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Imetelstat demonstrates clinical activity for myelofibrosis, but may cause myelosuppression
The telomerase inhibitor imetelstat demonstrates clinical activity in patients with myelofibrosis, according to the results of a pilot study.
However, imetelstat (Geron Corporation) may potentially cause clinically significant myelosuppression, the researchers reported.
“Allogeneic stem cell transplantation is currently the only method of treatment for patients with myeloproliferative neoplasm-associated myelofibrosis that has been shown to induce long-term disease-free remission,” Ayalew Tefferi, MD, hematologist and professor of medicine at Mayo Clinic in Rochester, Minnesota, and colleagues wrote. “Unfortunately, allogeneic stem cell transplantation is associated with a relatively high rate of treatment-related death and complications, including chronic graft-versus-host disease. Furthermore, many older patients are not eligible for this intervention.”
Current therapies for myeloproliferative neoplasm-associated myelofibrosis — including JAK inhibitors — do not induce complete or partial remission, according to the researchers.
Imetelstat — which received FDA orphan drug designation in June 2015 — is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase reverse transcriptase.
Tefferi and colleagues sought to obtain preliminary information on the therapeutic activity and safety profile of imetelstat in patients with high-risk or intermediate-2–risk myelofibrosis. They administered IV imetelstat (starting dose, 9.4 mg/kg of body weight) in 2-hour doses every 1 to 3 weeks.
Overall response rate (ORR) served as the primary endpoint. Secondary endpoints included adverse events, spleen response and independence from red-cell transfusions.
The study included data from 33 patients (median age, 67 years; 67% men) with myelofibrosis. Fifty-two percent of patients had high-risk myelofibrosis and 48% of patients had intermediate-2–risk myelofibrosis.
Seventy-nine percent of patients received previous treatment for myelofibrosis, including 48% of patients who received previous JAK inhibitor therapy.
Seven patients (21%) achieved a complete or partial remission, with a median duration of response of 18 months (range, 13-20) for complete remission and 10 months (range, 7-10) for partial remission.
Bone marrow fibrosis reversal occurred in all patients who achieved complete remission (n = 4), with a molecular response occurring in three patients.
Seventy-nine percent of patients (n = 26) had a JAK2 mutation (JAK2 V617F for all), whereas 18% (n = 6) had a CALR mutation (type 1 [L367fs*46] for all) and 3% (n = 1) had an MPL mutation (W515S). Further, 33% of patients (n = 11) had an ASXL1 mutation, 9% (n = 3) had an IDH1 mutation and 33% (n = 11) had a mutation in a spliceosome component gene (U2AF1 mutation, n = 5; SRSF2 mutation, n = 3; SF3B1 mutation, n = 3).
Patients with a JAK2 mutation achieved a 27% response rate, compared with 0% of patients without a JAK2 mutation. Thirty-two percent of patients with an ASXL1 mutation responded, compared with 0% of patients without an ASXL1 mutation.
Further, a greater proportion of patients with SF3B1 or U2AF1 mutations achieved a complete response compared with patients without these mutations (38% vs. 4%; P = .04).
Responses did not correlate with baseline telomere length.
Seventy-six percent of patients (n = 25) had discontinued treatment at data cutoff, with an overall median duration of treatment of 8.6 months (range, 1.4-21.7). Insufficient response (n = 16) served as the most common reason for treatment discontinuation.
Myelosuppression served as the most clinically significant adverse event, which necessitated a protocol-mandated dose reduction in 67% (n = 22) of patients. Other treatment-related adverse events included grade 4 thrombocytopenia (18%), grade 4 neutropenia (12%), grade 3 anemia (30%) and grade 1 or grade 2 elevation in levels of total bilirubin (12%), alkaline phosphatase (21%) and aspartate aminotransferase (27%).
“The current study suggests the potential value of telomerase-targeting treatment strategies in patients with myelofibrosis and identifies imetelstat as an active drug for this disease,” Tefferi and colleagues wrote. “A much larger clinical and laboratory study is needed to establish the most effective dosing schedules, clarify the mechanism of action, and address concerns about toxic effects of the drug, including the induction of genomic instability to telomerase-competent normal and clonal hematopoietic stem cells and progenitor cells.”
Although more information is needed, telomerase inhibitors may lead to better cancer treatment options, Mary Armanios, MD, and Carol W. Greider, PhD, both of Johns Hopkins University School of Medicine, wrote in an accompanying editorial.
“Telomerase is up-regulated in most cancers, and the concept of inhibiting telomerase to treat cancer was proposed more than 25 years ago,” Armanios and Greider wrote. “The recent evidence of frequent somatic mutations that up-regulate telomerase levels in many cancers lends further support to the idea that telomerase inhibition is an important target in cancer. However, if the mechanism of action is through off-target effects, the generalizability of imetelstat for treatment of other cancers in drawn into question. … Further analysis of both the mechanism and, more importantly, the long-term side-effect profile of imetelstat may provide a new approach to treat these debilitating disorders.” – by Cameron Kelsall
Disclosure: Geron Corporation provided funding for this study. Please see the full study for a list of all researchers’ relevant financial disclosures.