AMSTERDAM – For patients with low-risk myelodysplastic syndrome (MDS) for whom erythropoietin therapy has failed, the novel telomerase inhibitor imetelstat may provide long-lasting independence from transfusion, investigators reported.
Among 38 patients with low-risk MDS who had relapsed or were refractory to treatment with an erythropoiesis stimulating agent (ESA) who received imetelstat, 16 (42%) were free from the need for transfusion for at least 8 weeks, with one patient being transfusion free for up to 141 weeks, reported Pierre Fenaux, MD, of Hôpital Saint-Louis in Paris.
Patients with a generally worse prognosis “tended to respond better to imetelstat in terms of transfusion independence, which suggests that the drug is promising for higher-risk MDS,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.
Imetelstat is a first-in-class telomerase inhibitor targeting cells with short telomere lengths and active telomerase, the enzyme that maintains telomere length. Higher telomerase activity and shorter telomeres are predictive of shorter overall survival in patients with MDS, Dr. Fenaux explained.
He and colleagues enrolled 38 patients, median age 71.5 years, with low-risk MDS, with an International Prognostic Scoring System (IPSS) score of low or intermediate-1, whose disease was relapsed or refractory to ESA or to erythropoietin at a dose of more than 500 mU/mL. Of this group, 24 patients had IPSS low disease, 14 had intermediate-1 disease.
The median transfusion burden was 8 units per 8 weeks (range 4-14). The majority of patients (34, or 89%) had received prior ESAs.
The patients were transfusion dependent, defined as the need for 4 or more units of red blood cells within 8 weeks over the 16 weeks prior to study entry.
No patients had the 5q deletion, and no patients had received either a hypomethylating agent or lenolidamide (Revlimid), neither of which are approved for this indication in Europe.
The patients received imetelstat 7.5 mg/kg intravenously every 4 weeks.
As noted earlier, 16 patients (42%) achieved the primary endpoint of 8-week transfusion independence, with a median duration of 85.9 weeks (range 8-141 weeks).
Eleven patients (29%) had transfusion independence lasting at least 24 weeks – a secondary endpoint – and 26 (68%) met International Working Group 2006 criteria for a HI-E (erythroid) response, with 12 of these patients having an increase in hemoglobin of 1.5 g/dL or greater lasting for at least 8 weeks, and all 26 having a reduction in transfusions of 4 or more units over 8 weeks.
There was evidence to suggest a disease-modifying effect of imetelstat, with five patients achieving a complete response (CR), and five having a marrow CR.
The most frequent adverse events were manageable and reversible grade 3 or greater cytopenias, but there were no new safety signals seen. Two patients were hospitalized for febrile neutropenia, but there were no treatment-related deaths.
Based on these results, investigators are planning a phase 3 study comparing imetelstat with placebo in a 2:1 ratio. The trial is scheduled to begin in the late summer or fall of 2019.
When asked if imetelstat might have off-target effects by inhibiting telomerase in other cells, Dr. Fenaux replied that the mechanism of action is unclear, and that its potential effects on erythropoiesis are still unknown.
Briefing moderator Anton Hagenbeek, MD, of Amsterdam University Medical Center, commented on the drug’s potential for treating MDS, and asked whether investigators are considering combining it with other therapies for MDS.
“I think the first step will be to study it in high-risk MDS as a single agent before combining it, including with hypomethylating agents, et cetera,” Dr. Fenaux replied.
SOURCE: Fenaux P et al. EHA 2019, .