Telomerase Inhibitor Imetelstat Reverses Marrow Fibrosis

Neil Osterweil

September 03, 2015

The investigational telomerase inhibitor imetelstat (Geron) shows significant activity against two chronic myeloproliferative disorders, researchers in two small studies report.

In a phase 2 open-label study, 16 of 18 patients with essential thrombocythemia had a complete hematologic response to once-weekly intravenous infusions with imetelstat, write Gabriela M. Baerlocher, MD from the University Hospital of Bern, Switzerland, and colleagues in an article published in the September 3 issue of the New England Journal of Medicine.

In a separate pilot study of imetelstat in myelofibrosis published in the same issue of the journal, 7 of 33 patients had complete or partial remissions, and the four patients who had complete responses had complete reversal of bone marrow fibrosis, the hallmark sign of myelofibrosis, report Ayalew Tefferi, MD, from the Mayo Clinic in Rochester, Minnesota, and colleagues.

Imetelstat is an antisense oligonucleotide that inhibits telomerase activity and impedes the growth of malignant cells, but whether telomere shortening or different "off-target" mechanisms of action are responsible for the drug's apparent efficacy is still unclear, comment Mary Armanios, MD, and Carol W. Greider, PhD, from the Johns Hopkins University School of Medicine in Baltimore, Maryland, in an accompanying editorial.

"Whether the mechanism is on target or off, the results of the clinical studies published here spark new possibilities for the treatment of myeloproliferative neoplasms. 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," the editorialists write.

Essential Thrombocythemia Study

Essential thrombocythemia is a myeloproliferative neoplasm marked by hyperproliferation of platelets by megakaryocytes in bone marrow.

Dr Baerlocher and colleagues had previously shown that imetelstat inhibited telomerase activity of malignant cell samples from patients with essential thrombocythemia, but did not inhibit telomerase activity in cells from healthy donors that had been treated with cytokines to ramp up telomerase. Those data suggested that imetelstat might have specific action against telomerase activity in megakaryocytes from patients with essential thrombocythemia.

To test this, investigators at seven centers in the United States, Germany, and Switzerland enrolled 18 patients with essential thrombocythemia and assigned them to receive imetelstat at an initial dose of either 7.5 mg (7 patients) or 9.4 mg (11 patients) imetelstat per kg of body weight via once-weekly infusion until they reached platelet counts of approximately 250,000 to 300,000 per cubic millimeter. Patients were put on maintenance doses at reduced frequency once they had attained a complete or partial hematologic response.

All 18 patients had a hematologic response (the primary efficacy endpoint), and 16 (89%) had a complete response. Ten patients were still receiving treatment with imetelstat at the time of the analysis, at a median follow-up of 17 months.

Of eight patients who were positive for a mutation in the Janus kinase pathway associated with essential thrombocythemia (JAK2 V617F), seven had molecular responses. Similar but smaller reductions were seen in the burden of other mutant alleles associated with the disorder, the investigators note.

Four of the 18 patients (22%) had grade 3 or 4 neutropenia, and 2 (11%) had grade 3 or 4 anemia, headache, and syncope. All patients had at least one abnormal liver function test, but none were higher than grade 2

Myelofibrosis Study

Although myelofibrosis is associated with mutations in the JAK pathway, JAK-inhibiting agents can relieve symptoms and reduce splenomegaly, but cannot induce remissions or reverse bone marrow fibrosis. At this time, allogeneic stem cell transplantation is the only therapy shown to induce long-term remissions, but this therapy is fraught with perils for patients, Dr Tefferi and colleagues note.

In their study, they enrolled 33 patients with myelofibrosis to receive imetelstat infusions at a dose of 9.4 mg per kilogram of body weight every 1 to 3 weeks,

The overall response rate, the primary endpoint, was 21% (seven patients: four with complete remission and three with partial remissions. As noted earlier, all four patients with complete remission had reversal of bone marrow fibrosis, and three of the four had a molecular response.

Responses occurred in 27% of patients with a JAK2 mutation, but no responses were seen in patients who did not carry a JAK2 mutation. In contrast, 32% of patients without mutations in ASXL1, a gene encoding for a protein complex, had responses, whereas no patients with an ASXL1 mutation had a response.

Mutations in SF3B1 and U2AF1 were also associated with favorable responses to imetelstat, with 38% of patients with these mutations having a complete response compared with no responses among patients with no mutations in either gene. The responses did not correlate with telomere length at baseline, the authors note.

As in the essential thrombocythemia study, myelosuppression was the most common adverse event, including grade 4 thrombocytopenia in 18% of patients, grade 4 neutropenia in 12%, and grade 3 anemia in 30%. Mild, grade 1 or 2 liver function abnormalities were also common.

So What's Going On?

In their editorial, Dr Armanios and Dr Greider note that "[s]hort telomeres trigger a DNA-damage response that induces cell death or senescence, which is the primary effect that limits tumor growth; telomerase inhibition itself is not sufficient. Thus, an effective telomerase inhibitor would be expected to shorten telomeres in malignant cells to exert its therapeutic effect."

However, they note that neither study showed a link between telomere length at baseline and a treatment effect, although this could have been a result of the use of less precise telomere measuring techniques.

Instead of telomere shortening, it is possible that the treatment effect seen with imetelstat could be related to its myelosuppressive actions, they suggest.

"These side effects are independent of the antisense sequence and are thought to be mediated through mechanisms that include binding to cell-surface receptors such as [toll-like receptor 9]. If such an off-target effect is the primary mechanism of imetelstat action in myeloproliferative neoplasms, this knowledge will be critical for patient selection, for understanding mechanisms of resistance, and for future drug development in myeloproliferative neoplasms," they write.

Both studies were supported by Geron. Dr Tefferi, Dr Baerlocher, and Dr Armanios have disclosed no relevant financial relationships. Dr Greider reported receiving patents related to telomerase.

N Engl J Med. 2015;373;908-928, 965-966. Baerlocher abstract, Tefferi abstract, Editorial extract

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