For patients with intermediate- to high-risk myelofibrosis, the combination of imetelstat (Rytelo) and ruxolitinib (Jakafi) may represent a promising strategy to enhance disease modification and deepen responses when introduced earlier in the treatment course, according to John Mascarenhas, MD.
In the second part of our interview, Mascarenhas shared preliminary findings from the phase 1/1b trial IMproveMF study (NCT02426086) presented at 2025 ASCO Annual Meeting, evaluating imetelstat in combination with ruxolitinib in patients with suboptimal response to ruxolitinib alone.
No dose-limiting toxicities (DLTs) were reported with the combination, and the recommended phase 2 dose of imetelstat was established at 8.9 mg/kg. The combination also led to symptom reductions and spleen volume reductions.
Mascarenhas is a professor of medicine at the Icahn School of Medicine at Mount Sinai, director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and a member of The Tisch Cancer Institute in New York.
OncLive: What was the rationale for combining these two agents in patients with intermediate- to high-risk myelofibrosis?
Mascarenhas: We have all of this data now—and the ongoing phase 3 [IMpact-MF] trial [NCT04576156]—on the benefit of imetelstat as monotherapy. However, the field has definitely moved toward combination therapies in this setting. We’ve seen a lot of data demonstrating synergy and deeper responses, and I would argue it’s very similar here.
We have data showing that combining the two drugs [imetelstat and a JAK inhibitor] makes sense, and that data initially comes from preclinical studies demonstrating that there is biological synergy when you combine imetelstat with JAK inhibitors like ruxolitinib. Interestingly, the sequencing of the drugs actually had the most potent anticlonal activity in the lab.
We took that into the clinic to ask: Can we synergize? First, in this phase 1b study, is it safe, and can we identify a DLT? And second, can we enhance the activity seen with imetelstat monotherapy in the relapsed/refractory setting, where the biology is more advanced, by adding it earlier on in combination before patients [progress on a] JAK inhibitor?
The idea is to move treatment earlier in the disease course as a combination approach to achieve deeper, more meaningful responses. That’s the developmental trajectory.
What were the results from this study thus far?
This phase 1b study, at least the initial results we presented at ASCO 2025, enrolled 19 patients in a dose-escalation design. Four dose cohorts were evaluated in patients with myelofibrosis who were already on ruxolitinib for at least 48 weeks. Most patients had been on therapy for 12 to 15 months. Investigators determined there was a suboptimal response to ruxolitinib, and then imetelstat was added to that stable dose.
We didn’t observe any DLTs, so we escalated up to the highest dose of 8.9 mg/kg IV every 4 weeks, and found that the toxicity profile was quite favorable. We did not see significant additive non-hematologic or hematologic toxicities. In fact, only one patient experienced grade 3/4 thrombocytopenia, and no patients came off study due to hematologic toxicity.
Overall, the regimen proved to be quite well tolerated in combination, and we were able to reach the full dose of [imetelstat].
We also saw some preliminary efficacy signals [in terms of] spleen responses, symptom responses, and reductions in driver mutations, including JAK2, CALR, and subclonal high-risk mutations like ASXL1. Again, we’ve seen this kind of effect with imetelstat as monotherapy in the relapsed/refractory setting, but this is the first data showing tolerability and potential clinical impact when combined earlier with ruxolitinib.
As we continue to follow patients and expand the cohort, we’ll gather more efficacy data, including changes in bone marrow fibrosis and cellularity, circulating CD34-positive cells, and other biomarkers. Most importantly, we’ll evaluate whether patients can stay on this drug and derive clinical benefit. This is where the phase 1b expansion becomes critical.
There is also a part 2 of this study now ongoing, which is combining imetelstat with ruxolitinib in the JAK inhibitor–naive population. This aligns with other trials looking to combine therapies up front, earlier in the disease course.
What would you say are the potential future clinical implications of these data?
Imetelstat is already an approved drug for transfusion-dependent, lower-risk MDS based on the phase 3 IMerge trial [NCT02598661]. It has clear potential to move forward as monotherapy in the relapsed/refractory myelofibrosis setting, and that’s the goal of the IMpact-MF.
This new combination study may also offer a pathway to use the drug earlier in the disease course. Rather than waiting for patients to [progress on] ruxolitinib, we might be able to introduce imetelstat in combination earlier. I could see imetelstat moving toward the commercial space as a future combination partner.
Reference
Mascarenhas J, Bradley TJ, Scott BL, et al. IMproveMF update: a phase I/IB trial of imetelstat (IME) plus ruxolitinib (RUX) in patients with intermediate-1, intermediate-2, or high-risk myelofibrosis (MF). J Clin Oncol. 2025;43(suppl 16):6515. doi:10.1200/JCO.2025.43.16_suppl.6515