Dr Mascarenhas on the Safety of Imetelstat Plus Ruxolitinib in Higher-Risk Myelofibrosis

"The toxicity profile was quite remarkable; we didn’t see a lot of additive, nonhematologic toxicity, or even hematologic toxicity."

John O. Mascarenhas, MD, a professor of medicine at the Icahn School of Medicine at Mount Sinai; as well as director of the Center of Excellence for Blood Cancers and Myeloid Disorders, director of the Adult Leukemia Program, and a member of The Tisch Cancer Institute, discussed the safety profile of imetelstat (Rytelo) in combination with ruxolitinib (Jakafi) for patients with intermediate-1, intermediate-2, and high-risk myelofibrosis.

In the phase 1b IMproveMF dose-escalation study (NCT05371964), 19 patients with myelofibrosis who had experienced a suboptimal response to ruxolitinib were enrolled to receive intravenous imetelstat every 4 weeks and continue a stable ruxolitinib dose. The trial explored 4 escalating dose levels of imetelstat, culminating in a maximum dose of 8.9 mg/kg. Treatment continued for a minimum of 48 weeks, with most patients receiving therapy for 12 to 15 months, Mascarenhas said.

According to Mascarenhas, no dose-limiting toxicities (DLTs) were observed in any of the cohorts, enabling escalation to the highest planned dose. The combination was well tolerated, with only 1 patient experiencing grade 3/4 thrombocytopenia, he said. Importantly, no patients discontinued treatment due to hematologic toxicity, and there were no signals of additive nonhematologic toxicity. Mascarenhas emphasized that the absence of significant overlapping adverse effects supports the feasibility of dual pathway inhibition in this setting.

He noted that the trial’s findings represent an important step toward optimizing outcomes in patients with suboptimal responses to JAK inhibition. Imetelstat, a first-in-class telomerase inhibitor, may complement ruxolitinib’s mechanism of action by targeting malignant stem cell populations, and its administration every 4 weeks offers logistical convenience for long-term therapy. The trial investigators concluded that the favorable safety profile observed in this trial supports continued evaluation of the imetelstat/ruxolitinib combination in larger, later-phase trials.