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FAQs: Treating Myelofibrosis
Rapid-fire Answers to Key Questions in Treating Myelofibrosis

Released: July 24, 2023

John Mascarenhas
John Mascarenhas, MD
Ruben A. Mesa
Ruben A. Mesa, MD
Brady L. Stein
Brady L. Stein, MD, MHS
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Key Takeaways
  • JAK inhibitors are effective in reducing spleen volume and improving symptoms of myelofibrosis, both of which are key treatment goals for patients.
  • Platelet count is key when determining treatment approaches for patients with myelofibrosis.
  • Symptom tracking with patients is crucial to determine efficacy of JAK inhibitor treatment. 

Primary goals in treating myelofibrosis (MF) include reduction of splenomegaly, improvement in symptoms and quality of life, and extension of survival. For patients with higher-risk prognostic scores, allogeneic stem cell transplant should be considered. For those with disease-related symptoms and/or splenomegaly independent of transplantation decision-making, 3 FDA-approved oral JAK inhibitors can be considered: ruxolitinib, fedratinib, and pacritinib. In this commentary derived from a live symposium, 3 experts provide their thoughts on current and emerging issues and nuances in the management of patients with MF.

How should JAK inhibitors be positioned for treating patients with MF?

Brady L. Stein, MD, MHS:
Prognostic scores can be very discrepant from clinical presentation and symptomatology; for example, some patients with low-risk MF can have a high symptom burden. So, when we are thinking about a nontransplant approach to management of patients with MF, we generally are thinking about symptomatology.

We currently have 3 approved JAK inhibitors, and a fourth likely will be commercially available in the near future. In the first-line setting, if the platelet count is >50 x 109/L, there are 2 options: ruxolitinib or fedratinib. Overwhelmingly in clinical practice, based on experience, ruxolitinib is the first choice. For a patient who has a platelet count of <50 x 109/L, pacritinib can be considered, and for a patient who has an indication for a JAK inhibitor but who is transfusion dependent, momelotinib could be considered, if this becomes available.

Let’s briefly discuss the most recently approved JAK inhibitor: pacritinib. The approval of pacritinib was supported by data from several randomized phase III clinical trials, including PERSIST-1 and PERSIST-2, both of which assessed pacritinib for patients with higher-risk MF. The PERSIST-1 study included patients with any platelet count, and  PERSIST-2 looked at different dosing options in patients with thrombocytopenia. These trials showed that pacritinib improved spleen volume reduction and symptom improvement vs best available therapy, including in patients with low platelet counts.

Pacritinib also has clinical data in patients with anemia, for which there is currently an unmet need in treatment for patients with MF. What we learned from PERSIST-2 is that some patients who received pacritinib experienced hematologic stability or improvement, and some patients who were transfusion dependent appeared to have clinical improvement in anemia.

John Mascarenhas, MD:
Let’s also look at momelotinib, which is not yet approved for treating patients with MF. MOMENTUM was a randomized, double-blind phase III study evaluating momelotinib vs danazol in patients with MF and anemia who had previously received ruxolitinib but had a symptom and spleen burden and platelet count of ≥25 x 109/L.

In terms of symptom improvement, momelotinib was associated with a ≥50% total symptom score reduction at Week 24 in 25% of patients compared with 9% of patients receiving danazol. Danazol, as we have seen, is not a great drug for symptom improvement, but it can be effective for treating anemia. In terms of spleen volume reduction, momelotinib outperformed danazol in the second-line setting with ≥35% spleen volume reduction in 22% of patients vs 3% of patients receiving danazol.

It was recognized early in the development of this drug that there did seem to be durable anemia responses. In total, 30% of patients in MOMENTUM were transfusion independent at Week 24 with momelotinib vs 20% with danazol.

What are some tips to optimize ruxolitinib use?  

Brady L. Stein, MD, MHS:
Ruxolitinib is effective regardless of mutational status, so a patient does not have to have a JAK2 mutation to respond. We also observe responses even if they are CALR or MPL positive.

Dosing based on platelet count is important. In patients with anemia, you may consider starting at lower doses and working your way up. In clinical practice, we often approach patients in the way the REALISE clinical trial presents. Their strategy involved starting patients with MF and anemia at 10 mg ruxolitinib twice daily and gradually escalating their dose based on platelet count. By using this gradual ramp-up strategy, patients had excellent spleen volume control, and compared with their baseline, there were no significant changes in hemoglobin or transfusion requirements.

What do you ask your patients to track in terms of symptoms or other disease-related factors?

Brady L. Stein, MD, MHS:
I think it is important to track basic symptoms. The symptoms I always ask them about in clinic are the symptoms I also want them to think about: Energy level, night sweats, weight, and itching are important. It also depends on why we started JAK inhibitor therapy. If there are considerable spleen-related symptoms, tracking those takes precedence. We use a lot of visits to educate about what we expect in terms of effectiveness and safety.

What are current gaps in treating patients with MF?

Ruben A. Mesa, MD, FACP:
Currently, there are numerous gaps in treating patients with MF. How do we define who needs treatment vs prognostic risk? Do we treat patients who are lower risk, and by which set of prognostic scores? I think we also transplant too few patients with MF, and we probably wait too long when we do. People ask me what the best time to have a transplant is, and the best answer is probably before you think you need one.

Our JAK inhibitors clearly have been helpful, but how do we optimize which agent when, and which dose? Finally, we have the gap of how we predict progressive disease. We still are flying somewhat blind until we have better biology parameters regarding progression.

How should patients be transitioned to second-line JAK inhibitor therapy?

Ruben A. Mesa, MD, FACP:
The reasons people discontinue ruxolitinib include lack of response, loss of response, ruxolitinib-related adverse events, and disease progression. As we think about a definition, it is something of a sliding scale. What does failure look like in your practice?

John Mascarenhas, MD:
It is hard to define JAK inhibitor failure in practice. Failure can appear in the form of nonresponse to ruxolitinib with continued large spleen and high symptom burden—a primary refractory type of patient. Then you get the patients who have a suboptimal response, and that is a form of failure, I would argue. You get patients who have a fantastic initial response, and you watch that response lessen over time with progressive spleen size, worsening symptom burden, or blood counts. At some point you must draw the line to say there was failure, but it is not always black and white.

Ruben A. Mesa, MD, FACP:
What about using a different JAK inhibitor? Let’s say you switch from one commercial agent to another. What is your threshold?

Brady L. Stein, MD, MHS:
It is important for us to have commercially available options. We always prefer a trial, but one is not always feasible for a patient.

The threshold is variable. Although we can see a sudden change in leukemic progression, which is very difficult, what I tend to see is more like what Dr Mascarenhas described: a gradual creep in symptoms or spleen size, such that every time you measure the spleen, it is closer to the size it was before the patient started treatment. When they are getting back to where they were before they were receiving ruxolitinib, that is typically my threshold for changing therapy.

John Mascarenhas, MD:
For the minority of patients with primary refractory disease, I generally consider an alternative JAK inhibitor. For patients with suboptimal response, dose optimizing the current JAK inhibitor first is important, as is looking at add-on therapy options to ameliorate the symptom or spleen burden.

Your Thoughts?
What are some key considerations in your practice when approaching treatment for patients with MF? How do you currently approach treatment following JAK inhibitor failure, and what investigational approaches do you feel address the biggest clinical practice gaps? Please answer the polling question and join the conversation by posting a comment in the discussion section.

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In your current practice, for which of the following do you most commonly switch patients from a first-line JAK inhibitor to a second-line JAK inhibitor?

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