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  • ||||||||||  cytarabine / Generic mfg.
    Journal:  Isocitrate dehydrogenase 2 mutation promotes cytarabine resistance in acute myeloid leukemia by Warburg effect. (Pubmed Central) -  Nov 15, 2024   
    To investigate cellular responses, the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) was administered to the cells...The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells...BEZ235 significantly inhibits the expression of phosphorylated PI3K (p-PI3K), phosphorylated Akt (p-Akt), mTOR, glycolytic metabolism, and Ara-C resistance both in vitro and in vivo. Overexpression and mutation of IDH2 coordinate with the Warburg effect through the PI3K/Akt/mTOR pathway to promote Ara-C resistance in AML.
  • ||||||||||  Review, Journal:  Safety considerations for drugs newly approved for treating acute myeloid leukemia. (Pubmed Central) -  Nov 13, 2024   
    Since 2017, nine molecules were registered for newly-diagnosed AML: midostaurin, gilteritinib, quizartinib, enasidenib, ivosidenib, gemtuzumab ozogamicin, CPX-351, glasdegib, and venetoclax...However, in addition to their well-known cytotoxic activity, new molecules cause several unique, off-target toxicities. Also, potential drug-drug interactions (DDI) should be taken into consideration when choosing optimal first-line therapy; this remains a challenge in clinical practice.
  • ||||||||||  Rezlidhia (olutasidenib) / Rigel, Tibsovo (ivosidenib) / Servier
    Review, Journal:  Looking Beyond the Surface: Olutasidenib and Ivosidenib for Treatment of mIDH1 Acute Myeloid Leukemia. (Pubmed Central) -  Nov 6, 2024   
    In biochemical studies, olutasidenib selectively inhibits mutant but not wild-type IDH1, whereas ivosidenib appears to potently block both mutant and wild-type IDH1. Although they have the same target, olutasidenib and ivosidenib have unique molecular features, which may translate to selectivity differences in their inhibitory activity against IDH1.
  • ||||||||||  Tibsovo (ivosidenib) / Servier
    Indirect Treatment Comparison of Ivosidenib and Other Therapies in Patients with Newly Diagnosed Acute Myeloid Leukemia (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_6268;    
    P3
    Following the SLR and feasibility assessment, six studies were considered eligible for inclusion in the NMA, which reported outcomes for the treatments IVO + AZA, AZA, low-dose cytarabine (LDAC), decitabine, venetoclax + AZA, venetoclax + LDAC and glasdegib + LDAC... ITCs using both NMA and MAIC methods generated consistent results, demonstrating a benefit of IVO + AZA versus other therapies for the treatment of newly diagnosed IDH1m AML in patients who are ineligible for iCI.
  • ||||||||||  Treatments and Outcomes of Adult Patients with AML in the Real-Life  (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_6200;    
    P
    Those initiating VEN-HMA also had shorter time to treatment initiation. New agents like gemtuzumab ozogamicin (GO), FLT3 or IDH inhibitors, or CPX-351 have been approved for some patient subsets...In these 476 patients, treatment decision was intensive in 266 (median age, 62y [18-79]; 210 7+3
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie, Rezlidhia (olutasidenib) / Rigel, Tibsovo (ivosidenib) / Servier
    The Argument for Targeted Therapy in IDH1 Mutated Myelodysplastic Syndromes (MDS): Poor Outcomes Post-Hypomethylating Agent Failure in Higher Risk MDS and Reduced Leukemia Free Survival in Lower Risk MDS (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_5783;    
    The upfront HMA regimens included azacitidine (61.5%), decitabine (14.4%), oral decitabine (1.5%), HMA with venetoclax (11.1%), and other HMA combinations (11.5%)...Four IDH1-MT pts received IDH1 inhibitors post-HMA failure (ivosidenib, n=3; olutasidenib, n=1), showing a significantly improved median OS of 28.6 months compared to 5.1 months for those who did not receive IDH1 inhibitors (n=28) (p<0.05)...In IDH1-MT LR-MDS, a higher rate of AML transformation and worse LFS are observed. Our data provide the historical outcomes for IDH1-MT HR-MDS post-HMA and provide rational to target IDH1 mutation among LR-MDS given high rate of leukemia transformation.
  • ||||||||||  Association between Targeted Therapy and Survival in Patients with MDS (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_5741;    
    In addition, our study confirms that a significant number of biomarker-positive MDS patients do not receive targeted therapies, highlighting challenges such as disparities in access to care and provider awareness. Addressing these issues is essential to ensure all eligible patients benefit from advancements in targeted therapies, ultimately improving survival and quality of life.
  • ||||||||||  Characterizing Secondary-Site Mutations in Isocitrate-Dehydrogenase-1 (IDH1) (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_5302;    
    Conclusion Second-site mutants of mIDH1 exhibit different leukemogenic properties and differentiation potential in vivo, and show distinct patterns of resistance and sensitivity to ivosidenib, olutasidenib and other mIDH1 inhibitors. Our study provides a rationale to choose an IDH1 inhibitor in patients with secondary site IDH1 mutations.
