Approved Treatments for Myelofibrosis


A review of the approved treatments for myelofibrosis, including dosing guidelines and supporting clinical trial data.

John Mascarenhas, MD: There are multiple treatment options. I’ll start with Srdan. How would you first embark in treating the patient I’m describing?

Srdan Verstovsek, MD, PhD: Raajit [Rampal, MD, PhD] described very well that the unified biological problem in every patient is hyperactivity of the JAK-STAT [Janus kinase-signal transducer and activator of transcription] pathway. Then you have other biological parameters and different clinical problems on top of it. But therapy with JAK inhibitors would certainly be advised, and that can then lead to a choice of different JAK inhibitors based on the clinical scenario. But inhibition of the JAK-STAT pathway in general is called for.

Ruxolitinib, pacritinib, and fedratinib are the 3 JAK inhibitors approved in the United States for use in myelofibrosis patients. With inhibition of the JAK-STAT pathway, you’d improve the quality of life of the patients and decrease the spleen [size]. This is known for ruxolitinib. Many years ago, ruxolitinib was approved based on the COMFORT-I [NCT00952289]and COMFORT-II [NCT00934544] studies in patients with platelets above 100,000 per mm3, and later in patients with platelets above 50,000 per mm3 in subsequent studies. It would be very good for control of the spleen and symptoms, but unfortunately at the expense of worsening anemia and thrombocytopenia. That’s why it’s difficult to use it in people with very low platelets.

Fedratinib followed suit in 2019 when it was approved based on studies that were similar to the ruxolitinib studies. In particular, the JAKARTA [NCT01437787] study in the frontline setting showed a similar response in the spleen and in symptoms with fedratinib at 400 mg a day. That’s once a day, unlike ruxolitinib, which is twice-a-day dosing. In that setting, you had improvement in the spleen and symptoms, but the potential for worsening anemia and thrombocytopenia.

Only recently, pacritinib, a JAK inhibitor that improves the spleen and symptoms, was approved for people with low platelets, perhaps based on several distinctive factors that pacritinib has over ruxolitinib and fedratinib. One of them might be an additional mode of action. It’s now shown that pacritinib may inhibit IRAK1, and through that, inhibit the signaling through NF-kappaB and decrease the cytokine levels in the blood of the patients, which would lead to more of the anti-inflammatory potential of it, in addition to the antiproliferative JAK2 inhibition. A fine balance between the inhibition of the 2 parallel signaling pathways—one through the JAK-STAT and the other through NF-kappaB—leads to the safety of pacritinib, which is called for in people with low platelets.

We know that pacritinib was approved 3 months ago specifically for patients with platelets below 50,000 per mm3. It’s the balance between these biological activities that leads to the ability of pacritinib to control the spleen and symptoms without causing much anemia or thrombocytopenia at all. In fact, some results suggest that anemia improves for a fraction of patients. The red blood cell count goes up in some patients. It’s quite a different JAK inhibitor. But in overall assessment of needs, you’d say, “We need a JAK inhibitor for control of the spleen and symptoms,” and then you go to the next step and ask, “Which one?” That’s based on the clinical scenario of the individual patient.

John Mascarenhas, MD: Aaron, the next question is for you. Are there distinct clinical scenarios or situations, as Srdan alluded to and described nicely, in which you’d clearly prescribe pacritinib vs ruxolitinib vs fedratinib?

Aaron Gerds, MD: Srdan nicely laid out the development of each of these drugs and some of the key differences among them. Now that we have 3 JAK inhibitors commercially available, and possibly 4 in the future, how are we going to try to sort through using all of these? Back when there was just ruxolitinib, the choice wasn’t hard. There was just 1. Now it’s a little more difficult. Thinking about how each of these performs in different patient populations is the key. Ruxolitinib has been around a lot longer, at least in commercial availability, and everyone has a high degree of familiarity and comfort when prescribing it. That’s the one that we have to start with.

In which patients does this tend to work best? Certainly patients who have higher counts, where you can be more forgiving with the anemia and thrombocytopenia adverse effects. Ruxolitinib typically seems to perform quite well in patients who have more cytokine-type disease with night sweats, fevers, and really big spleens. The other clear answer here is that pacritinib seems to outperform ruxolitinib in folks who have more suppressed marrows, low platelet counts, and higher degrees of anemia, not only based on data from the PERSIST [NCT01773187] studies but also from the PAC203 [NCT03165734] study and a lot of the subsequent analyses that have been done ad hoc looking at patients treated with lower doses of ruxolitinib. That’s because you’re limited due to the cytopenias vs pacritinib, with the concept that Srdan brought up that you can get full-dose JAK inhibition without totally trashing the counts.

The bigger challenge is what to do with fedratinib in this situation. Where do we use it? There are frontline data for fedratinib where it performs quite well. But you’re also challenged with some of the adverse effects of fedratinib, particularly the off-target effect on FLT3 that leads to GI [gastrointestinal] symptoms and adverse effects, and trying to balance that out. There are some data suggesting that fedratinib performs quite well in patients with platelet counts between 50,000 and 100,000 per mm3. That middle spot might be a role for fedratinib. There are good data for fedratinib in the second-line setting based on the JAKARTA-2 [NCT01523171] study and the re analysis of the JAKARTA-2 study, where patients previously treated with ruxolitinib then go on to get fedratinib, where they can get good spleen responses and symptom burden control. That’s another situation where fedratinib can be beneficial.

John Mascarenhas, MD: Aaron, thanks for laying that out. As you pointed out, there are multiple options, and that makes it good and challenging at the same time in trying to figure out where to place the optimal drug in each situation.

Transcript edited for clarity.

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