Exploring Imetelstat in the Second-Line Setting in MDS

Managing lower-risk patients with myelodysplastic syndromes (MDS) presents a long-standing clinical challenge with few therapies approved over the past 2 decades.

In a Case-Based Roundtable event in Charlotte, North Carolina, moderator Thomas LeBlanc, MD, associate professor of medicine, Duke University School of Medicine, Durham, North Carolina, discussed second-line management of lower-risk MDS following luspatercept (Reblozyl) failure, with a focus on the evidence supporting imetelstat (Rytelo), the first and only telomerase inhibitor approved for this indication.

LeBlanc reviews the National Comprehensive Cancer Network (NCCN) guideline recommendations for this setting,¹ examines the design and efficacy outcomes of the IMerge trial (NCT02598661),² and discusses the hemoglobin and transfusion burden data that distinguish imetelstat’s clinical profile. He also addresses the practical management of imetelstat’s hematological toxicity, including the cytopenia pattern observed during the first cycles of therapy, dosing considerations, and the low rate of treatment discontinuation due to adverse events observed in the trial.

Register today to join a Case-Based Roundtable near you.

This is part 2 of 2. Read Part 1 here.

Targeted Oncology: What do the National Comprehensive Cancer Network (NCCN) guidelines recommend for second-line management of MF after luspatercept failure?

Thomas LeBlanc, MD: The NCCN guidelines¹ indicate that imetelstat is the preferred option. Other recommended options include erythropoietin [EPO] with or without granulocyte-colony stimulating factor. Though as discussed, while the guideline specifies an EPO level of less than 500 [mU/mL], 200 [mU/mL] may be a more appropriate threshold.

Lenalidomide [Revlimid] is also listed, and there are data suggesting it can yield red cell transfusion independence and responses in some patients with non-del(5q) MDS, making it a reasonable consideration. That said, clinical experience with it has been less consistent, though the supporting data do exist.

Please highlight the findings of the IMerge trial.²

The IMerge trial enrolled 178 patients with lower-risk MDS. The trial was designed prior to the widespread adoption of the IPSS-R [Revised International Prognostic Scoring System], so risk stratification was based on the original IPSS. Eligible patients were required to have either erythropoiesis-stimulating agent [ESA] refractoriness or failure, or an EPO level greater than 500 [mU/mL], rendering them ESA-ineligible.

A defining feature of this trial population, distinguishing it even from the COMMANDS trial [NCT03682536] with luspatercept and other MDS studies, was the high transfusion burden at entry. Patients were required to have received 4 or more units of red blood cells over an 8-week period within the 16 weeks prior to randomization. The only additional exclusion criteria were prior disease-modifying therapy and inadequate neutrophil and platelet counts, the relevance of which becomes apparent given the cytopenias observed with this drug.

The trial used a 2:1 randomization of imetelstat vs placebo. The placebo-controlled design was clinically appropriate; as standard of care for lower-risk patients with MDS following ESA failure is largely supportive care, transfusion support is the norm rather than immediate escalation to hypomethylating agents. Imetelstat was administered intravenously at the labeled dose and schedule of 7.5 mg/kg every 4 weeks as a 2-hour infusion, with premedication and 1 hour of post-infusion observation.²

The primary end point was red blood cell transfusion independence for 8 or more consecutive weeks, the same end point used for luspatercept in the COMMANDS³ and MEDALIST trials [NCT02631070].⁴

Results demonstrated a statistically and clinically significant difference in favor of imetelstat, with approximately 40% of patients achieving transfusion independence compared with roughly 15% in the placebo arm. This benefit was sustained at 16 weeks, 24 weeks, and 1 year. A Kaplan-Meier analysis further illustrated this benefit on the 8-week transfusion independence end point, showing a clear separation between the imetelstat and placebo arms. Multiple secondary and exploratory end points were also reported.

What do the hemoglobin and transfusion burden data from the IMerge trial tell us about imetelstat’s broader efficacy, and how does that compare to what you tend to see with luspatercept?

One of the challenges with all MDS studies is that they take quite a while to complete, which results in an overrepresentation of ring sideroblast (RS)-positive patients on trials. Although real-world epidemiology suggests RS-positive patients make up perhaps 20% to 30% of the MDS population, trials consistently enroll closer to 60% RS-positive patients, largely because these patients tend not to progress and are therefore more able to remain on trial. This is a logistical issue inherent to conducting trials in this population.

Additionally, next-generation sequencing (NGS) was not standard of care when many of these trials were initiated, so that data may not be available. It would be valuable to see that kind of analysis, as some patients enrolled as lower-risk may not have truly had lower-risk disease.