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie, Idhifa (enasidenib) / BMS, Servier, Tibsovo (ivosidenib) / Servier
    Single-Cell Proteogenomic Analysis of Clonal Evolution in Patient-Derived Xenograft Models of AML Treated with IDH Inhibitors (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_4322;    
    Here, we used single-cell DNA sequencing (scDNA-seq) and surface protein profiling to monitor the clonal evolution and differentiation of an isocitrate dehydrogenase 1 (IDH1)-mutated leukemic sample in response to ivosidenib (IVO), a mutant IDH1 inhibitor, either as monotherapy or in combination with venetoclax (VEN) or azacitidine (AZA)...As proof-of-principle, we generated an IDH1R132H/IDH2R140Q mPDX to model isoform switching in both directions by treating the animals with either IVO or enasidenib (ENA), a mutant IDH2 inhibitor...Further studies are underway to demonstrate whether dual mutant IDH1 and IDH2 inhibition (IVO+ENA) will circumvent resistance driven by isoform switching. In summary, we demonstrate the utility of applying single-cell proteogenomic analysis in traditional and mixed PDX models to gain crucial insights into mechanisms of resistance and potential strategies to overcome it.
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie
    Venetoclax Enhances Human ??t Cells Anti-Leukemia Immunity through Metabolic Reprogramming (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_3757;    
    Combining Venetoclax with ??T cells decreased tumor burden in THP-1-bearing mice. We found upregulated activation markers CD25 and CD69 and cytotoxic molecules NKG2D and DNAM-1 on drug-treated ??T cells when these cells were exposed to tumor targets.
  • ||||||||||  Idhifa (enasidenib) / BMS, Servier, Onureg (azacitidine oral) / BMS
    Opening Pandora's Box: Ultra-Deep Duplex Sequencing in Long Survivors with Acute Myeloid Leukemia (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_2953;    
    However, low-level persistence and/or appearance of mutations in known pathogenic hotspots were frequently observed after years of ongoing remission, including for pts receiving maintenance. Further investigation of the clinical relevance of low-level mutations in long-term remission is needed to inform decision-making and prevent over-treatment.
  • ||||||||||  Association between Targeted Therapy and Survival in Patients with AML (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_2854;    
    However, a significant number of biomarker-positive AML patients do not receive targeted therapies, highlighting challenges such as disparities in access to care and provider awareness. Addressing these issues is essential to ensure all eligible patients benefit from advancements in targeted therapies, ultimately improving survival and quality of life.
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie, Tibsovo (ivosidenib) / Servier
    Outcomes By Frailty in IC-Ineligible Newly Diagnosed AML  (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_2827;    
    With respect to treatment, IVO+HMA showed improved response and EFS compared with VEN+HMA in the less frail cohort. Patients receiving VEN were often treated with <21 days and this may have impacted the regimen's efficacy.
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie, Tibsovo (ivosidenib) / Servier
    A Phase Ib/II Study of Ivosidenib with Venetoclax  (Seaport Ballroom EFGH (Manchester Grand Hyatt San Diego)) -  Nov 6, 2024 - Abstract #ASH2024ASH_1376;    
    P1/2
    Patients with co-mutations in RUNX1, SETBP1 or BCOR may be associated with iHR and may be less likely to benefit from therapy. Triplet therapy with IVO + VEN
  • ||||||||||  Tibsovo (ivosidenib) / Servier
    Enrollment change, Trial completion date, Trial primary completion date:  Ivosidenib for Patients With Clonal Cytopenia of Undetermined Significance and Mutations in IDH1 (clinicaltrials.gov) -  Oct 29, 2024   
    P2,  N=20, Recruiting, 
    However, firsocostat should not be coadministered with strong OATP1B/3 inhibitors, such as rifampin and cyclosporine A. Firsocostat can be administered with CYP3A substrates or combined oral contraceptives without dose modification. N=15 --> 20 | Trial completion date: Jun 2026 --> Jan 2030 | Trial primary completion date: Jun 2026 --> Jan 2030
  • ||||||||||  Firsocostat (GS-0976) / Gilead
    Journal:  Regulation of Rice Grain Weight by Fatty Acid Composition: Unveiling the Mechanistic Roles of OsLIN6 by OsARF12. (Pubmed Central) -  Oct 28, 2024   
    Field trials showed that 1000-grain weight was significantly reduced when treated with the fatty acid synthesis inhibitor, Firsocostat S enantiomer (FSE), at the heading and flowering stages...Importantly, OsARF12 was shown to bind to the OsLIN6 promoter and activate its expression. In summary, this study highlights the crucial role of the fatty acid synthesis gene, OsLIN6, which was regulated by OsARF12, in rice grain weight determination, thus establishing the molecular link between fatty acid synthesis and auxin signaling.
  • ||||||||||  Idhifa (enasidenib) / BMS, Servier
    Journal:  Measurable residual mutated IDH2 before allogeneic transplant for acute myeloid leukemia. (Pubmed Central) -  Oct 26, 2024   
    Patients testing negative for IDH2m prior to transplant had low relapse-related death, regardless of conditioning intensity. Post-transplant relapse rates for those with persistently detectable IDH2m in pre-transplant remission were lower after the FDA approval of enasidenib in August 2017.
  • ||||||||||  Review, Journal:  Contemporary Management of Acute Myeloid Leukemia: A Review. (Pubmed Central) -  Oct 17, 2024   
    Additionally, patients are now referred for hematopoietic cell transplant on a more rational basis. In the era of genomic medicine, AML treatment is customized to the patient's comorbidities and AML genomic profile.