Reaching for the Holy Grail in Myelofibrosis With Imetelstat Combinations

In an exclusive interview with Blood Cancers Today (BCT) at the ASH Annual Meeting 2024, John Mascarenhas, MD, Icahn School of Medicine at Mount Sinai, New York, New York, talked about the development of the human telomerase inhibitor imetelstat for the treatment of myelofibrosis (MF). He shared updates about imetelstat as an investigational monotherapy and as a combination therapy with Janus kinase (JAK) inhibitors, including data from the IMproveMF study, which was presented at ASH.

BCT: Could you tell us about the rationale of the IMproveMF study and the unmet need that may be addressed by this trial?“

The rationale of the trial is based on the cumulative evidence that targeting telomerase, which is an enzyme that’s constitutively activated in CD34-positive cells of patients with MF, is a potential disease-modifying approach to MF,” explained Dr. Mascarenhas. Imetelstat is an approved drug for patients with transfusion-dependent lower-risk myelodysplastic syndrome, and there is evidence that it has the potential to reduce clonal markers of the disease. “We have all of this preclinical data, a lot of it generated from work that Dr. Ron Hoffman has done here at Mount Sinai, indicating that imetelstat is an anticlonal stem cell–directed therapy. Dr. Ayalew Teferry was the first pioneer to test imetelstat in patients with MF as a single agent in the relapsed/refractory setting, demonstrating pretty profound responses in the bone marrow and promising histopathologic and molecular responses.”¹

Consequently, Dr. Mascarenhas and colleagues designed a larger, randomized, phase 2 multicenter study in the relapsed and refractory setting. In this trial, imetelstat was associated with spleen volume reductions and a modest degree of symptom improvement. “The results were comparable to symptom improvement with second-line JAK inhibitors,” clarified Dr. Mascarenhas. “However, most notable and most impactful was the survival that we saw in the 9.4 mg/kg dose arm. We observed a median overall survival of almost 30 months, compared with about 19 or 20 months in the 4.7 mg/kg arm.² This compares favorably to multiple independent reports showing that patients with MF who failed on JAK inhibitors have a median survival somewhere between 12 and 15 months.” Dr. Mascarenhas further explained that the responses appeared to be correlated with on-target activity: modulation of hTERT [human telomerase reverse transcriptase] RNA expression levels, telomerase activity, and markers of disease biology, such as driver mutation and bone marrow fibrosis grade. “All this data suggested that the drug was anticlonal, which endorsed the randomized, phase 3 study. In this trial, imetelstat will be compared with the best available therapy, excluding a JAK inhibitor, in patients with MF who have progressed on a JAK inhibitor.”³

“At this point, I think it’s natural to ask some questions with regard to the application of imetelstat in MF,” Dr. Mascarenhas continued. “Do we wait for patients to fail on ruxolitinib? Should we add imetelstat earlier on?” A number of years ago, Dr. Hoffman’s group presented a preclinical abstract at ASH that provided the rationale for combining the two agents, ruxolitinib and imetelstat, in targeting these MF CD34 cells.⁴ “This is pretty much the holy grail,” according to Dr. Mascarenhas. “Based on these findings we decided to do a phase 1b study. We dose escalated imetelstat, starting at a dose of 4.7 mg/kg, and went up in several dose cohorts to 9.4 mg/kg, every 4 weeks. Imetelstat is intravenously administrated in this group of patients with MF that had been on a stable dose of ruxolitinib for at least 4 weeks. It was the investigators’ decision whether patients showed a suboptimal response in terms of anemia, spleen reduction, or symptom burden. Subsequently, imetelstat was added to the treatment regimen of these suboptimally responding patients.” The data, which are being presented at ASH 2024,⁵ show that the combination is well tolerated. “We didn’t see any dose-limiting toxicities in the 17 enrolled patients,” said Dr. Mascarenhas. “We did see some myelosuppression, anemia, and neutropenia, as was expected. Fortunately, these were manageable and reversible cases. Moreover, we did not see grade 3 or 4 thrombocytopenia.” Dr. Mascarenhas mentioned that musculoskeletal pain of the extremities was a notable, but not necessarily concerning, toxicity.

