Evaluation of Two Doses of Imetelstat in Patients With Relapsed or Refractory Myelofibrosis After JAK Inhibitor Treatment

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In a phase II trial reported in the Journal of Clinical Oncology, John Mascarenhas, MD, and colleagues found that treatment with the telomerase inhibitor imetelstat at a dose of 9.4 mg/kg produced clinical benefit in patients with relapsed or refractory myelofibrosis after Janus-associated kinase (JAK) inhibitor treatment. 

As stated by the investigators, “Patients with myelofibrosis who are relapsed or refractory to JAK inhibitors have poor clinical outcomes, including dismal overall survival that ranges between 13 and 16 months.”

John Mascarenhas, MD

John Mascarenhas, MD

Study Details

In the global single-blind trial, 107 patients from 55 sites were randomly assigned between August 2015 and September 2016 to receive intravenous imetelstat at 9.4 mg/kg (n = 59) or 4.7 mg/kg (n = 48) once every 3 weeks until disease progression or unacceptable toxicity. The trial was not designed for statistical comparison between groups; findings were to be tested against null hypotheses within each group.

The co-primary endpoints were spleen response (≥ 35% spleen volume reduction) and symptom response (≥ 50% reduction in total symptom score on the modified Myelofibrosis Symptom Assessment Form v2) at week 24.

Treatment Outcomes

Trial enrollment was closed early due to futility in spleen response in the 4.7 mg/kg group. Patients receiving the lower dose were permitted to continue treatment with the 9.4 mg/kg dose. Early closure prevented achievement of sufficient statistical power to test within-group hypotheses, with the results thus being considered observational only.  

At week 24, spleen and symptom response rates were 10.2% and 32.2% in the 9.4-mg/kg group and 0% and 6.3% in the 4.7-mg/kg group. All symptoms improved in patients in the 9.4-mg/kg group, with patients having improvement in individual symptoms even when not meeting criteria for symptom response based on total score.

At a median follow-up of 27.4 months, median overall survival was 29.9 months (95% confidence interval [CI] = 22.8 months–not estimable) in the 9.4-mg/kg group and 19.9 months (95% CI = 17.1 months–not estimable) in the 4.7-mg/kg group, with 1- and 2-year rates of 84.0% and 78.6% and 57.5% and 41.8%.

Reduction of ≥ 1 grade in bone marrow fibrosis occurred in 15 (40.5%) of 37 evaluable patients in the 9.4-mg/kg group and 4 (20.0%) of 20 evaluable patients in the 4.7-mg/kg group. Patients with vs without such reduction had numerically improved overall survival (median = 31.6 vs 24.6 months; hazard ratio = 0.54, 95% CI = 0.23–1.29).


  • Imetelstat at 9.4 mg/kg was associated with benefit in spleen and symptom response, reduction in fibrosis and driver mutation VAF, and promising overall survival.
  • A phase III trial of imetelstat in JAK inhibitor–refractory disease—with overall survival as the primary endpoint—is underway.

Reductions in variant allele frequency (VAF) in JAK2 V617F, CALR, or MPL driver mutations by ≥ 25% were observed in 42.1% of patients in the 9.4-mg/kg arm and 5.6% in the 4.7-mg/kg group. Patients with vs without ≥ 20% VAF reduction had higher rates of spleen response, symptom response, and fibrosis improvement, as well as longer median overall survival.

Reduction of ≥ 50% in telomerase activity—defined as the threshold for optimal pharmacodynamic effect—was observed in 23 (57.5%) of 40 patients in the 9.4-mg/kg arm and 10 (30.3%) of 33 in the 4.7-mg/kg arm. Nearly all patients who achieved spleen and symptom response at week 24 had optimal pharmacodynamic effect; achievement of optimal pharmacodynamic effect was associated with longer median overall survival.

Adverse Events

Grade ≥ 3 adverse events occurred in 88% of patients in the 9.4-mg/kg group and 81% of the 4.7-mg/kg group, with the most common being hematologic events: anemia in 39% vs 31%, thrombocytopenia in 41% vs 23%, and neutropenia in 32% vs 10%. In the 9.4-mg/kg group, 84% of neutropenia events and 72% of thrombocytopenia events resolved to grade ≤ 2 within 4 weeks.

The most common grade 3 or 4 nonhematologic adverse events in the 9.4-mg/kg group were asthenia (10%) and fatigue (7%). A total of six patients in the total population had grade ≥ 3 liver toxicity, consisting of alkaline phosphatase, bilirubin, or aspartate aminotransferase elevations; none of these events were considered related to imetelstat.  

The investigators concluded, “In this phase II study of two imetelstat doses, 9.4 mg/kg once every 3 weeks demonstrated clinical benefits in symptom response rate, with an acceptable safety profile for this poor-risk JAK inhibitor relapsed/refractory population. Biomarker and bone marrow fibrosis assessments suggested selective effects on the malignant clone. A confirmatory phase III study is currently underway.”

Dr. Mascarenhas, of Icahn School of Medicine at Mount Sinai, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Janssen Research & Development LLC and Geron Corporation. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.