Telomerase Inhibitor Imetelstat Shows Activity in Myelofibrosis


Key Points

  • Response to imetelstat was observed in 21% of patients, including complete response in 12%.
  • Response was more likely in patients with vs without JAK2 mutation and without vs with ASXL1 mutation.

In a pilot study reported in The New England Journal of Medicine, Tefferi et al found that imetelstat, which targets the RNA template of telomerase reverse transcriptase, produced responses in patients with myelofibrosis. Treatment was associated with myelosuppression in some patients. Current drugs for myeloproliferative neoplasm-associated myelofibrosis, such as JAK inhibitors, do not produce complete or partial remissions in this setting.

Study Details

In the study, 33 patients with high-risk (52%) or intermediate-2–risk (48%) myelofibrosis were treated at the Mayo Clinic with a 2-hour infusion of imetelstat at a starting dose of 9.4 mg/kg every 3 weeks or weekly for 4 weeks followed by once every 3 weeks. Patients had a median age of 67 years, 67% were male, 55% had primary myelofibrosis, and 48% had received prior JAK inhibitor therapy. The primary endpoint was overall response rate.


Overall, seven patients (21%) had a complete response (n = 4) or a partial response (n = 3). The median time to onset of response was 3.5 months (range = 1.4–7.2 months), and the median duration of response was 18 months (range = 13–20+ months) in those with a complete response and 10 months (range = 7–10+ months) in those with a partial response. The four patients with complete response had documented reversal of bone marrow fibrosis, with three also having molecular remission.

Response was observed in 7 (27%) of 26 patients with JAK2 mutation vs 0 (0%) of 7 without JAK2 mutation (P = .30) and in 7 (32%) of 22 without ASXL1 mutation vs 0 (0%) of 11 with ASXL1 mutation (P = .07). Complete response was observed in 3 (38%) of 8 patients with mutations in SF3B1 or U2AF1 vs 1 (4%) of 25 patients without such mutations (P = .04). Responses did not correlate with baseline telomere length.

Adverse Events

Grade 3 or 4 treatment-related adverse events included grade 3 and grade 4 thrombocytopenia in 17% and 18%, grade 3 and grade 4 neutropenia in 15% and 12%, and grade 3 anemia in 30%. Other treatment-related adverse events included grade 1 or 2 elevations in aspartate transaminase in 27%, alkaline phosphatase in 21%, and total bilirubin in 12%.

The investigators concluded: “Imetelstat was found to be active in patients with myelofibrosis but also had the potential to cause clinically significant myelosuppression.”

Ayalew Tefferi, MD, of Mayo Clinic, is the corresponding author of The New England Journal of Medicine article.

The study was funded by Geron. For full disclosures of the study authors, visit

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