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.