Turning to additional efficacy data from IMerge, the hemoglobin findings are particularly noteworthy and contrast somewhat with what is typically observed with luspatercept. Importantly, this is not limited to responders; across all patients on the trial, there was a meaningful mean increase in hemoglobin with imetelstat. Between weeks 13 and 17, that mean increase reached 2 to 3 g/dL and was sustained throughout the trial. In the placebo arm, as expected, hemoglobin levels fluctuated modestly with ongoing transfusion support but showed no meaningful change.

The reduction in red blood cell transfusion requirements in imetelstat-treated patients was also notable, with a larger gap between the treatment and placebo curves than is typically seen with other therapies, including luspatercept.

Although head-to-head data are not available, it should be noted that most patients will need both therapies, making sequencing the more relevant clinical question. These findings suggest that imetelstat may demonstrate efficacy across a broader range of patients.

With luspatercept, the clinical experience tends to be more binary: it either works well or produces little benefit. With imetelstat, there appears to be more of a gray zone, a pattern that is at least anecdotally observed and supported by these data.

Please discuss the safety findings from IMerge.²

Regarding the safety data from IMerge, the toxicity profile is notable. Comparing imetelstat with placebo, there are little to no differences in the majority of toxicities, with the exception of hematological toxicity, where a significant difference is observed. This is very consistent with clinical experience with this therapy post-approval.

Imetelstat definitively causes cytopenias, and grade 3 to 4 thrombocytopenia or neutropenia occurs in 62% to 68% of patients. Importantly, data presented at ASH [American Society of Hematology Annual Meeting]⁵ suggest that the incidence and depth of cytopenias actually correlate with response to this drug, which is not necessarily a pattern seen with other therapies. Understanding how telomerase inhibition works in MDS is still an area of active investigation.

From a practical standpoint, the cytopenia pattern with imetelstat is important to understand. The cytopenias typically occur before the second dose. At that point, the second cycle is delayed until platelets or neutrophils recover to an acceptable level, and depending on the severity of the cytopenia, the dose may be reduced for the second cycle or maintained at the original starting dose. After 2 or 3 cycles, the cytopenias generally do not recur. This is the opposite of what is typically expected with cytotoxic therapies or hypomethylating agents.

It is also worth noting that clinical benefit may not be apparent with the first dose and sometimes does not emerge until the end of cycle 2 or later. For this reason, it is recommended to continue treatment for 6 months or 6 doses before concluding that the drug is not working.

Were there patients who discontinued therapy on imetelstat?

Regarding discontinuation of therapy, the rate of discontinuation due to adverse events on the IMerge trial was relatively low at 16%. There was no acute myeloid leukemia progression signal observed with imetelstat compared with placebo. However, dose reductions due to adverse events were common, and these were driven almost entirely by hematological toxicity.

DISCLOSURES: LeBlanc previously reported receiving honoraria for consulting/advisory boards from AbbVie, Agilix, Agios/Servier, Apellis, Astellas, AstraZeneca, Beigene, BlueNote, BMS/Celgene, Genentech, GSK, Lilly, Meter Health, Novartis, and Pfizer; speaking-related honoraria from AbbVie, Agios, Astellas, BMS/Celgene, Incyte, and Rigel; equity interest in Dosentrx (stock options in a privately held company); royalties from UpToDate; research funding from the AbbVie, American Cancer Society, AstraZeneca, BMS, Deverra Therapeutics, Duke University, GSK, Jazz Pharmaceuticals, the Leukemia and Lymphoma Society, the National Institute of Nursing Research/National Institutes of Health, and Seattle Genetics.

REFERENCES

1. NCCN. Clinical Practice Guidelines in Oncology. Myelodysplastic syndromes, version 3.2026. Accessed May 4, 2026. https://tinyurl.com/2s4y78m9

2. Platzbecker U, Santini V, Fenaux P, et al. Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;403(10423):249-260. doi:10.1016/S0140-6736(23)01724-5

3. Della Porta MG, Garcia-Manero G, Santini V, et al. Luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): primary analysis of a phase 3, open-label, randomised, controlled trial. Lancet Haematol. 2024;11(9):e646-e658. doi:10.1016/S2352-3026(24)00203-5

4. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140-151. doi:10.1056/NEJMoa1908892

5. Zeidan M, Santini V, Diez-Campelo M, et al. Correlation between treatment-emergent cytopenias and clinical response with imetelstat (IME) in patients (Pts) with lower-risk myelodysplastic syndromes (LR-MDS): analysis from the IMerge trial. Blood. 2025;146(suppl 1):490. doi:10.1182/blood-2025-490