Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis

Sara Griffin, Mercer University College of Pharmacy

According to the Leukemia and Lymphoma Society, myelofibrosis (MF) is a rare type of chronic leukemia that causes a disruption the body’s normal production of blood cells. It is characterized by the replacement of bone marrow by fibrous tissue. Portal hypertension, decreased serum levels of albumin, total cholesterol and high-density lipoprotein (HDL) are noted as potential complications as MF progresses. 1

The guideline for the diagnosis and management of myelofibrosis does not include the use of telomerase inhibitors as treatment for myelosuppressive therapy. The current treatment options included in this guideline are hydroxycarbamide, interferon-alpha (INF-α) or pegylated-INF-α2a, or anagrelide. The guidelines go on to state that patients who have failed hydroxycarbamide therapy and are ineligible for bone marrow transplant (BMT) should be considered for trials with Janus kinase (JAK) inhibitors. 2

Title: A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis3
Design Investigator-driven, single-center study; N= 33
Objective Obtain preliminary information on the therapeutic activity and safety of imetelstat in patients with advanced myelofibrosis (MF).
Study Groups Imetelstat once every 3 weeks (Arm A, n= 19) or weekly for 4 weeks followed by once every 3 weeks (Arm B, n= 14). Dose reductions and dose holds allowed for toxicity.
Methods Patients with previous, but not concomitant, therapy with Janus kinase (JAK) inhibitors or other MF drugs were allowed. Initial administration of imetelstat was given by a 2-hour intravenous infusion at a starting dose of 9.4 mg/kg of body weight. Three different dose-schedules were planned: every three weeks (Arm A), weekly for four weeks followed by every three weeks (Arm B), and weekly (Arm C).   Each arm was planned to commence once the previous arm was shown to be safe after treatment of 11 patients. Accordingly, Arm C was never initiated because of observations in some Arm B patients that included severe and protracted cytopenias, including one patient who experienced severe and protracted grade 4 myelosuppression that was complicated by intracranial bleed and subsequent death. The occurrence of grade 4 neutropenia or thrombocytopenia or grade 3 or higher non-hematologic toxic effects warranted dose interruption, followed by dose reduction to 7.5 mg/kg or 6 mg/kg after recovery from the drug-related toxic effects.
Duration December 17, 2012 to December 5, 2014; Median duration of treatment: 11 cycles (range 2 to 21)
Primary Outcome Measure Overall response rate, determined according to conventional criteria of response, during the first nine cycles of treatment.
Baseline Characteristics Age, median: 67 years; Male: 67%; Primary MF: 55%; Post-polycythemia vera (post-PV) MF: 30%; Post-essential thrombocythemia (post-ET) MF: 15%; Prior JAK inhibitors: 58%
Results A complete (n= 4) or partial remission (n= 3) 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 (additional sex combs like 1) 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 [ribonucleic acid (RNA) splicing factor 3B, subunit 1] or U2AF1 (U2 auxiliary factor 1) versus 4% among patients without a mutation in these genes (p= 0.04). Responses did not correlate with baseline telomere length.
Adverse Events Common Adverse Events: Anemia (39%), neutropenia (27%), fatigue (18%), nausea (18%)
Serious Adverse Events: Death due to drug-induced grade 4 thrombocytopenia (3%), thrombocytopenia (45%), neutropenia (27%)
Percentage that Discontinued due to Adverse Events: A total of 76% of patients discontinued treatment by the data cut-off date and of those, 12% (n= 2, 6.1% excluding the death) discontinued due to adverse events.
Study Author Conclusions Imetelstat was found to be active in patients with myelofibrosis but also had the potential to cause clinically significant myelosuppression.

This study, with the data as of December 5, 2014, was presented at the American Society of Hematology’s meeting in December 2014. Cytopenias are the main dose-limiting toxicity noted with imetelstat therapy. This toxicity appears to be managed with dose modifications and retreatment guidelines. Further evaluation of the potential correlation between individual response and specific mutations are warranted in future studies. The data presented in the pilot study suggests that imetelstat has disease-modifying activity in MF. 4

References:

  1. Myelofibrosis Facts. Leukemia and Lymphoma Society. http://www.lls.org/sites/default/files/file_assets/FS14_Myelofibrosis_Fact%20Sheet_Final9.12.pdf. Revised April 2012. Accessed September 11, 2015.
  2. Reilly JT, McMullin MF, Beer PA, Butt N, Conneally E, Duncombe A, Green AR, George Michaeel N, Gilleece MH, Hall GW, Knapper S, Mead A, Mesa RA, Sekhar M, Wilkins B, Harrison CN, Writing group: British Committee for Standards in Haematology. Guideline for the diagnosis and management of myelofibrosis. Br J Haematol. 2012 Aug;158(4):453-71.
  3. Tefferi A, Lasho TL, Begna KH, et al. A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis. N Engl J Med. 2015;373(10):908-19.
  4. Lane S, Scarlett JA. ASH 2014 Analyst and Investor Event; December 8, 2014; San Francisco, CA. http://www.geron.com/PDFs/Geron-ASH2014-Investor-Event.pdf. Accessed September 13, 2015.
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