- |||||||||| Journal: Advancing Drug Development in Myelodysplastic Syndromes. (Pubmed Central) - Jan 12, 2025
Challenges to advancing drug development in MDS are multifold but may be grouped into specific categories including criteria for risk stratification and eligibility, response definitions, time-to-event endpoints, transfusion endpoints, functional assessments, and biomarker development. Strategies to address these challenges and optimize future clinical trial design for patients with MDS are presented here.
- |||||||||| Journal: Beyond HMAs: Novel Targets and Therapeutic Approaches. (Pubmed Central) - Dec 14, 2024
Furthermore, imetelstat has recently been added to the FDA-approved therapeutic armamentarium for lower-risk MDS...While several novel hypomethylating agent combinations have and are being studied in large randomized phase 3 clinical trials, including the combination of azacitidine and venetoclax, no combination to date have improved overall survival to azacitidine monotherapy...Despite recent advancements, the lack of therapeutic agents, particularly after the failure of first line therapy in higher risk MDS, continues to be a major hurdle in the management of MDS. In this review, we discuss the current treatment landscape of MDS and provide an overview of novel agents currently in clinical development that have the potential to alter our current treatment paradigms.
- |||||||||| Rytelo (imetelstat) / Geron, Reblozyl (luspatercept-aamt) / BMS, Merck (MSD)
Journal: Treatment of high risk myelodysplastic syndrome. (Pubmed Central) - Dec 5, 2024 Current challenges encompass to decrease the relapse risk, the main cause of HSCT failure. This review will summarize current knowledge of options of transplant- and non-transplant treatment approaches for these patients and demonstrate the unmet clinical need for more effective therapies.
- |||||||||| Rytelo (imetelstat) / Geron
Journal: Telomerase in Cancer Therapeutics. (Pubmed Central) - Dec 2, 2024 While imetelstat has been recently approved by the Food and Drug Administration (FDA), several other approaches are in late-stage clinical development. The pros and cons of the major approaches will be reviewed.
- |||||||||| Tibsovo (ivosidenib) / Servier
Phase 3 Study of Either Ivosidenib (IVO) Monotherapy or Azacitidine (AZA) Monotherapy in Patients with IDH1 Mutant Myelodysplastic Syndromes (MDS) Who Are Hypomethylating Agent (HMA) Naive (PyramIDH) (Halls G-H (San Diego Convention Center)) - Nov 21, 2024 - Abstract #ASH2024ASH_7171; P3 Other secondary endpoints are CR+PR at 6 months as per IWG 2006 criteria; CR+PR at 4 and 6 months as per IWG 2023 criteria; overall response rate (ORR) per IWG 2023 criteria, duration of response, EFS, OS, duration of transfusion independence, time to transfusion independence, AML transformation, quality of life, PK/PD, and safety. The global trial will begin enrollment by December 2024.
- |||||||||| Rytelo (imetelstat) / Geron
Imetelstat Versus Best Available Therapy in Patients with Intermediate-2 or High-Risk Myelofibrosis Relapsed or Refractory to Janus Kinase Inhibitor in IMpactMF, a Randomized, Open-Label, Phase 3 Trial (Halls G-H (San Diego Convention Center)) - Nov 21, 2024 - Abstract #ASH2024ASH_7169; P2, P3 The global trial will begin enrollment by December 2024. Randomization is to imetelstat sodium 9.4 mg/kg (8.9 mg/kg active dose) intravenously every 21 days or investigator-selected BAT (eg, hypomethylating agents, hydroxyurea, interferon, thalidomide, danazol, chemotherapy, or other non
- |||||||||| Rytelo (imetelstat) / Geron
Journal: Imetelstat: A new addition to the Therapeutic Landscape of Lower-Risk MDS. (Pubmed Central) - Nov 16, 2024 Imetelstat, an oligonucleotide telomerase inhibitor, was recently approved for RBC-TD LR-MDS adults who are ineligible or failed prior ESA therapy. While not yet approved worldwide, here, we spotlight the current data for imetelstat and where it may fit in the therapeutic landscape of LR-MDS.
