients Discontinuing Post-First Line Therapy (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_4000;    
    P=N/A
    Duration of TKI treatment seems to be the most relevant prognostic factor also in this category of pts. More observations are needed to safely include second line resistant pts in an elective discontinuation process.
  • ||||||||||  Nailike (olverembatinib) / Takeda
    Combination of Olverembatinib and VP Regimen for Newly Diagnosed Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_2625;    
    The combination of third-generation TKI Ponatinib can achieve a higher percentage of early molecular remission and significantly improve the prognosis, but the safety is unsatisfactory; Olverembatinib is a novel third-generation TKI, which has demonstrated better efficacy and safety in patients with CML; This study is intended to explore the efficacy and safety of Olverembatinib in combination with VP regimen in the treatment of newly diagnosed adult PH+ALL...Patients were treated with a combination of Olverembatinib (40mg QOD d1-28), Vindesine 4mg d1,8,15, Prednisone1mg/Kg/d d1-14, and then gradually tapered off for 28d in induction therapy, Post-induction treatment to be decided by each centre...Conclusion The combination of Olverembatinib and reduced-intensity chemotherapy (VP) is a safe and effective regimen in patients with newly diagnosed Ph+ ALL. The regimen results in high rates of CMR in the absence of intensive chemotherapy, and promises to improve long-term survival in patients with PH+ALL.
  • ||||||||||  Differential in Vitro Sensitivity of BCR::ABL1 Kinase Domain Mutations to Tyrosine Kinase Inhibitors Depending on the p190 or p210 Background (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_2532;    
    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. The resulting wildtype and 134 mutant Ba/F3 cell lines generated in this way, i.e. 67 cell lines carrying a large spectrum of single and compound mutations in the p190 and p210 background, respectively, were tested in vitro against different concentrations of eight TKIs including imatinib, nilotinib, dasatinib, bosutinib, ponatinib, vamotinib, asciminib, and flumatinib using the CellTiter-Glo
  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka
    Sex-Related Differences in CML Outcomes in a Real-World Prospective Registry (GQR LMC-NMP) (Grand Hall B (Manchester Grand Hyatt San Diego)) -  Nov 6, 2024 - Abstract #ASH2024ASH_2342;    
    Exclusion criteria for this analysis were a CML diagnosis prior to 2008, accelerated/blastic phase at diagnosis and ponatinib as first line (1L) treatment...Imatinib was the 1L TKI in a similar proportion of women (n=217; 71.6%) and men (n=257; 71.4%)...These results shed light on disparities between sexes in regard to CML clinical trajectories. This could potentially be leveraged to tailor toxicity management and dose reduction for women, especially when MMR is obtained or when TFR is not an objective.
  • ||||||||||  Scemblix (asciminib) / Novartis
    Update of the Ascend-CML Study of Frontline Asciminib: High Rate of Optimal Response and Resistance Due to Mutations Is Rare (Harbor Ballroom DEFG (Manchester Grand Hyatt San Diego)) -  Nov 6, 2024 - Abstract #ASH2024ASH_1702;    
    Pts with treatment failure (BCR::ABL1 >10% at 3 or 6 mos; BCR::ABL1 >1% at 12 or 18 mos) continued ASC, and add either imatinib, dasatinib (DAS) or nilotinib, according to physician preference...Pt 88 achieved MR4.5 at 3 mos, then lost MMR at 12 mos with BCR::ABL1 of 0.16% and T315I (35%) / M224V (70%) mutations in the P-loop domain; ponatinib 45mg for 6 mos has re-established MMR...Pts without MMR at 12 mos may achieve this milestone with continuing treatment, and numbers are too small to assess the benefit of dose escalation. BCR::ABL1 mutation acquisition rates appears similar to second generation TKIs in the frontline setting; these were mostly myristoyl pocket mutations which have so far responded well to salvage with DAS.