The telomerase inhibitor imetelstat showed promise against advanced myelofibrosis and essential thrombocythemia in two industry-funded preliminary studies, according to separate reports published online Sept. 3 in the New England Journal of Medicine.
In previous in vitro and animal studies, imetelstat inhibited the proliferation of various types of malignant cells but was not active in normal somatic tissue. Researchers assessed the agent for advanced myelofibrosis in part because, at present, only one available treatment – allogeneic stem-cell transplantation (ASCT) – sometimes induces long-term remission. ASCT carries a relatively high rate of treatment-related death and complications, and is contraindicated in many older patients.
In the first report, researchers conducted a small, single-center cohort study to collect preliminary data on the agent’s efficacy and safety in 33 patients with primary myelofibrosis (18 participants), myelofibrosis that was related to polycythemia (10 participants), or myelofibrosis associated with essential thrombocytopenia (10 participants). Imetelstat was administered in 2-hour intravenous infusions given in 3-week cycles, said Dr. Ayalew Tefferi of the division of hematology, Mayo Clinic, Rochester Minn.
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The median duration of treatment was 8.6 months (range, 1.4-21.7 months). Seven patients (21%) had either a complete or partial response; the 4 patients with a complete response had documented complete reversal of bone marrow fibrosis. The time to onset of response was 3.5 months (range, 1.4-7.2 months), and the median duration of response was 18 months (range, 13-20 months).
These remissions “confirm selective anticlonal activity, which has not previously been documented in drug treatment of myelofibrosis,” noted Dr. Tefferi and his associates (N Engl J Med 2015 Sep 3. doi:10.1056/NEJMoa1310523). Three of the seven patients who responded to imetelstat “had been heavily dependent on red-cell transfusions at study entry and became transfusion-independent and sustained a hemoglobin level of more than 10 g/dL for a minimum of 3 months during therapy,” they noted.
In addition, 8 of 10 patients who had marked leukocytosis at baseline had either a complete resolution (3 patients) or a reduction of at least 50% in white-cell counts (5 patients). All 11 participants who had thrombocytosis at baseline had either complete resolution (10 patients) or a reduction in platelet count of at least 50% (1 patient). Of the 27 participants who had leukoerythroblastosis at baseline, 22 showed either complete resolution (13 patients) or a reduction of at least 50% in the percentage of immature myeloid cells and nucleated red cells (9 patients). Also, 17 of the 21 participants who had at least 1% circulating blasts at baseline had either a complete disappearance of circulating blasts (14 patients) or a reduction of at least 50% (3 patients).
The most clinically significant adverse effect of imetelstat, myelosuppression, occurred in 22 patients (67%) and often necessitated dose reductions. Low-grade elevations in liver enzymes also were a concern. One patient died from an intracranial hemorrhage that the treating physician attributed to drug-induced grade 4 thrombocytopenia. Other adverse events that may or may not have been treatment related included fever, epistaxis, bruising, hematoma, lung infection, skin infection, and upper-GI hemorrhage.
These findings not only identify imetelstat as a possible treatment for myelofibrosis, they also suggest that other telomerase-targeting strategies may be beneficial in this disease, Dr. Tefferi and his associates added.
In the second report, researchers performing a phase-II study at seven medical centers in the United States, Germany, and Switzerland found that imetelstat produced rapid and durable hematologic and molecular responses in all 18 patients in their study of essential thrombocythemia refractory to other treatments. This result is particularly encouraging because current standard therapies “induce nonspecific reductions in platelet counts but do not typically eliminate or alter the biologic characteristics of the disease,” said Dr. Gabriela M. Baerlocher of the department of hematology and the Stem Cell Molecular Diagnostics Laboratory, University of Bern, Switzerland.
These study participants had either failed to respond to hydroxyurea, anagrelide, and interferon therapy or were forced to discontinue these agents because of adverse effects. After weekly treatment with imetelstat at one of two doses, 100% of the patients achieved a hematologic response, attaining platelet counts of 250,000-300,000 per cc. Sixteen participants (89%) achieved a complete hematologic response. The median time to complete response was 6.1 weeks, Dr. Baerlocher and her associates said (N Engl J Med. 2015 Sep 3. doi:10.1056/NEJMoa1503479).
After a median follow-up of 17 months on a maintenance dose of imetelstat, 10 patients were still receiving treatment. The median duration of response had not been reached as of press time (range, 5-30 months).
The most important adverse events were neutropenia (15 patients) and abnormal results on liver-function tests (14 patients). The treating physicians attributed 18 adverse events of grade 3 or higher to the study drug, including headache, anemia, and one syncopal episode. Other adverse events included fatigue, nausea, diarrhea, infections, and rash.