Imetelstat Demonstrates Promising Efficacy in Myelofibrosis


An investigator reported at the 55th annual meeting of the American Society of Hematology (ASH) that imetelstat, a telomerase inhibitor, has demonstrated significant activity in myelofibrosis, including complete responses.

Ayalew Tefferi, MD

An investigator reported at the 55th annual meeting of the American Society of Hematology (ASH) that imetelstat, a telomerase inhibitor, has demonstrated significant activity in myelofibrosis, including complete responses.

Nine of 22 patients had objective responses, four of which were complete remissions. Two thirds of the patients met criteria for objective response or had a greater-than-50% reduction in white blood cell count.

“Imetelstat is capable of producing complete remission in some patients with myelofibrosis, suggesting disease-modifying activity,” said Ayalew Tefferi, MD, a hematologist at the Mayo Clinic in Rochester, Minnesota. “Imetelstat reverses bone marrow fibrosis and induces morphologic and molecular remissions in some patients with myelofibrosis.”

“Imetelstat activity in myelofibrosis might be affected by the presence or absence of specific mutations,” he added. “A possible correlation between complete response and spliceosome mutations suggests a broader therapeutic application for the drug.”

The findings follow a report that was detailed at the18th Annual Congress of the European Hematology Association in 2013 showing a 100% hematologic response rate in 18 patients with essential thrombocytopenia treated with imetelstat, including 16 complete responses. Those results added to a favorable report at the 2012 ASH Annual Meeting involving fewer patients and a shorter duration of follow-up.

Phase I studies showed that imetelstat reduces platelet counts, and laboratory studies demonstrated selective inhibition of proliferation of malignant progenitors and good distribution of the drug to bone marrow obtained from patients with essential thrombocytopenia.

Outcomes of the preceding studies led to a pilot study at the Mayo Clinic to evaluate imetelstat in myeloid malignancies. The study had several objectives: establish a safety profile, demonstrate a therapeutic signal, optimize the dose and administration schedule, identify diseases and subtypes most likely to respond to imetelstat, and provide a basis for multicenter studies.

The pilot study focused on myelofibrosis. An analysis of survival data for 773 patients referred to the Mayo Clinic for primary myelofibrosis showed a poor prognostic outlook for patients with anything other than a low-risk profile (J Clin Oncol. 2011;29:392-397).

Moreover, currently available therapies have a modest impact, at best, on the disease course of myelofibrosis. Of 166 patients treated with JAK inhibitors at the Mayo Clinic, none of the patients had a complete response, and one of 100 patients treated with momelotinib had a partial response.

“The results are consistent with the fact thatJAK2mutations are neither specific nor pathogenetically essential for the disease,” Tefferi said. “Other available drugs for myelofibrosis are equally ineffective in terms of disease-modifying activity.”

Patients enrolled in the pilot study were assigned to three treatment groups defined by the administration schedule. All patients received imetelstat at an intravenous infusion of 9.4 mg/kg. The three administration schedules were weekly, once every 3 weeks, or weekly for3weeks followed by once every 3 weeks.

Myelosuppression associated with continuous weekly administration proved to be unacceptable, and patients in that group were reassigned to the other two groups on the basis of the presence or absence of spliceosome mutations. Tefferi reported outcomes for 19 patients treated every 3 weeks and 14 patients who received weekly infusions (×3) followed by every 3 weeks.

Grade 3-4 extramedullary adverse events (AEs) associated with administration every 3 weeks consisted of atrial fibrillation in two patients and one case each of fatigue, liver enzyme elevation (ALP), heart failure, hyponatremia, and gastrointestinal bleeding. In the other group, two patients had grade 3/4 fatigue and one patient each had ALP elevation, hyperkalemia, pruritus, and intestinal obstruction. None of the AEs were associated with myelosuppression, according to Tefferi.

Grade 3/4 myelosuppression consisted of seven cases of neutropenia, 10 cases of thrombocytopenia, and four cases of anemia.

Tefferi assessed response according to 2013 criteria of the International Working Group-Myeloproliferative Neoplasms Research and Treatment. The overall response rate (ORR) was 23% for 22 evaluable patients. Four of 22 patients had reversal of fibrosis, two had megakaryocyte morphologic remission, and two had complete molecular remission.

Additionally, four patients had clinical improvement (CI), resulting in an ORR of 41% (complete response-partial remission-[CR-PR]-CI). Six patients had at least a 50% decline in leukocytosis in the absence of clinical response or improvement.

Overall, 15 of 22 patients (68%) obtained clinical benefit from treatment with imetelstat.

Analysis of response by mutation status suggested that presence of mutations inASXL1or spliceosome mutations might adversely affect response to imetelstat.

Tefferi A, Begna K, Laborde RR, et al. Imetelstat, a telomerase inhibitor, induces morphologic and molecular remissions in myelofibrosis and reversal of bone marrow fibrosis. Presented at: 55th ASH Annual Meeting; December 7-10, 2013; New Orleans, LA. Abstract 662.


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