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

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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

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Primary Myelofibrosis
Telomerase
Mutation
Janus Kinases
imetelstat
Telomere
Aspartate Aminotransferases
Neutropenia
Bilirubin
Intravenous Infusions
Oligonucleotides
Alkaline Phosphatase
Anemia
Therapeutics
Spleen
Body Weight
RNA

ASJC Scopus subject areas

  • Medicine(all)

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A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. / Tefferi, Ayalew; Lasho, Terra L.; Begna, Kebede; Patnaik, Mrinal M; Zblewski, Darci L.; Finke, Christy M.; Laborde, Rebecca R.; Wassie, Emnet; Schimek, Lauren; Hanson, Curtis A.; Gangat, Naseema; Wang, Xiaolin; Pardanani, Animesh D.

In: New England Journal of Medicine, Vol. 373, No. 10, 03.09.2015, p. 908-919.

Research output: Contribution to journalArticle

Tefferi, A, Lasho, TL, Begna, K, Patnaik, MM, Zblewski, DL, Finke, CM, Laborde, RR, Wassie, E, Schimek, L, Hanson, CA, Gangat, N, Wang, X & Pardanani, AD 2015, 'A pilot study of the telomerase inhibitor imetelstat for myelofibrosis', New England Journal of Medicine, vol. 373, no. 10, pp. 908-919. https://doi.org/10.1056/NEJMoa1310523
Tefferi, Ayalew ; Lasho, Terra L. ; Begna, Kebede ; Patnaik, Mrinal M ; Zblewski, Darci L. ; Finke, Christy M. ; Laborde, Rebecca R. ; Wassie, Emnet ; Schimek, Lauren ; Hanson, Curtis A. ; Gangat, Naseema ; Wang, Xiaolin ; Pardanani, Animesh D. / A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. In: New England Journal of Medicine. 2015 ; Vol. 373, No. 10. pp. 908-919.
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AU - Lasho, Terra L.

AU - Begna, Kebede

AU - Patnaik, Mrinal M

AU - Zblewski, Darci L.

AU - Finke, Christy M.

AU - Laborde, Rebecca R.

AU - Wassie, Emnet

AU - Schimek, Lauren

AU - Hanson, Curtis A.

AU - Gangat, Naseema

AU - Wang, Xiaolin

AU - Pardanani, Animesh D

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N2 - 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.

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