- |||||||||| Rytelo (imetelstat) / Geron
Telomere Content Diversity in Myeloid Neoplasia Could Inform on Differential Sensitivity to Telomerase Inhibitors (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5857; In addition, mutations driving hyperproliferation (e.g., NRAS, KRAS) might exceed the compensatory capacity of normal telomere lengthening as also suggested by the negative correlation between TL and blast percentage. These results open the question as to whether TC might be used as a marker of response to Imetelstat and whether can identify disease phenotypes more likely to respond to the drug (MN relying on high TC (e.g., TP53 mutants) vs MN reaching a critical level of telomeres shortening (e.g., NRAS/KRAS mutated).
- |||||||||| Rytelo (imetelstat) / Geron
Trial Update from IMproveMF, an Ongoing, Open-Label, Dose-Escalation and -Expansion, Phase 1/1B Trial to Evaluate the Safety, Pharmacokinetics, and Clinical Activity of the Novel Combination of Imetelstat with Ruxolitinib in Patients with Intermediate-1, Intermediate-2, or High-Risk Myelofibrosis (MF) (Harbor Ballroom DEFG (Manchester Grand Hyatt San Diego)) - Nov 6, 2024 - Abstract #ASH2024ASH_2276; P1, P2 This trial is ongoing across the US at 6 sites and will continue to enroll at the 9.4 mg/kg imetelstat sodium dose level to confirm the RP2D before starting part 2. These early results demonstrate promise for the tolerability of the combination of IME+RUX in this pt population with high unmet needs.
- |||||||||| Rytelo (imetelstat) / Geron
Overcoming Ven/Aza Resistance through Imetelstat-Mediated Lipophagy in Acute Myeloid Leukemia (Grand Hall B (Manchester Grand Hyatt San Diego)) - Nov 6, 2024 - Abstract #ASH2024ASH_2054; The autophagy inhibitors chloroquine (CQ), bafilomycin A1, or 3-methyladenine prevented imetelstat-induced cell death, lipid peroxidation, lipid ROS production, and colocalization of lipid droplets with the late endosomal marker LAMP-1...Importantly, increased fatty acid metabolism in pre-treatment AML LSCs is associated with resistance to venetoclax and azacitidine (ven/aza) combination therapy...Imetelstat is an acute inducer of lipophagy, promoting the formation of PUFA-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress resulting in ferroptosis in AML. These mechanistic insights may be leveraged to develop an optimized therapeutic strategy using imetelstat to target ven/aza resistant AML subclones, providing significantly improved disease control for AML.
- |||||||||| MODULE 4: Future Directions in the Management of MF (Manchester Grand Hyatt San Diego, Seaport Ballroom EFGH; In-Person; Virtual) - Oct 5, 2024 - Abstract #ASH2024ASH_130;
These mechanistic insights may be leveraged to develop an optimized therapeutic strategy using imetelstat to target ven/aza resistant AML subclones, providing significantly improved disease control for AML. This program is supported by educational grants from CTI BioPharma, a Sobi Company, Geron Corporation, GSK, Incyte Corporation and Karyopharm Therapeutics.Mechanism of antitumor activity of navitoclax and biological rationale for its evaluation for MF Available efficacy and safety findings from the Phase III TRANSFORM-1 study of navitoclax in combination with ruxolitinib versus ruxolitinib alone for patients with previously untreated MF Potential role of navitoclax in the up-front setting and ongoing evaluation for relapsed/refractory (R/R) disease in the Phase III TRANSFORM-2 study Rationale for the evaluation of BET inhibitors for MF; updated findings from the Phase III MANIFEST-2 study combining pelabresib to ruxolitinib for JAK inhibitor-na
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Rytelo (imetelstat) / Geron, Reblozyl (luspatercept-aamt) / BMS, Merck (MSD)
Review, Journal: Targeted therapies for myelodysplastic Syndromes/Neoplasms (MDS): current landscape and future directions. (Pubmed Central) - Oct 5, 2024 Despite some promising results, many therapies remain in early development or have faced setbacks, emphasizing the need for a more comprehensive understanding of the disease's pathobiology. Continued research into targeted therapies, homogenous clinical trial designs, as well as increased incorporation of molecular prognostic tools and artificial intelligence into trial design are essential for developing effective treatments for MDS and improving patient outcomes.
