Imetelstat, a telomerase inhibitor, improved rates of red blood cell (RBC) transfusion independence (TI) among patients with lower-risk myelodysplastic syndromes (MDS) who were RBC transfusion–dependent and who relapsed or were refractory to erythropoiesis-stimulating agents (ESAs), according the results of a phase 2/3 trial reported in the Journal of Clinical Oncology.

Imetelstat is a first-in-class oligonucleotide that targets the RNA template of telomerase, thus inhibiting telomerase activity. MDS has been associated with elevated activity and expression of telomerase and shortened telomeres in blood mononuclear cells. The aim of this trial was to determine if targeting MDS clones with imetelstat could improve patient outcomes.

The phase 2 part of the study treated 57 patients with RBC transfusion–dependent MDS with imetelstat. All patients had relapsed disease or were refractory to ESAs. The primary endpoint was RBC TI at week 8, and secondary endpoints included the RBC TI rate at 24 weeks, time to onset of TI, duration of TI, and hematologic improvement-erythroid (HI-E) response rate, MDS response, and safety.

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At baseline, the median patient age was 71 years, and 56% of patients were male. Most patients were classified as low risk by International Prognostic Scoring System (IPSS)-revised criteria. The median RBC transfusion burden was 7 units per 8 weeks (range, 4-14 units/8 weeks).

At 8 weeks, 37% of patients were TI, with a median onset of 8.3 weeks (range, 0.1-100.6 weeks) and a median duration of 65 weeks (range, 17-140.9 weeks). At 24 weeks, 23% of patients maintained RBC TI.  HI-E was achieved by 65% of patients, including 26% who experienced a ≥1.5 g/dL increase in hemoglobin that lasted for at least 8 weeks.

In a subset of 38 patients with non-del(5q) and who were hypomethylating agent– and lenalidomide-naive, 42% and 29% of patients demonstrated RBC TI at 8 weeks and 24 weeks, respectively. The median time to onset was 8.3 weeks and the median duration of TI was 85.9 weeks. The rate of HI-E was 68% in this subset population.

Treatment-emergent adverse events (TEAEs) were most commonly hematologic, with 54% of patients experiencing grade 3 or higher thrombocytopenia, 60% experiencing neutropenia, and 19% experiencing anemia. The most common nonhematologic grade 3 or higher TEAEs were back pain, elevated liver enzymes, and bronchitis.

The authors concluded that “imetelstat induced meaningful and durable TI and high HI-E rate in population of heavily RBC-dependent, ESA-relapsed/refractory lower-risk MDS, irrespective of presence of [ringed sideroblasts].” The phase 3 part of the trial is ongoing.


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. Published online October 27, 2020. doi:10.1200/JCO.20.01895