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Randomized, Single-Blind, Multicenter Phase II Study of Two Doses of Imetelstat in Relapsed or Refractory Myelofibrosis. | LitMetric

AI Article Synopsis

  • Myelofibrosis patients who don't respond to JAK inhibitors have a poor survival rate of about 13-16 months; a phase II study was conducted to evaluate the telomerase inhibitor imetelstat in these patients.
  • In this study, patients received either 9.4 mg/kg or 4.7 mg/kg of imetelstat to assess responses in spleen size reduction and symptom improvement, with results showing better outcomes for the higher dose.
  • The higher dose (9.4 mg/kg) led to a median overall survival of 29.9 months and significant benefits in symptom relief, despite common side effects like reversible cytopenias, prompting further phase III studies.

Article Abstract

Purpose: Patients with myelofibrosis who are relapsed or refractory (R/R) to Janus-associated kinase inhibitors (JAKis) have poor clinical outcomes including dismal overall survival (OS) that ranges between 13 and 16 months. Imetelstat, a telomerase inhibitor, was evaluated in patients with intermediate-2 or high-risk myelofibrosis R/R to JAKi in a phase II multicenter study (ClinicalTrials.gov identifier: NCT02426086).

Patients And Methods: Patients were randomly assigned to receive either imetelstat 9.4 mg/kg or 4.7 mg/kg intravenous once every 3 weeks. Spleen response (≥ 35% spleen volume reduction) and symptom response (≥ 50% reduction in total symptom score) rates at week 24 were coprimary end points. Secondary end points included OS and safety.

Results: Study enrollment was closed early, and patients treated with 4.7 mg/kg were permitted to continue treatment with 9.4 mg/kg. At week 24, spleen and symptom response rates were 10.2% and 32.2% in the 9.4-mg/kg arm and 0% and 6.3% in the 4.7-mg/kg arm. Treatment with imetelstat 9.4 mg/kg led to a median OS of 29.9 months and bone marrow fibrosis improvement in 40.5% and variant allele frequency reduction of driver mutations in 42.1% of evaluable patients. Fibrosis improvement and variant allele frequency reduction correlated with OS. Target inhibition was demonstrated by reduction of telomerase activity and human telomerase reverse transcriptase level and correlated with spleen response, symptom response, and OS. Most common adverse events on both arms were grade 3 or 4 reversible cytopenias.

Conclusion: 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 JAKi R/R population. Biomarker and bone marrow fibrosis assessments suggested selective effects on the malignant clone. A confirmatory phase III study is currently underway.

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Source
http://dx.doi.org/10.1200/JCO.20.02864DOI Listing

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