Rytelo (imetelstat)

New therapeutic options to reduce the red blood cell (RBC) transfusion burden have emerged since 2020 and include luspatercept and imetelstat. Erythropoiesis-stimulating agents and lenalidomide also address anemia and are generally recommended to start at the time of transfusion dependency, although emerging data suggest that an earlier start of these interventions might offer clinical benefits...Targeted therapy directed to the presence of an IDH1 mutation is U.S. Food and Drug Administration (FDA) approved for the rare IDH1 mutated MDS (<10% of the time) and consideration to use an IDH2 inhibitor for IDH2 mutated MDS (<5% of the time) is reasonable. Interestingly, IDH mutations seem to appear with increased frequency in older patients and in patients with underlying autoimmune/rheumatological disorders.1.

P3, N=320, Active, not recruiting, Geron Corporation | Recruiting --> Active, not recruiting

Several recent targeted drug approvals including luspatercept and imetelstat have greatly expanded the treatment arsenal for lower-risk MDS. Standard of care therapy options for high-risk MDS, in particular TP53-mutated, remain limited beyond HMAs and transplant and are an active area of investigation.

The pooled SVR of 10%, 20% and 35% was 22.40 (95% CI 0.0-50.76, p = 0.0001), 11.44 (95% CI 0.00-30.95, p = 0.0006), and 4.42 (95% CI 0.0-14.31, p = 0.0152), respectively, while the pooled reduction of more than one grade in BM fibrosis was reported in 14.79% (95% CI: 4.70-24.88, p = 0.04, I2=67.5%). This meta-analysis demonstrates the efficacy of Imetelstat in MF patients who have relapsed on or are refractory to JAK inhibitors.

Erythropoiesis-stimulating agents (ESAs) and lenalidomide are the standard therapies; however, their effectiveness is limited by resistance and patient selection criteria. Additionally, the real-world use of these new agents remains limited in some regions owing to issues with local introduction and reimbursement. This review summarizes recent clinical data on luspatercept and imetelstat, highlights their current limitations, and discusses areas for future research based on recent trial outcomes and evolving clinical practices.

Only the hypomethylating agents (HMA) lenalidomide and imetelstat reduced the mutational burden, and then only in a small subset of cases. Here we summarize the current standard therapeutic approaches for MDS patients and discuss major advances in MDS research and treatments. We also discuss major challenges and potential solutions to overcome these challenges for future MDS research and drug development.

P1, N=51, Recruiting, Geron Corporation | Trial completion date: Aug 2027 --> Aug 2028 | Trial primary completion date: Feb 2026 --> Feb 2027

The novel therapeutic agents luspatercept and imetelstat have been particularly impactful. These agents exemplify personalized medicine, emphasizing treatment selection and timing based on individual molecular and clinical features. Current research focuses on optimizing therapeutic strategies and exploring combination treatments to improve clinical outcomes.

We discuss investigational therapies in the MDS pipeline, such as venetoclax, emavusertib, canakinumab and olutasidenib...We discuss how the identification of biomarkers of response to therapeutics may help guide clinical trial design for certain subsets of patients. Finally, we discuss how multicentre randomized trials can help facilitate the clinical rollout of emerging MDS therapeutics.

P2, N=6, Active, not recruiting, Australasian Leukaemia & Lymphoma Group

Novel agents such as Luspatercept and Imetelstat have shown promise, but their availability remains restricted and their long-term efficacy is to be investigated. Emerging strategies targeting metabolic mis-splicing (e.g., COASY) with vitamin B5, pyruvate kinase activators, and inhibitors of oncogenic pathways like MYC and BCL-2 represent potential future avenues for treatment, but their clinical utility remains to be fully explored. The current limitations in treatment underscore the urgency of developing novel, more effective therapies for patients with SF3B1-mutated MDS.

P3, N=320, Recruiting, Geron Corporation | Trial completion date: Nov 2026 --> Jun 2028 | Trial primary completion date: Nov 2026 --> Jun 2028