Among patients with myelofibrosis (MF) who had progressed after or were refractory to Janus-associated kinase inhibitors (JAKis), treatment with imetelstat, a competitive inhibitor of telomerase activity, demonstrated clinical benefits in symptom response rate and potential disease-modifying activity with an acceptable safety profile, according to the results of a study published in the Journal of Clinical Oncology.

Most patients with MF stop responding to the current standard treatment with JAKis within 3 years and they generally have a dismal overall survival (OS) ranging from 13 to 16 months, the study authors noted.

“Development of novel agents to target the underlying malignant clones in MF remains a significant area of unmet need,” the authors stated. These patients have a high level of telomerase activity, and telomerase inhibition may be an effective therapeutic strategy in this population.

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In a phase 2 multicenter study ( Identifier: NCT02426086), researchers investigated the safety and efficacy of 2 doses of imetelstat in a cohort of patients with intermediate-2 or high-risk myelofibrosis who had relapsed or were refractory (R/R) to JAKi treatment.

The study enrolled 107 patients at 55 institutions, who were randomly assigned to receive 9.4 mg/kg (59 patients) or 4.7 mg/kg (48 patients) of imetelstat. Patients who received 4.7 mg/kg of imetelstat were allowed to continue treatment with a 9.4 mg/kg dose of imetelstat.

At week 24, spleen response (defined as a 35% or higher reduction in spleen volume by MRI) was observed in 10.2% (95% CI, 3.8-20.8) of the patients who received 9.4 mg/kg while patients treated with 4.7 mg/kg dose had no spleen response. The symptom response rate (defined as 50% or more total symptom score reduction) was 32.2% (95% CI, 20.6-45.6) in the 9.4 mg/kg arm and 6.3% (95% CI, 1.3-17.2) in the 4.7 mg/kg arm.

At a median follow up of 27.4 months, the median OS was 29.9 months in the 9.4 mg/kg arm (95% CI, 22.8-not estimable [NE]) and 19.9 months in the 4.7 mg/kg arm (95% CI, 17.1-NE). Of the evaluable patients in the 9.4 mg/kg arm, 40.5% (15 of 37) showed an improvement in bone marrow fibrosis compared with 20.0% (4 of 20 evaluable patients) in the 4.7 mg/kg arm.

There was also a reduction in the variant allele frequency (VAF) of driver mutations (JAK2V617F, CALR, or MPL) by at least 25% among 42.1% of evaluable patients in the 9.4 mg/kg arm and 5.6% of patients in the 4.7 mg/kg arm. Patients with a 20% or more VAF reduction had better rates of spleen response, symptom response, bone marrow fibrosis improvement, and a longer median OS than those who did not. The on-target activity of imetelstat was demonstrated by a reduction of telomerase activity and human telomerase reverse transcriptase level, which correlated with spleen response, symptom response, and OS.

Grade 3 or 4 cytopenias were the most common adverse events (AEs) observed in both treatment arms, which were manageable and reversible within 4 weeks. The most common grade 3 or worse nonhematologic treatment-emergent AEs included asthenia (10%) and fatigue (7%), which occurred in the 9.4 mg/kg arm, and dyspnea (13%), asthenia (6%), and fatigue (6%), which were reported in the 4.7 mg/kg arm.

“The novel telomerase inhibition [mechanism of action] offers a new treatment option for patients with MF that may alter the course of their disease,” the authors stated. “A confirmatory phase [3] study is currently underway.”

Disclosure: This research was supported by Janssen Research & Development LLC and Geron Corporation. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Mascarenhas J, Komrokji RS, Palandri F, et al. Randomized, single-blind, multicenter phase II study of two doses of imetelstat in relapsed or refractory myelofibrosis. J Clin Oncol. Published online June 17, 2021. doi:10.1200/JCO.20.02864