Safety Outcomes for Imetelstat in Lower-Risk MDS


Within the therapeutic realm for hematologic disorders known as myelodysplastic syndromes (MDS), the pursuit of safer and more effective treatment strategies remains an essential endeavor. Imetelstat, a first-in-class telomerase inhibitor, has potential to address unmet needs in MDS treatment.1 Clinical trial data support its efficacy to decrease transfusion needs, enhance hematologic response, and induce remission in some patients.1 A comprehensive analysis of adverse events (AEs) and their varying severity observed in patients treated with imetelstat sheds light on the nuanced safety profile of MDS therapeutic options. Evaluation of available clinical trial and patient data may provide a more profound understanding of safety considerations involved when integrating imetelstat into the management of lower-risk MDS.

Lower-Risk MDS

Lower-risk MDS are disorders within the bone marrow that disrupt the maturation of blood cells, resulting in anemia, fatigue, and related symptoms. Lower-risk MDS remains challenging to treat with few approved therapies beyond supportive care, which includes red blood cell and platelet transfusions and use of erythropoiesis-stimulating agents (ESAs). Novel therapies, such as the telomerase inhibitor imetelstat and TGF-β superfamily inhibitor luspatercept, have shown promise in late phase trials for lower-risk, transfusion-dependent patients with MDS whose disease has relapsed or has become refractory to ESA therapy.2-5

The telomerase inhibitor imetelstat represents a new treatment option for patients with MDS that has relapsed or become refractory to ESA therapy; these patients would be at lower risk and transfusion-dependent, and they would not have disease involving a deletion in the short arm of chromosome 5 (del[5q]).5 In the phase 3 IMERGE trial (NCT02598661), 39.8% of heavily transfusion-dependent patients achieved transfusion independence with imetelstat compared with only 15.0% on placebo. Patients treated with imetelstat had a 42.4% overall response rate.4-6 Other current treatment options for lower-risk MDS include growth factors, hypomethylating agents and immunotherapy to minimize disease progression, lenalidomide for patients with del(5q) MDS, luspatercept for those with anemia, and eltrombopag for patients with low platelet counts.2-5 The recent approval of luspatercept and the emergence of other novel therapies like imetelstat have started to change the treatment landscape. However, imetelstat represents the first targeted therapy that specifically reduces transfusion dependence in the lower-risk, ESA-refractory MDS population.4,5

Imetelstat Safety Profile

In the IMERGE phase 3 clinical trial, imetelstat therapy was evaluated in patients with lower-risk MDS that were unresponsive to treatment with ESAs. Data on AEs were consistent with safety data observed in previous trial phases. Notably, higher rates of cytopenias were observed among patients treated with imetelstat compared with those given placebo. Grade 3/4 thrombocytopenia affected 61.9% of imetelstat patients versus 8.5% of those given placebo.5,6 Imetelstat-treated patients received growth factor treatment to manage cytopenias, allowing for their prompt resolution—more than 80% of affected patients experienced resolution of cytopenias to grade 2 or less within 4 weeks.5 With appropriate monitoring and dose modifications, the reversible and treatable nature of myelosuppression related to imetelstat therapy allows patients to continue treatment.6 Hematologists are accustomed to managing cytopenias, so the safety profile presents minor clinical consequences in lower-risk MDS.

In addition to cytopenias, other AEs observed with imetelstat use in the IMERGE trial included fatigue, nausea, gastrointestinal symptoms, abdominal pain, and asthenia.5,6 Close monitoring and timely management are important to minimize impact on patients.7 Regular blood counts, liver function tests, and symptom assessments are recommended to promptly detect and address any emerging AEs. With appropriate monitoring and support, the overall tolerability profile of imetelstat is consistent with that of other MDS treatments. Most AEs observed with imetelstat are manageable for patients through dose modification, use of growth factors, and symptomatic treatment.6

Comparative Safety Profiles: Imetelstat and Other MDS Therapies

The myelosuppressive effects of imetelstat are comparable to those of other MDS treatments, such as lenalidomide and ESAs.3,4 Agents that include azacitidine, decitabine, and luspatercept have similar potential for occurrence of such AEs as cytopenias, diarrhea, rash, nausea, and fever.3,4 Close monitoring and prompt intervention is essential across MDS therapies to resolve AEs, sustain the treatment regimen, and mitigate disease progression.4,7 With active monitoring and AE management strategies, the safety profile of imetelstat enables continued treatment to provide transfusion independence for patients with lower-risk MDS.

Future Directions in the Treatment of MDS

Ongoing research into immunotherapies and targeted therapies continue to drive progress in the treatment of MDS, offering effective outcomes while maintaining a focus on patient well-being and overall quality of life. Precision medicine also holds promise in tailoring therapies based upon individual patient profiles. Emerging developments in immunotherapies, spliceosome modulators, mutant splicing factor inhibitors, and combination approaches targeting novel pathways are poised to advance MDS treatment and overcome resistance mechanisms.8


  1. Steensma DP, Fenaux P, Van Eygen K, et al. Imetelstat achieves meaningful and durable transfusion independence in high transfusion–burden patients with lower-risk myelodysplastic syndromes in a phase II study. J Clin Oncol. 2021;39(1):48-56. doi:10.1200/jco.20.01895
  2. Fenaux P, Platzbecker U, Ades L. How we manage adults with myelodysplastic syndrome. British J Haematol. 2019;189(6):1016-1027. doi:10.1111/bjh.16206
  3. Garcia‐Manero G. Myelodysplastic syndromes: 2023 update on diagnosis, risk‐stratification, and management. Am J Hematol. 2023;98(8):1307-1325. doi:10.1002/ajh.26984
  4. NCCN. Clinical Practice Guidelines in Oncology. Myelodysplastic syndromes, version 1.2023. Accessed August 24, 2023.
  5. Platzbecker U, Santini V, Fenaux P, et al. S165: continuous transfusion independence with imetelstat in heavily transfused non-del(5q) lower-risk myelodysplastic syndromes relapsed/refractory to erythropoiesis stimulating agents in IMerge phase 3. Hemasphere. Published online August 8, 2023. doi:10.1097/01.hs9.0000967572.05685.92
  6. Zeidan AM, Platzbecker U, Santini V, et al. IMerge: results from a phase 3, randomized, double-blind, placebo-controlled study of imetelstat in patients (pts) with heavily transfusion dependent (td) non-del(5q) lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA). J Clin Oncol. 2023;41(suppl 16):7004. doi:10.1200/jco.2023.41.16_suppl.7004
  7. Platzbecker U, Komrokji RS, Fenaux P, et al. Phase III IMerge trial of imetelstat in lower-risk MDS. J Clin Oncol. 2021;30(suppl 15):TPS7056. doi:10.1200/JCO.2021.39.15_suppl.TPS7056
  8. Rodriguez-Sevilla JJ, Adema V, Garcia-Manero G, Colla S. Emerging treatments for myelodysplastic syndromes: biological rationales and clinical translation. Cell Rep Med. 2023;4(2):100940. doi:10.1016/j.xcrm.2023.100940
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