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Imetelstat demonstrates safety, efficacy for essential thrombocythemia
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Patients with essential thrombocythemia who did not respond to or had unacceptable side effects from previous therapies experienced rapid and durable hematologic and molecular responses with imetelstat, according to findings from an international phase 2 study.
Imetelstat (Geron) — a first-in-class telomerase inhibitor that was granted FDA orphan drug status last June for the treatment of myelofibrosis — has been shown to inhibit megakaryocytic proliferation in vitro in cells from patients with essential thrombocythemia, a clonal disorder of a hematopoietic progenitor cell. Patients with essential thrombocythemia are at increased risk for thrombotic issues and hemorrhaging.
Gabriela M. Baerlocher, MD, researcher in the department of hematology at University Hospital of Bern in Switzerland, and colleagues sought to determine whether imetelstat could confer hematologic and molecular responses in patients with essential thrombocythemia who had refractory disease or who had experienced unacceptable side effects from previous therapies.
The investigators enrolled 18 patients between 2010 and 2013 into two sequential cohorts that received either 7.5 mg/kg or 9.4 mg/kg IV imetelstat until the patient achieved a platelet count between 250,000 and 300,000 per cubic millimeter or toxic effects occurred.
Best overall hematologic response served as the primary endpoint of the study. Secondary end points included adverse event frequency and severity; duration of response; and the molecular response in patients with JAK2 V617F mutations, MPL W515L or MPL W515K mutations or CALR mutations.
All 18 patients experienced a hematologic response and 16 (89%) patients had a complete hematologic response with imetelstat. The median time to a complete response was 6.1 weeks (range, 5.1-12.1) and appeared similar in patents who did and did not harbor JAK2 V617F mutations. However, patients who received the 9.5 mg/kg initial dose had a more rapid time to response than patients who received 7.5 mg/kg (median, 6.1 weeks vs. 12.1 weeks).
At the time of primary analysis, 10 patients were still receiving treatment with a median follow-up of 17 months (range, 7-32+ months).
Eighty-eight percent of patients (95% CI, 47-100) who harbored a JAK2 V617F mutation (n = 8) experienced a molecular response. The median JAK2 V617F mutant allele burden reduced 71% at month 3, and MPL and CALR mutant allele burdens reduced to 66%.
The toxicity profile during treatment appeared mild to moderate, according to the researchers. Grade 3 or higher neutropenia occurred in 22% of the patients and grade 3 or higher anemia, headache and syncope occurred in 11% of the cohort.
Every patient had at least one abnormal liver-function value and all persistent elevations were considered either grade 1 or grade 2.
The trial was disrupted after the FDA issued a full clinical hold on imetelstat on March 11, 2014, based on a lack of evidence or reversibility of hepatotoxicity, the risk for chronic liver injury, and a lack of follow-up in patients with hepatotoxic events. All patients still receiving imetelstat discontinued treatment immediately and were observed for safety.
Follow-up data showed that treatment-related abnormalities on liver-function testing resolved in most patients, allowing the FDA to lift the clinical hold on imetelstat on October 31, 2014.
“Imetelstat … had a clinically significant effect on disease burden in patients with essential thrombocythemia who had not had a response to previous treatment or who had had unacceptable side effects from conventional therapies,” Baerlocher and colleagues wrote. “This finding suggests therapeutic activity in the malignant clones that are the underlying source of essential thrombocythemia.” – by Anthony SanFilippo
Disclosure: The study was funded by Geron. Baerlocher reports grant support from Geron Corporation and non-financial support from Janssen Research and Development during the conduct of the study. He also reports grant support from Bristol-Myers Squibb and Novartis Pharma Schweiz AG and personal fees from Ariad Pharmaceuticals and Pfizer AG outside the submitted work. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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