Imetelstat Promising Across Myeloproliferative Neoplasms

John Scarlett, MD

The telomerase inhibitor imetelstat has shown encouraging signs of clinical activity in patients with myelofibrosis and essential thrombocythemia, according to findings from two clinical trials that were published in The New England Journal of Medicine.

In the first study,¹ treatment with imetelstat induced a hematologic response in 100% of patients with essential thrombocythemia, with 89% experiencing a complete hematologic response. In the second study,² the objective response rate (ORR) with imetelstat was 21% for patients with myelofibrosis. In both trials, responses to imetelstat were durable and adverse events (AEs) were largely reversible.

“The data in the essential thrombocythemia and myelofibrosis study publications in The New England Journal of Medicine provide compelling evidence that use of a telomerase inhibitor, such as imetelstat, may result in ground-breaking changes in how we approach the future treatment of hematologic myeloid malignancies,” John A. Scarlett, MD, president and chief executive officer at Geron, the company developing the drug, said in a statement.

The first study, which was a phase II open-label trial, enrolled 18 patients with essential thrombocythemia who had received one or more previous therapies, including hydroxyurea (94%), anagrelide (72%), and interferon (22%). Fifty percent of patients were resistant to prior therapy and 78% had stopped their prior therapy due to AEs. Patients had a median baseline platelet count of 788,000 mm³.

Intravenous imetelstat was administered weekly at 7.5 mg/kg (n = 7) or 9.4 mg/kg (n = 11) until platelet counts reached 250,000 mm³ to 300,000 mm³. For those who achieved a response, the dose frequency was reduced to once every 2 weeks or less frequently.

At a median follow-up of 17 months, 10 patients continued to receive treatment. By European LeukemiaNet clinicohematologic response criteria, 94% of patients treated with imetelstat had a complete response while 6% experienced a partial response. Complete responses were achieved within 1.4 months of receiving treatment.

A molecular response was seen in 88% of patients who tested positive for a JAK2 V617F mutation. At 3 months, the JAK V617F mutant allele burden was reduced by 71% and at 12 months the allele burden was reduced by 59%. CALR mutation burden was reduced by 15% to 58% across 5 patients. MPL W515L/K burden was reduced by 16% and 66% in 2 patients.

“The molecular responses suggest that imetelstat may have broad activity across hematologic myeloid malignancies, which warrants further clinical study in other myeloproliferative neoplasms,” co-principal investigator Gabriela M. Baerlocher, MD, of the University Hospital and University of Bern, Switzerland, said in a statement.

In this study, the most common all-grade AEs were fatigue (83%), diarrhea (78%), nausea (72%), dizziness (61%), ALT increase (56%), and AST increase (56%). Grade 3/4 AEs were reported by 83% of patients, the most common of which was neutropenia (22%). Grade 3/4 anemia, headache, and syncope each occurred in 11% of patients. At least one abnormal liver-function test was seen for all patients in the study, most of which were grade 1 or 2.

“This study was a first look at what happens when you treat essential thrombocythemia patients with a drug that has a totally novel mechanism of action,” co-principal investigator David S. Snyder, MD, associate chair, Hematology & Hematopoietic Cell Transplantation, City of Hope, said in a statement. “In the study, imetelstat had a clinically significant effect on disease burden in essential thrombocythemia patients.”

The second study enrolled 33 patients with myelofibrosis, 52% with high-risk disease and 48% with intermediate-2 risk disease. Fifty-five percent of patients had primary myelofibrosis, 30% had post-polycythemia vera myelofibrosis, and 15% had post-essential thrombocythemia myelofibrosis. Seventy-nine percent of patients were pretreated, including 48% who received a JAK inhibitor.

Imetelstat was administered at a starting dose of 9.4 mg/kg once every 3 weeks (n = 19; group A) or weekly for 4 weeks followed by once every 3 weeks (n = 14; group B). Based on AEs, the dose could be reduced to 7.5 mg/kg or 6 mg/kg.

Of the 7 patients who responded, 4 had complete responses and 3 had partial responses. The median response duration for patients who experienced a complete response was 18 months. Those with a partial response had a median response duration of 10 months. Patients who experienced a complete response had documented reversal of bone marrow fibrosis and 3 experienced a molecular remission.

"Typically, myelofibrosis is characterized by marrow scarring, and, although patients may derive symptomatic relief from other treatments, such as ruxolitinib, they usually do not revert back to normal bone marrow," lead author Ayalew Tefferi, MD, a hematologist at Mayo Clinic, said in a statement. "Some patients treated with imetelstat have reverted back to normal bone marrow."

The ORR was 27% in 26 patients with a JAK2 mutation (n = 26) versus 0% in the 7 patients without this alteration (P = .3). In those without an ASXL1 mutation (n = 22) the ORR was 32% versus 0% in the 11 patients with this alteration (P = .07). The complete response rate was 38% among 8 patients with mutations in SF3B1 or U2AF1 versus 4% in the 25 patients without a mutation in these genes (P = .04).

"We noted a difference in response rates, especially in complete remission rates, in patients with and without certain specific gene mutations, such as ASXL1, SF3B1 and U2AF1," Tefferi said. "This underscores the need for laboratory correlative studies in future clinical trials."

Across both treatment doses, all-grade AEs were seen in 45% of patients treated with imetelstat. Grade 3 AEs were apparent in 27% of patients and grade 4 in 18%. Adverse events were found to be more severe in group A compared with group B (P = .48). Treatment-related AEs included grade 4 thrombocytopenia (18%), grade 4 neutropenia (12%), grade 3 anemia (30%), and grade 1 or 2 elevations AST (27%), ALP (21%), and bilirubin (12%).

On March 11, 2014, the FDA placed a full clinical hold on the development of imetelstat following concerns over consistent low-grade liver function test abnormalities. However, follow-up safety data showed a resolution of these symptoms for most patients resulting in the FDA lifting the hold on October 31, 2014.

In November 2014, Geron entered into an exclusive license and collaboration agreement with Janssen to develop and commercialize imetelstat worldwide. Under the collaboration, imetelstat will be explored in separate phase II studies for patients with myelofibrosis, myelodysplastic syndrome, and acute myeloid leukemia (AML). Additionally, based on phase II findings, a phase III AML study could also be conducted.

References

1. Baerlocher GM, Leibundgut EO, Ottmann OG, et al. Telomerase Inhibitor Imetelstat in Patients with Essential Thrombocythemia. N Engl J Med. 2015; 373:920-928
2. Tefferi A, Lasho TL, Begna KH, et al. A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis. N Engl J Med. 2015; 373:908-919.