Evolving Approaches: Low-Risk MDS / MDS 07/28/2026

The Role of Imetelstat in Lower-Risk Myelodysplastic Syndromes

Professional woman with blonde hair wearing a black pinstripe blazer, smiling confidently with arms crossed in a modern office setting. Hetty Carraway, MD Smiling man with beard wearing a white shirt, professional headshot, suitable for oncology or cancer research content, emphasizing healthcare and medical expertise. Rahul Gosain, MD, MBA Close-up portrait of a woman wearing a purple and pink patterned hijab, looking confidently at the camera with a neutral background. Yasmin Abaza, MD Professional portrait of a smiling man in a suit and blue shirt against a gray background, suitable for medical or healthcare-related content. Thomas LeBlanc, MD, MA Portrait of a male doctor in a white lab coat at Yale Cancer Center, smiling confidently, with a neutral background. Amer Zeidan, MBBS, MD

Key Points

  • Imetelstat is a first-in-class agent approved for patients with lower-risk myelodysplastic syndromes (MDS) who lost response to or are ineligible for erythropoiesis-stimulating agents (ESAs).
  • The IMerge trial showed imetelstat improved transfusion independence rates for patients with prior ESA treatment and those ineligible for ESAs.
  • Imetelstat may be preferred in the frontline setting over luspatercept and ESAs for patients with serum erythropoietin (EPO) levels above 500 mU/mL.
  • Thrombocytopenia and neutropenia are the most common adverse effects of imetelstat, but they are associated with treatment response and typically resolve over time as cycles continue.

Treating Low-Risk MDS and the Role of Imetelstat

On the Oncology Brothers podcast Clinical Insights series, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Hetty Carraway, MD, of Cleveland Clinic, moderated a panel discussion on the role of imetelstat in the treatment of patients with low-risk MDS. They were joined by three MDS experts: Yasmin Abaza, MD, of Northwestern Medicine; Thomas LeBlanc, MD, MA, of Duke Cancer Center; and Amer Zeidan, MD, MBBS, of Yale School of Medicine.

Frontline Treatment Options for Low-Risk MDS

Currently, frontline treatment of low-risk MDS is primarily a choice between ESAs or luspatercept, with luspatercept preferred for most patients. ESAs may be more viable for patients with ring sideroblast–negative MDS or with serum EPO under 200 mU/mL, although luspatercept is still slightly favored for transfusion independence and anemia responses. Some patients also experience long-term, durable responses with luspatercept, although the mechanisms responsible for these “super responders” are still unclear. Notably, patients with a serum EPO above 500 mU/mL are less likely to respond to luspatercept or ESAs, and the doctors noted that they use frontline imetelstat for this subgroup.

Imetelstat and the IMerge Trial

Imetelstat is a first-in-class oligonucleotide telomerase inhibitor that was evaluated for lower-risk MDS in the phase 3 IMerge trial. IMerge compared imetelstat with placebo in the second-line setting in patients with transfusion-dependent anemia. All participants had not responded to, lost response to, or were ineligible for ESAs. The primary end point was red blood cell transfusion independence for 8 consecutive weeks.

The trial randomized 118 patients to imetelstat and 60 to placebo. Median follow-up was 19.5 months (interquartile range [IQR], 12-23.4) in the imetelstat group and 17.5 months (IQR, 12.1-22.7) in the placebo group. Overall, 40% (95% CI, 30.9-49.3) of patients in the imetelstat group versus 15% (95% CI, 7.1-26.6) in the placebo group achieved transfusion independence for at least 8 weeks (95% CI, 9.9-36.9; P = .0008). Grade 3 to 4 treatment-emergent adverse events occurred in 91% of patients in the imetelstat group and 47% of the placebo group. The most common events in the imetelstat group were neutropenia (68%) and thrombocytopenia (62%), according to a report in The Lancet.

The IMerge data were very compelling considering how difficult it is to reverse transfusion dependency in patients ineligible for ESAs or with prior ESA treatment, said Dr. Carraway. Based on the findings, the FDA approved imetelstat on June 6, 2024, for transfusion-dependent patients with intermediate-1 or low-risk MDS who lost response to or were ineligible for ESAs.

Managing Adverse Effects of Imetelstat

The most common adverse effects reported with imetelstat are neutropenia and thrombocytopenia, which occur in approximately 70% and 60% of patients, respectively. Importantly, these cytopenias are essentially on-target effects of imetelstat and have been correlated with response in post hoc analyses of IMerge, said Dr. Zeidan. In addition, although the cytopenia incidence is high, Dr. Abaza said she usually does not see related complications such as bleeding or infections. 

Patients starting imetelstat should undergo weekly laboratory testing for the first 2 cycles to monitor cytopenias. In patients who develop thrombocytopenia or neutropenia, oncologists should hold cycle 2 until counts recover. Platelet transfusions or granulocyte colony-stimulating factors may be helpful, although the doctors largely agreed that they do not typically use these interventions in their practice, as counts typically recover over time. If patients develop grade 3 thrombocytopenia or neutropenia, imetelstat can be restarted at the same dose once, but the dose should be reduced after the second and third occurrences and stopped after the fourth. If patients develop grade 4 cytopenias, the dose should be reduced immediately. In addition to managing cytopenias, oncologists should monitor liver enzyme levels and take precautions for potential infusion reactions.

Treatment Sequencing for Low-Risk MDS

In patients who received frontline luspatercept, second-line ESAs may be effective if patients have serum EPO under 200 mU/mL; otherwise, imetelstat is typically the next-line therapy, especially in patients who have become transfusion-dependent. After exhausting luspatercept, ESAs, and imetelstat, the panel generally prefers lenalidomide followed by hypomethylating agents (HMAs). However, lenalidomide and especially HMAs are generally weaker options, and Dr. Abaza noted that when starting a patient on an HMA, she always refers them for a transplant evaluation.

Ultimately, patients with lower-risk MDS will live several years, and most will develop anemia and transfusion dependence. With current therapies, responses tend to fade over time, so most patients will be exposed to all available agents. Treatment sequencing in low-risk MDS should aim to maximize duration of benefit while maintaining functionality and quality of life, said Dr. LeBlanc.