Novel Agents in the Pipeline for Myelofibrosis


A comprehensive review of novel agents currently under investigation with a potential role in the myelofibrosis treatment landscape.


Pankit Vachhani, MD: Pelabresib—or CPI-0610—is a first-in-class oral small molecule inhibitor of the BET [bromodomain and extraterminal domain] proteins. These are proteins which are involved in the modification of the expression of genes in the NF [nuclear factor] kappa B pathway, which is activated and contributes to the pathogenesis and symptoms associated with myelofibrosis. Dr Marina Kremyanskaya [MD, PhD, at the Icahn School of Medicine at Mount Sinai, New York City, New York] presented the results of cohort 1 of the MANIFEST study, which is an ongoing, global, open-label phase 2 study with many cohorts. Dr Kremyanskaya presented the results at ASH [American Society of Hematology Annual Meeting] 2021. In cohort 1, which was the cohort that looked into patients with advanced MF [myelofibrosis], who were either intolerant or refractory to or ineligible for ruxolitinib therapy, they received pelabresib monotherapy.

Overall, 86 patients were eligible for analysis, and more than 90% of the patients had either intermediate-2 or high-risk myelofibrosis. In terms of the transfusion dependency to transfusion independency conversion, that rate was 16%, and the median time to that transfusion independency conversion was 32 weeks. In patients who were not transfusion dependent at baseline, there still was a hemoglobin response noted, which improved over time from baseline to as long as about 72 weeks or so from the presentation. The spleen volume reduction was also notable in the second-line setting. The SVR35 [35% spleen volume reduction from baseline] rate, which is the classically looked-upon rate where we look into 35% or more spleen volume reduction, that rate using pelabresib monotherapy, was 11% at week 24, while SVR25 or 25% volume reduction was 31%. In terms of a 50% reduction in the total symptom burden, 28% of patients achieved this at 24 weeks. Additionally, the investigators also showed that about 23% of patients had an improvement of their bone marrow fibrosis grade, while around 43% of patients had bone marrow fibrosis stabilization. Wonderfully, they additionally also showed that the improvement or stabilization in the bone marrow fibrosis grading also corresponded with an improvement in hemoglobin. They also further showed a downregulation of very many different cytokines when they looked into about a 68-cytokine panel, from baseline to a later time point, [such as] around 24 weeks.

Ruben Mesa, MD: Momelotinib is a JAK1 and JAK2 inhibitor that has been tested now in numerous clinical trials, including the simplified trials of which I was a principal investigator in now the MOMENTUM study. The simplified trial was as frontline and a noninferiority study compared with ruxolitinib, where it was noninferior for splenomegaly. Over time, we found that it was probably noninferior for symptoms, and as we've done more in-depth analysis, potentially some superiority as it relates to cytopenias as we look through a variety of different analyses. The MOMENTUM [Multi-OutcoMe EvaluatioN of radiation Therapy Using the MR-Linac] study is a more recent study. We will be presenting the data formally at the upcoming 2022 ASCO [American Society of Clinical Oncology] Annual Meeting in June, where momelotinib was used as a second-line therapy for individuals with difficult symptoms and anemia compared with the current standard for an anemia-only drug out there, Danazol [danocrine], where it was found to be superior in terms of control of splenomegaly and symptoms—and not inferior to—better in terms of improvements in anemia. It is an interesting agent—a new agent that may become commercially available in the near future as these results and the kind of aggregate results from the numerous trials from momelotinib are reviewed by the regulatory bodies.

Stephen T. Oh, MD, PhD: As far as new or developing therapies, it's honestly a very exciting time in the field right now. We have, I think, at least 6 different agents that are in phase 3 studies for myelofibrosis, and this is in addition to pacritinib, which was just recently approved. Just to finish off the JAK inhibitor class, we now have ruxolitinib, fedratinib, pacritinib—which are all FDA [United States Food and Drug Administration] approved. Momelotinib is currently in phase 3 studies with the MOMENTUM study. The top-line results of that study were just recently announced, and they are positive. It's looking quite promising that that drug may be approved in the near future. In particular, momelotinib is unique in that it seems to provide some degree of anemia benefit, which is in contrast to the other JAK inhibitors and especially ruxolitinib, which, if anything makes anemia worse. If that drug becomes available in the near future, it seems like it will have a particular niche for patients who have anemia as a predominant feature of myelofibrosis.

Now, there are other agents in other categories which are also in phase 3 and looking quite promising. One example, imetelstat, is a telomerase inhibitor. This has been a bit of a torturous path, like some of these agents, as far as getting close to approval. But really what's intriguing about imetelstat in particular is the suggestion that it may be able to provide some degree of prolongation of survival. This is something where, with the JAK inhibitors, you're mostly focused on symptom benefits, or in the case of, for instance, momelotinib, anemia benefits. Now, there may be some degree of survival benefits with the JAK inhibitors as a class, as well as in particular with specifically achievement of anemia benefit or transfusion independence, but with imetelstat as being in a completely different class of drugs with the suggestion that it may provide a survival benefit—is certainly very encouraging.

Transcript edited for clarity.

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