Emerging Therapies in Myelofibrosis Could Extend Beyond JAK Inhibitors

Raajit K. Rampal, MD, PhD

The September 2023 FDA approval of momelotinib (Ojjaara) for the treatment of patients with primary and secondary myelofibrosis with anemia provided the treatment paradigm with its fourth FDA-approved JAK inhibitor, a class of drugs that has helped improve symptoms associated with myelofibrosis and decrease spleen size, according to Raajit Rampal, MD, PhD.

Additional classes of drugs, such as BET inhibitors and immunotherapy agents, are also currently under investigation in clinical trials and could become “game-changers” if effective, Rampal noted.

“The major [message is] that myelofibrosis is not a monolithic disease, and the selection of the treatment needs to be tailored to the underlying issues and challenges the patient is facing,” said Rampal in an interview with OncLive®.

In the interview, Rampal discussed currently available JAK inhibitors and their limitations, emerging treatments for myelofibrosis, tips for treatment selection, and his takeaways from the 6th Annual Miami Cancer Institute Global Summit on Immunotherapies for Hematologic Malignancies.

Rampal is a hematologist-oncologist, the director of the Center for Hematologic Malignancies, and the director of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive: How effective are the FDA-approved JAK inhibitors in managing myelofibrosis, and what are their limitations?

Rampal: [JAK inhibitors are] beneficial for patients. They help with symptoms and reduce the size of the spleen, but they don’t do either of those things to the extent that we want. There’s also a question of the durability of response [achieved with these agents], which wanes over time. Therefore, we need [to develop] therapies that can help us [improve upon] the important benefits [patients receive] from the currently available JAK inhibitors.

What therapies are emerging for patients with myelofibrosis, and how might these continue to shape the treatment paradigm?

A lot of different treatments are emerging, which is great because we have more potential options for patients. A lot of combination therapies are being explored right now, such as pelabresib [CPI-0610], which is a BET inhibitor and has finished phase 3 trials. The topline data [from the phase 3 MANIFEST-2 trial (NCT04603495) of this agent plus ruxolitinib (Jakafi) in patients with JAK inhibitor–naive myelofibrosis were] presented [in December 2023], and a paper pertaining to [findings from this trial was published in March 2025]. [The study] showed that patients achieved a better spleen response and a trend toward a better symptom profile with combination therapy [consisting of pelabresib plus ruxolitinib vs placebo plus ruxolitinib]. There also seemed to be a better durability of response with the combination, so we have to see how these data mature.

Other agents are now in phase 3 trials that we don’t know the data from yet. Selinexor [Xpovio], which is FDA-approved for relapsed/refractory multiple myeloma, is being studied in combination with ruxolitinib [in patients with JAK inhibitor–naive myelofibrosis in the phase 3 XPORT-MF-034 trial (NCT04562389)], and navtemadlin—an MDM2 inhibitor—[is under investigation as an add-on therapy to ruxolitinib in patients who have a suboptimal response to ruxolitinib in the] phase 3 [POIESIS] trial [NCT06479135]. Those trials are still accruing, so we don’t know much about them yet. Beyond that, novel JAK inhibitors are now in clinical trials, including JAK inhibitors that may be a bit more potent and selective than the ones we have. Those are in early-phase trials.

Additionally, among the more exciting [developmental classes of agents is] immunotherapy. We have calreticulin-targeted antibodies, of which 2 are in trials. Those have the potential to be game changers if they’re effective, but we’ll have to see because we don’t have current data [with those agents], as those trials are accruing.

In your practice, what factors do you consider when selecting treatment for patients with myelofibrosis?

[My decisions] depend on the problem. If a patient has profound symptoms and a large spleen, then any of the JAK inhibitors could be used, including ruxolitinib and fedratinib [Inrebic]. However, if the patient is very anemic, then I consider momelotinib. If they have profound thrombocytopenia, then pacritinib [Vonjo] makes sense. We’re fortunate to be in an era where we can be selective about the drugs we use.

What is your main message regarding the future evolution of myelofibrosis management strategies?

It’s good to be aware of the JAK inhibitors we have, as well as the limitations and danger signs [associated with these agents]. Spleen size reduction correlates with survival, and we need to measure patients’ spleens on a serial basis during their treatment. In patients who show [signs of] red flags, meaning that their spleen is getting bigger or not shrinking, we need to prioritize [their treatment and recommend] clinical trials or other therapies. Those are important landmarks to be aware of.