For patients with relapsed or refractory myelofibrosis, imetelstat (Rytelo) may offer a promising treatment option aimed at prolonging survival and modifying disease course following JAK inhibitor failure, according to John Mascarenhas, MD.
In an interview with OncLive®, Mascarenhas discussed the rationale for investigating imetelstat in this setting, reviewed key findings from the preceding phase 2 data, and outlined the objectives of the ongoing phase 3 IMpact-MF trial (NCT04576156), which is evaluating imetelstat vs best available therapy.
Mascarenhas is a professor of medicine at the Icahn School of Medicine at Mount Sinai and director of the Adult Leukemia Program at The Tisch Cancer Institute in New York, New York.
OncLive: Can you provide an overview of the IMpact-MF trial and the rationale for evaluating imetelstat in patients with relapsed or refractory myelofibrosis?
Mascarenhas: The IMpact-MF study is an ongoing, randomized phase 3 study evaluating imetelstat, which is a telomerase inhibitor. It’s a drug that has rationale [in this setting] and targets an enzyme that’s important for elongating DNA, which is critical for cell survival and proliferation. [hTERT] is a well-described and validated target in myelofibrosis that is upregulated in myelofibrosis hematopoietic stem cells and only transiently [expressed] in normal stem cells.
What were the key findings from the prior phase 2 IMbark trial (NCT02426086) that evaluated imetelstat in JAK inhibitor–pretreated myelofibrosis and informed the design of the IMpact-MF study?
We have phase 2 data demonstrating a [potential] improvement in overall survival [OS] in the relapsed/refractory setting in myelofibrosis. [For] patients who [progress on] ruxolitinib [Jakafi], their median survival is estimated to be approximately 12 to 14 months. And [in IMbark] we saw that [with imetelstat given] at 8.9 mg/kg every 3 weeks intravenously administered, median OS was 29.9 months [95% CI, 22.8-not evaluable (NE)]. It did suggest an [OS] benefit there. We had a lower-dose arm, I should point out, that had a median OS of 19.9 months [95% CI, 17.1-NE]. Therefore, [we saw] a dose-dependent improvement in survival, as well as improvement in symptomatology.
Thirty-two percent [of patients treated at the 8.9-mg/kg dose achieved] a total symptom score reduction of 50% or greater, and a 10% [achieved] a 35% spleen volume reduction or better. It hit multiple disease feature hallmarks, and we were able to show a relationship between the biomarkers for telomerase inhibition with these clinical outcome measures.
What is the primary goal of this ongoing phase 3 trial, and what differentiates imetelstat from currently available treatment options in this setting?
The randomized phase 3 study of patients who [progressed on] ruxolitinib or other JAK inhibitor therapy is looking for improvement in disease burden [and] prolongation of OS as an outcome. [Enrolled patients] are randomly assigned to imetelstat vs best available therapy [BAT]. Imetelstat, again, is intravenously administered every 3 weeks, and BAT could be investigator’s choice, with the exception of a JAK inhibitor; the study does exclude JAK inhibitors in that control arm.
The primary end point is OS. That is unique in the myelofibrosis field because spleen and symptom assessment that are typically the regulatory endpoints. This study is ongoing, and I’m hoping we’ll finish accrual in 2025. Then, of course, we need to follow these patients [closely].
This is [seeking to fulfill] an unmet need: improving OS. We do look at end points beyond survival, including spleen response, symptom response, [and] anemia response. We did see anemia responses with this drug in the phase 2 study.
I should point out that imetelstat is an approved drug in myelodysplastic syndromes [MDS] for lower-risk, transfusion-dependent MDS, [based on data from the phase 3 IMerge trial (NCT02598661)]. There’s a lot of rationale for why this drug would work in myeloid malignancies.
What important factors and potential challenges should clinicians consider when evaluating patients for trial enrollment?
[One] barrier may be [that] patients are often really sick and may not qualify for a trial once they [progress on a] JAK inhibitor. My recommendation always is, don’t just wait for the patient to become quite ill. If they’re not doing well on ruxolitinib or another JAK inhibitor that they’re on, get them into centers that have [the Impact-MF study] ongoing so they can be evaluated for this trial, particularly those patients where the emphasis might be on prolongation of survival, which is not always the case for every patient.
You might have a very elderly patient where the focus is on comfort, and [the goal is] not necessarily trying to improve survival. The goal of therapy obviously dictates what treatment makes sense for each individual patient. It has to be personalized.
[Imetelstat] is an infusional agent, so a patient needs to be at the infusion center every 3 weeks for a drug like this. There is the potential for myelosuppression, so patients who already have significant cytopenias are probably not great candidates for a drug like this. The cytopenias are reversible, but that’s also a factor that might influence decision-making for treatment like this.
For some patients, it may [also] be a nice bridge to the ultimate treatment, which is the only treatment we have that has curative potential, which is a bone marrow transplant. [However], not every patient is a transplant candidate; in fact, many patients are not. For many patients, this drug could be used outside of the usual world of JAK inhibition, for those patients that are looking to achieve disease course modification, progression-free survival, [and] OS.
Reference
Mascarenhas J, Harrison C, Bose P, et al. IMpactMF, randomized, open-label, phase 3 trial of imetelstat versus best available therapy in patients with intermediate-2 or high-risk myelofibrosis relapsed or refractory to Janus kinase inhibitors. Presented at: 2025 EHA Congress; June 13, 2025; PF841.