The IMpactMF trial is a phase 1/1b study evaluating the addition of Imetelstat to ruxolitinib for myelofibrosis patients who show an inadequate response to ruxolitinib alone. By combining these therapies earlier in treatment, the study aims to assess safety, tolerability and potential efficacy, offering hope for improved outcomes. In this interview, touchHAEMATOLOGY Editorial Board member Dr. John Mascarenhas (Icahn School of Medicine at Mount Sinai, New York, NY, USA) shares insights into the trial’s design, findings and implications for the future of myelofibrosis care.
Q1. Can you share an overview of the trial and its primary objectives?
Certainly. The IMpactMF trial is an early-phase study – specifically phase 1/1b – examining the addition of Imetelstat to patients who have been on a stable dose of ruxolitinib for at least 12 weeks. These patients were deemed by their investigators to have an inadequate response to ruxolitinib alone, so this study was very much investigator-driven. The primary question being addressed is whether Imetelstat can be delivered in this manner and, importantly, whether it is tolerable.
To provide some context, Imetelstat has shown activity as a single agent in prior studies, such as the IMbark trial. In that study, a dose of 9.4 mg/kg administered every three weeks demonstrated promising outcomes in patients with relapsed or refractory disease who had failed JAK inhibitors. There were indications of a survival benefit, along with improvements in spleen size and symptoms. What we’re exploring in the IMpactMF trial is whether this drug could be moved earlier in the treatment paradigm and used in combination with ruxolitinib.
While the phase III single-agent study of Imetelstat in the relapsed/refractory setting is ongoing, we’re taking a proactive approach here by investigating its potential synergy when combined with ruxolitinib earlier in the treatment timeline. This approach aligns with a broader theme in myelofibrosis treatment: starting with single-agent use in later stages and, if the results are promising, moving to combination therapies earlier in the disease course.
Q2. What was the design and dosing strategy of the IMpactMF study?
The study included cohorts starting at a dose of 4.7 mg/kg of Imetelstat, escalating up to 9.4 mg/kg administered intravenously every four weeks, all in combination with ruxolitinib. To get straight to the main finding: the combination was very well tolerated, with no dose-limiting toxicities (DLTs). We were able to expand the cohort receiving 9.4 mg/kg, which we now recognize as the recommended phase II dose.
Interestingly, we did not observe significant grade 3 or 4 thrombocytopenia, which I had anticipated might be a limiting factor. Nor did we encounter much in the way of severe non-hematologic toxicities. The one side effect that stood out was musculoskeletal pain, reported by about 40% of patients, typically in their arms and legs. This was unexpected since we hadn’t seen it in prior studies of single-agent Imetelstat. It wasn’t dose-dependent and seemed to occur around the time of infusion. While it’s unclear what to make of this finding, it wasn’t a reason for treatment discontinuation.
In this early analysis involving 17 patients, the treatment was not only safe and tolerable but also showed hints of dose-dependent improvements in spleen size and symptom relief. However, the data are still preliminary, particularly for the 9.4 mg/kg cohort, which requires more time to fully read out. We’re eager to see the longer-term outcomes to assess not just the safety but also the efficacy of this approach.
Q3. As we await results from the ongoing phase III study, what factors do you think should be prioritized when evaluating Imetelstat’s clinical benefits compared to the best available therapy?
That’s a great question. The primary endpoint of the phase III study is overall survival, so the priority will be determining whether Imetelstat offers a clear survival benefit. Beyond that, we’ll need to evaluate the balance between efficacy and tolerability. For instance, does the drug lead to significant toxicities, such as myelosuppression or gastrointestinal side effects? How many treatment cycles can patients reasonably tolerate? And is there a minimum number of cycles required to achieve meaningful clinical benefits?
One intriguing possibility, based on prior studies, is that prolonged exposure to Imetelstat may not be necessary. In advanced, sick patients, even a relatively short course of 6–8 cycles might be enough to reduce the clonal stem cell pool and translate into a survival benefit. This hypothesis will need to be tested, but it’s a compelling idea as we consider ways to optimize the treatment’s risk-benefit profile.
Q4. How might the crossover feature for patients on best available therapy (BAT) who experience disease progression impact the final conclusions of the IMpactMF study?
The inclusion of a crossover option does add complexity to the survival analysis, but it’s an ethical necessity. If patients receiving BAT experience disease progression, it would be unfair to deny them access to a potentially beneficial therapy like Imetelstat. While this complicates the analysis, it’s important to remember that the trial is not placebo-controlled; all patients are receiving some form of active treatment.
That said, the trial excludes JAK inhibitors from the BAT arm, so some patients might leave the study to start a JAK inhibitor. It will be crucial for investigators and sponsors to continue monitoring these patients for survival outcomes. Ultimately, if Imetelstat is as effective as we hope, the survival benefit should persist regardless of subsequent therapies. I’m optimistic that an intention-to-treat analysis will demonstrate a meaningful survival advantage, even accounting for crossover. I look forward to seeing how these studies evolve and sharing more as the data mature.
Interview based on the oral abstract 1801.1: ‘Imetelstat Versus Best Available Therapy in Patients with Intermediate-2 or High-Risk Myelofibrosis Relapsed or Refractory to Janus Kinase Inhibitor in IMpactMF, a Randomized, Open-Label, Phase 3 Trial’, which was presented at the 66th ASH Annual Meeting & Exposition on 7–10 December 2024 in San Diego, CA, USA.
Disclosures: Dr Mascarenhas is a consultant for Incyte, Novartis, Geron, Keros, BMS, Sobi, karyopharm, GSK, Merck, Pfizer, Roche, PharmaEssentia, Morphosys, Keros. He has received grant/research support from Incyte, Novartis, BMS, SOBI, AbbVie, PharmaEssentia, Ajax, Geron, Kartos, Karyopharm, Disc.
Acknowledgement: Editorial Assistance was provided by Joey Heywood at Touch Medical Media.