“Furthermore, we did not observe a lot of dose modifications or discontinuations due to toxicity, which is the primary aim of a phase 1 study,” Dr. Mascarenhas continued. “Since we never hit a dose-limiting toxicity, the recommended phase 2 dose for the expansion going forward is going to be 9.4 mg/kg, intravenously administered, every 4 weeks.” Dr. Mascarenhas said there are preliminary efficacy data as well. “We will show some data with regard to spleen response, symptom reduction, and driver mutation response, but we do not have a lot of efficacy data yet.”

BCT: What are the next steps? Are you trying to identify which patients may respond well to the combination?

“It is not likely that we’ll identify the subset of patients for whom this combination is ideal,” responded Dr. Mascarenhas. “The question was, can we combine ruxolitinib and imetelstat safely? The answer is yes. If we continue on this road, we will probably have results in 2026 in terms of a readout for the randomized, phase 3 study and as a single agent with a survival endpoint. We should think about how to generate data with respect to earlier use of this combination therapy. One cohort that we are intending to do is an upfront cohort. That would be the next step. Thus, JAK inhibitor–naive patients would receive ruxolitinib and imetelstat in the first-line setting. This approach has been tested with different agents, such as pelabresib, navitoclax, and selinexor. The idea is to not wait for patients to have more advanced disease but to try and get synergy of combination therapies up front.”

BCT: Can you say something about the pharmacokinetic properties of this combination therapy?

“We looked at the pharmacokinetic profiles of imetelstat and ruxolitinib to ensure that one drug wasn’t interfering with the metabolism of the other drug,” answered Dr. Mascarenhas. “Fortunately, we did not see such an interference pattern. For imetelstat, we observed a dose-dependent C_max [maximum concentration] that was reached in approximately two hours after the start of infusion, and it mimicked what was seen in the monotherapy setting. So, it was not affected by ruxolitinib. Conversely, we noticed the dose-dependent C_max and clearance that you would expect to see for ruxolitinib monotherapy. Thus, there were no concerning drug-drug interactions.” 

BCT: What is the take home message for your colleagues?

“The current phase 1 study showed that the combination of ruxolitinib and imetelstat is well tolerated in patients with MF,” concluded Dr. Mascarenhas. “The recommended phase 2 dose of imetelstat will be 9.4 mg/kg, intravenously administered, every 4 weeks, in combination with ruxolitinib. With reassuring pharmacokinetic profiles and early signs of clinical activity, I look forward to the further development of this combination in MF.”

1. Tefferi A, Lasho T, Begna K et al. A Pilot study of the telomerase inhibitor imetelstat for myelofibrosis. N Engl J Med. 2015;373:908-919. doi: 10.1056/NEJMoa1310523
2. Mascarenhas J, Komrokji R, Palandri F, et al. Randomized, single-blind, multicenter phase ii study of two doses of imetelstat in relapsed or refractory myelofibrosis. J Clin Oncol. 2021;39(26):2881-2892. doi: 10.1200/JCO.20.02864
3. Mascarenhas J, Harrison C, Kiladjian J, et al.  randomized open label, phase 3 study to evaluate imetelstat versus best available therapy in patients with intermediate-2 or high-risk myelofibrosis refractory to janus kinase inhibitor. HemaSphere. 2022;6(suppl):938-939. doi: 10.1097/01.HS9.0000847060.14020.7d
4. Hu C, Huang F, Hoffman R, et al. Combination treatment with imetelstat, a telomerase inhibitor, and ruxolitinib depletes myelofibrosis hematopoietic stem cells and progenitor cells. Blood. 2019;134(Suppl 1):2963. doi: 10.1182/blood-2019-126189
5. Mascarenhas J, et al. Trial update from IMproveMF, an ongoing, open-label, dose-escalation and -expansion, phase 1/1B trial to evaluate the safety, pharmacokinetics, and clinical activity of the novel combination of imetelstat with ruxolitinib in patients with intermediate-1, intermediate-2, or high-risk myelofibrosis (MF). Abstract #998. Presented at the American Society of Hematology Annual Meeting; December 7-10, 2024; San Diego, California.