Evaluating Imetelstat for Patients With Relapsed/Refractory Myelofibrosis

In a phase II trial presented at the 2018 ASH Annual Meeting conducted in patients with higher-risk myelofibrosis (MF) who had relapsed following or had not responded to JAK inhibitor therapy, approximately one-third responded to treatment with imetelstat. The findings were presented by John Mascarenhas, MD, from Icahn School of Medicine at Mount Sinai in New York.

“Imetelstat is an oligonucleotide that specifically targets the RNA template of human telomerase and is a potent competitive inhibitor of telomerase enzymatic activity,” Dr. Mascarenhas explained. Its clinical activity and toxicity were established in an earlier pilot study of patients with intermediate-2 (int-2) or high-risk MF – nearly half of whom had been previously treated with a JAK inhibitor.

Patients were eligible for the analysis if they had int-2 or high-risk MF, active symptoms of MF, and measurable splenomegaly at baseline (palpable spleen ≥5 cm below the left costal margin). A total of 107 patients were enrolled, stratified based on spleen size (≥15 cm or <15 cm) and platelet counts (75-150×109/L or >150×109/L), then randomized to receive intravenous imetelstat at 9.4 mg/kg (n=59) or 4.7 mg/kg (n=48), every three weeks.

Baseline characteristics were well balanced between the two arms, Dr. Mascarenhas reported. In the entire population, the median age was 68 years (range = 31-86 years), 62 percent had a spleen that was ≥15 cm below the left costal margin, and 25 percent were red blood cell transfusion–dependent. Also, 98 percent of patients had at least one detectable mutation, and 74 percent had three or more mutations. “The median time to discontinuation of ruxolitinib was less than two months, and the duration of JAK inhibitor therapy was approximately two years,” he added, highlighting that this was a heavily pretreated patient population.

The researchers assessed spleen response and symptom response at week 24 (co-primary endpoints) and continued to follow patients to evaluate overall survival (OS).

At the planned interim analysis after 20 patients in each arm had been treated for at least 12 weeks, the lower-dose arm was closed because it didn’t meet its prespecified endpoints, the authors noted. Twelve of the 48 patients randomized to the 4.7-mg/kg group were able to escalate to the 9.4-mg/kg arm.

As of April 26, 2018 (data cutoff for the primary, 24-week analysis), patients had a median follow-up of 22.6 months (range = 0.2-27.4 months). The median duration of imetelstat treatment was 6.2 months (range = 0.0-27.2 months), although this was influenced by the early closure of the low-dose arm, Dr. Mascarenhas noted.

At week 24, six patients (10.2%) in the 9.4-mg/kg arm met the primary endpoint of spleen response per MRI (achieving ≥35% spleen volume reduction), while no patients on the 4.7-mg/kg arm had a response. Nineteen patients (32%) and three patients (6%), respectively, reached the endpoint for symptom reduction (achieving a ≥50% reduction in Total Symptom Score).

Treatment with imetelstat also appeared to improve bone marrow fibrosis: Among the 57 patients who had bone marrow assessments available at baseline and follow-up, 19 (33%) had at least one grade reduction in fibrosis.

Fifty patients (47%) had agreed to ongoing follow-up in the OS analysis, and, as of the October 22, 2018 data cutoff, median follow-up was 27.4 months (range = 0.2-33.0 months).

Median OS was 19.9 months (95% CI 17.1 months to not estimable) in the 4.7-mg/kg group and 29.9 months (95% CI 22.8 months to not estimable) in the 9.4-mg/kg group (p value not reported). “If we accounted for censoring at the time of dose escalation, subsequent JAK inhibitor use, or subsequent stem cell transplantation – which some patients were able to go on to – the survival was still superior at the higher dose,” Dr. Mascarenhas said.

The authors also looked specifically at patients with triple-negative disease (JAK2 V617F, CALR, and MPL mutations) to determine whether a certain molecular profile could predict poor outcome. They found no significant differences in survival in the low-dose arm but observed a higher median OS for triple-negative patients in the higher-dose arm: not estimable versus 24.6 months (range = 20.7 months to not estimable; p values not reported). “Patients [who] would likely do poorly – those with triple negativity – didn’t have worse outcome on this drug,” Dr. Mascarenhas noted.

Myelosuppression was the most common adverse event (AE) reported in the study and was “to be expected based on earlier trials,” he added. Rates of grade ≥3 cytopenias in the 4.7-mg/kg and 9.7-mg/kg groups were as follows:

  • thrombocytopenia: 11 (23%) and 24 (41%)
  • anemia: 15 (31%) and 23 (39%)
  • neutropenia: 5 (10%) and 19 (32%)
  • leukopenia: 3 (6%) and 8 (14%)

Most grade 3/4 cytopenias were reversible within four weeks, Dr. Mascarenhas reported.

Grade ≥3 non-hematologic AEs included dyspnea, asthenia, and fatigue, and seven patients experienced a grade 3/4 liver function test (LFT)elevation. The FDA previously placed imetelstat on a clinical hold over concerns about LFT elevations in earlier studies, but an independent committee reviewed the hepatic toxicities and found that none of the abnormalities in this trial were related to imetelstat treatment.

Overall, the safety profile was deemed manageable for this high-risk, poor-prognosis population, and, together with the median OS data, the authors concluded that imetelstat 9.4 mg/kg every three weeks warrants further testing in clinical trials.

The study is limited by the small patient population and lack of a comparator arm. Observations about the response rates with certain molecular profiles also will need to be confirmed and evaluated in larger studies, Dr. Mascarenhas added.

The authors report relationships with Janssen, which sponsored the trial.


Mascarenhas J, Komrokji RS, Cavo M, et al. Imetelstat is effective treatment for patients with intermediate-2 or high-risk myelofibrosis who have relapsed on or are refractory to Janus kinase inhibitor therapy: results of a phase 2 randomized study of two dose levels. Abstract #685. Presented at the 2018 ASH Annual Meeting, December 3, 2018; San Diego, CA.