Background: Current drugs in myelofibrosis (MF), including 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. A phase-2 study in essential thrombocythemia showed platelet-lowering activity of imetelstat accompanied by reduction in JAK2V617F allele burden, thus providing the main rationale for conducting the current study.

Methods: The current study (NCT01731951) is investigator-driven and IRB approved. Drug and research funding were provided by Geron Corporation (Menlo Park, CA, USA). The objective was to obtain preliminary information on therapeutic activity and safety of imetelstat in DIPSS-plus high or intermediate-2 risk MF. Adverse events (AEs) were monitored by Common Terminology Criteria for Adverse Events (Version 4.03) and responses by the International Working Group criteria (Blood2013). Laboratory correlative studies included measurement of plasma cytokines and analysis of mutations.

Results: 33 patients were accrued and met eligibility criteria (median age 67 years; 67% males); type of MF was primary 55% and post-PV/ET 45%; risk distribution was high 48% and intermediate-2 52%. Karyotype was abnormal in 16 (48.5%) patients. 79% of patients had received prior therapy including JAK inhibitors in 33%.

Protocol treatment: Imetelstat was administered by a 2-hour intravenous infusion (9.4 mg/kg) every three weeks (cohort A; n=19) or weekly x 3 followed by every three weeks (cohort B; n=16). As of 7/24/2014, 11 (33.3%) patients remain on active treatment (median number of cycles completed for all patients = 7; range 1-21). Three patients have died post-registration: intracranial hemorrhage (related), upper gastrointestinal hemorrhage (unrelated) and disease progression. Median follow-up for living patients was 11.0 months (range, 3.6 – 18.4). 22 (66%) patients have discontinued treatment, mainly because of suboptimal response (n=15) or disease progression (n=3).

Toxicity: Treatment-related grade 4 neutropenia was seen in 6 (18%) patients and grade 4 thrombocytopenia in 7 (21%). Grade 3 anemia was seen in 9 (27%) patients. Two patients experienced grade 4+ non-hematologic AE: grade 5 intracranial hemorrhage (related), grade 5 upper gastrointestinal hemorrhage (not related); other grade 3+ non-hematologic AEs were seen in only one patient. Regardless of attribution, treatment-emergent grade 1 or 2 liver function test abnormalities affected bilirubin 46%, ALP 52%, AST 55% and ALT 24%. There were 3 instances of grade 3 ALP and one of bilirubin elevations.

Efficacy: There were 7 (21.2%) complete (CR; n=4) or partial (PR; n=3) remissions, occurring at a median of 5 cycles of treatment (range 1-9). All 4 CR patients experienced reversal of BM fibrosis and 3 of them a complete molecular response. Six of the 7 CR/PR patients remain in remission (median 9.9 months, range 4.8-14.7). Other responses included anemia response in 4 (31%) of 13 transfusion-dependent patients, >50% reduction in palpable spleen size in 9 (39%) of 23 evaluable patients, ≥50% reduction in leukocyte count in 8 (80%) of 10 patients with marked leukocytosis (WBC >25 x 10(9)/L), resolution of leukoerythroblastosis in the majority of patients, and normalization of platelet count in 9 (75%) of 12 patients with thrombocytosis.

Laboratory correlative studies: Mutational frequencies were 79% for JAK2, 18% for CALR, 3% for MPL, 33% for ASXL1, 9% for IDH1/2 and 33% for spliceosome component mutations. CR/PR rates were 27% in JAK2-mutated vs 0% unmutated (p=0.3) and 32% in ASXL1-unmutated vs 0% mutated (p=0.07). CR rate was 38% in SF3B1/U2AF1-mutated vs 4% unmutated (p=0.036). Grade 3+ neutropenia or thrombocytopenia was more likely to occur in JAK2-unmutated (p=0.02) and ASXL1-mutated cases (p=0.049). Multi-cytokine panel screening showed significant differences between baseline and post-treatment samples involving several cytokines, including IL-1b, IL-5, IL-7, IL-17, VEGF, IL-8 and TNF-α (p<0.001 for all). CR/PR did not correlate with baseline cytokine levels.

Conclusions: The current study identifies imetelstat as an active drug in patients with MF, but also reveals its potential to cause significant myelosuppression. The association between CR/PR and specific mutations suggests potential targeted activity that might be exploited for patient and disease selection.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.

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