A pilot study of the telomerase inhibitor imetelstat for myelofibrosis

Ayalew Tefferi, Terra L. Lasho, Kebede Begna, Mrinal M Patnaik, Darci L. Zblewski, Christy M. Finke, Rebecca R. Laborde, Emnet Wassie, Lauren Schimek, Curtis A. Hanson, Naseema Gangat, Xiaolin Wang, Animesh D Pardanani

Research output: Contribution to journalArticle

166 Scopus citations

Abstract

Background: Current drugs for myeloproliferative neoplasm-associated myelofibrosis, including Janus kinase (JAK) inhibitors, do not induce complete or partial remissions. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase reverse transcriptase. Methods: We sought to obtain preliminary information on the therapeutic activity and safety of imetelstat in patients with high-risk or intermediate-2-risk myelofibrosis. Imetelstat was administered as a 2-hour intravenous infusion (starting dose, 9.4 mg per kilogram of body weight) every 1 to 3 weeks. The primary end point was the overall response rate, and the secondary end points were adverse events, spleen response, and independence from red-cell transfusions. Results: A total of 33 patients (median age, 67 years) met the eligibility criteria; 48% had received prior JAK inhibitor therapy. A complete or partial remission occurred in 7 patients (21%), with a median duration of response of 18 months (range, 13 to 20+) for complete responses and 10 months (range, 7 to 10+) for partial responses. Bone marrow fibrosis was reversed in all 4 patients who had a complete response, and a molecular response occurred in 3 of the 4 patients. Response rates were 27% among patients with a JAK2 mutation versus 0% among those without a JAK2 mutation (P = 0.30) and 32% among patients without an ASXL1 mutation versus 0% among those with an ASXL1 mutation (P = 0.07). The rate of complete response was 38% among patients with a mutation in SF3B1 or U2AF1 versus 4% among patients without a mutation in these genes (P = 0.04). Responses did not correlate with baseline telomere length. Treatment-related adverse events included grade 4 thrombocytopenia (in 18% of patients), grade 4 neutropenia (in 12%), grade 3 anemia (in 30%), and grade 1 or 2 elevation in levels of total bilirubin (in 12%), alkaline phosphatase (in 21%), and aspartate aminotransferase (in 27%). Conclusions: Imetelstat was found to be active in patients with myelofibrosis but also had the potential to cause clinically significant myelosuppression.

Original languageEnglish (US)
Pages (from-to)908-919
Number of pages12
JournalNew England Journal of Medicine
Volume373
Issue number10
DOIs
StatePublished - Sep 3 2015

ASJC Scopus subject areas

  • Medicine(all)

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    Tefferi, A., Lasho, T. L., Begna, K., Patnaik, M. M., Zblewski, D. L., Finke, C. M., Laborde, R. R., Wassie, E., Schimek, L., Hanson, C. A., Gangat, N., Wang, X., & Pardanani, A. D. (2015). A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. New England Journal of Medicine, 373(10), 908-919. https://doi.org/10.1056/NEJMoa1310523