A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis

作者：Tefferi, Ayalew^*; Lasho, Terra L.; Begna, Kebede H.; 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

来源：New England Journal of Medicine, 2015, 373(10): 908-919.

DOI：10.1056/NEJMoa1310523

• INTERNATIONAL WORKING GROUP
• MYELOPROLIFERATIVE NEOPLASMS
• TERMINAL TRANSFERASE
• POLYCYTHEMIA-VERA
• TETRAHYMENA
• MUTATIONS
• RNA
• RUXOLITINIB
• ASSOCIATION
• SEQUENCE

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. (Funded by Geron; ClinicalTrials. gov number, NCT01731951.)

• 出版日期2015-9-3