- |||||||||| Rytelo (imetelstat) / Geron
Review, Journal: Imetelstat: First Approval. (Pubmed Central) - Sep 28, 2024 In June 2024, imetelstat was approved in the USA for use in adult patients with low- to intermediate-1 risk myelodysplastic syndromes (MDS) with transfusion-dependent anemia requiring 4 or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents (ESA). This article summarizes the milestones in the development of imetelstat leading to this first approval for the treatment of adult patients with low- to intermediate-1 risk MDS with transfusion-dependent anemia.
- |||||||||| Rytelo (imetelstat) / Geron
Journal: Imetelstat (Rytelo) for myelodysplastic syndromes. (Pubmed Central) - Sep 21, 2024 Trial completion date: Apr 2026 --> Jun 2026 | Trial primary completion date: Apr 2026 --> Jun 2026 No abstract available
- |||||||||| Rytelo (imetelstat) / Geron
Review, Journal: Obesity-Senescence-Breast Cancer: Clinical Presentation of a Common Unfortunate Cycle. (Pubmed Central) - Sep 20, 2024 In this review, interlinked molecular mechanisms are looked over between the telomere length, lipotoxicity/glycolipotoxicity, and cellular senescence in the context of estrogen receptor alpha-positive (ER?+) postmenopausal breast cancers in obese women. Furthermore, the effect of the potential drugs, which are used for direct inhibition of telomerase and the inhibition of human telomerase reverse transcriptase (hTERT) or human telomerase RNA promoters as well as approved adjuvant endocrine therapies, the selective estrogen receptor modulator and selective estrogen receptor down-regulators are discussed.
- |||||||||| Progress in Lower-Risk MDS () - Aug 30, 2024 - Abstract #SOHO2024SOHO_1041;
Roxadustat, an oral HIF1- alpha hydroxylase inhibitor, was approved for treating anemia in Europe and China for chronic renal insufficiency...Both romiplostim and eltrombopag are approved for treating immune thrombocytopenic purpura, but their use in LR- MDS is still off label...Conclusions Significant progress has been obtained in treating anemia in LR- MDS, but there is still room for improvement by building a strategy to optimize the sequence of therapies with agents with different mechanisms of action and by evaluating combinations of them to achieve long-lasting TI. Target therapies like ivosidenib, a mutant IDH1 inhibitor, could be a candidate for LR-MDS cases with this mutation, as suggested by pivotal studies.
- |||||||||| Rytelo (imetelstat) / Geron
Journal: Imetelstat Sodium. (Pubmed Central) - Aug 12, 2024 Trial completion date: Apr 2027 --> Nov 2026 | Trial primary completion date: Apr 2027 --> Nov 2026 No abstract available
- |||||||||| Rytelo (imetelstat) / Geron, Reblozyl (luspatercept-aamt) / BMS, Merck (MSD)
Review, Journal: Treatment of Anemia in Lower-Risk Myelodysplastic Syndrome. (Pubmed Central) - Jul 3, 2024 For those without previous luspatercept exposure it can be considered particularly if there is an SF3B1 mutation or the presence of ring sideroblasts. Other options include HMAs or IST; the Phase III IMERGE trial supports the efficacy of the telomerase inhibitor imetelstat in this setting and this may become a standard option in the future as well.
- |||||||||| imetelstat (GRN163L) / Geron, Reblozyl (luspatercept-aamt) / BMS, Merck (MSD)
Review, Journal: Phase to phase: Navigating drug combinations with hypomethylating agents in higher-risk MDS trials for optimal outcomes. (Pubmed Central) - Jan 22, 2024 Effective therapeutic strategies require accurate reporting of adverse events, highlighting the need for clarity in criteria like the Common Terminology Criteria for Adverse Events (CTCAE). We provide an overview on negative clinical trials in HR MDS, analyze possible reasons and explore possibilities to optimize future clinical trials in this challenging patient population.
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