A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis.
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.).
From the Department of Internal Medicine, Division of Hematology (A.T., T.L.L., K.H.B., M.M.P., D.L.Z., C.M.F., R.R.L., E.W., L.S., N.G., A.P.), and Department of Laboratory Medicine, Division of Hematopathology (C.A.H.), Mayo Clinic, Rochester, MN; and Biometrics and Development Operations, Geron, Menlo Park, CA (X.W.).
Ayalew
A
Tefferi
Terra L
TL
Lasho
Kebede H
KH
Begna
Mrinal M
MM
Patnaik
Darci L
DL
Zblewski
Christy M
CM
Finke
Rebecca R
RR
Laborde
Emnet
E
Wassie
Lauren
L
Schimek
Curtis A
CA
Hanson
Naseema
N
Gangat
Xiaolin
X
Wang
Animesh
A
Pardanani
D000368:Aged; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D004252:DNA Mutational Analysis; D004334:Drug Administration Schedule; D005260:Female; D005355:Fibrosis / Q000188:drug therapy; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D007262:Infusions, Intravenous; D053614:Janus Kinase 2 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D009841:Oligonucleotides; D010865:Pilot Projects; D011087:Polycythemia Vera / Q000150:complications; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D012074:Remission Induction; D019098:Telomerase / Q000037:antagonists & inhibitors*; D013920:Thrombocythemia, Essential / Q000150:complications; D000637:Transaminases / Q000187:drug effects
D007211:Indoles; D009841:Oligonucleotides; D009536:Niacinamide; D000637:Transaminases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C509186:TERT protein, human; D019098:Telomerase; C519562:imetelstat