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Managing MF
Experts Discuss Key Questions in the Contemporary Management of Myelofibrosis

Released: July 23, 2024

Expiration: July 22, 2025

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Key Takeaways
  • Managing symptoms, splenomegaly, and anemia in patients with myelofibrosis (MF) is nuanced; in terms of JAK inhibitor therapy, momelotinib was recently FDA approved for patients with intermediate/high-risk MF with anemia.
  • Transitioning from 1 JAK inhibitor to another can be complicated, with key considerations surrounding definition of JAK inhibitor failure and appropriate tapering/overlap of therapy during transition. 

With 4 JAK inhibitors now FDA approved to treat myelofibrosis (MF), the treatment landscape for this disease continues to evolve. In this commentary based on a satellite symposium presented in conjunction with ASCO 2024, Drs Prithviraj Bose, Lucia Masarova, and Raajit Rampal discuss nuances and best practices in treating patients with higher-risk MF.

In practice, how do we integrate available JAK inhibitors into our treatment paradigm for a patient with anemia?

Lucia Masarova, MD: Ruxolitinib was the first JAK inhibitor approved for managing MF. Ruxolitinib can cause or exacerbate cytopenias, although dose modifications or interruptions or the addition of anemia treatments can mitigate this to some extent. However, we now have momelotinib FDA approved as therapy for patients with intermediate/high-risk MF with anemia. The phase III SIMPLIFY-1 and MOMENTUM studies both demonstrated favorable symptom and spleen volume reduction and transfusion independence with momelotinib in the front-line and refractory settings, and improvements in anemia and transfusion dependency have been associated with improved survival.

Raajit K. Rampal, MD, PhD: It is important to note that anemia is relative. For example, the scenario of a person with hemoglobin of 9 g/dL who is in their 50s and is a runner is different than that of a person who has a hemoglobin of 9 g/dL and has cardiovascular disease and COPD. Those are 2 different anemias. So thinking about the degree of anemia you might be willing to tolerate is relative. When you start a JAK inhibitor like ruxolitinib, there will be a decrease in the hemoglobin vs starting momelotinib, where hemoglobin levels might be preserved. There isn't exactly one size fits all.

Lucia Masarova, MD: I agree. For example, if a patient has anemia and heart failure and fluid overload, I would probably not recommend transfusion for long and would strongly consider momelotinib; however, for the 50-year-old runner who is anemic but doesn't really have any symptoms and could tolerate transfusion, I might consider that option. If a patient is anemic but platelets are low, I would also consider pacritinib because I might not want to compromise more platelets.

Prithviraj Bose, MD​: In general, if platelets levels are ≥50 x 109/L, I would favor momelotinib in a patient with anemia. If platelets levels are less than this, I might be more likely to consider pacritinib.

Raajit K. Rampal, MD, PhD: I would agree. For the first time, we actually have choices in treating patients with MF. There are nuances, exactly as you're pointing out, in terms of how to make the decision about what drug to use. It depends on what you are trying to achieve. Sometimes, pacritinib may be the better choice if you're dealing with a very myelodepleted patient, but for a patient whose platelet counts are relatively preserved and anemia is the major problem, I would recommend momelotinib.

Lucia Masarova, MD: As a follow-up question, what is the hemoglobin cut-off to start ruxolitinib vs momelotinib in the frontline setting? The MOMENTUM trial of momelotinib vs danazol for patients with previous JAK inhibitor treatment enrolled patients with hemoglobin below 10 g/dL. There are also data on patients below 12 g/dL, and most patients have benefited from momelotinib. There is some nuance to this question; for example, if a patient has considerable symptoms and splenomegaly and is fit but anemic, I would like to have an immediate reduction of the spleen and symptoms and would not worry about inducing some transfusion dependency for 1 to 2 months. I would probably use the highest dose of ruxolitinib the patient can tolerate, and then monitor. Conversely, if I have a patient who is 70 years of age or older and frail, with hemoglobin of 9 to 10 g/dL, I might use momelotinib upfront because this patient would be at high risk of developing severe anemia with ruxolitinib. I think there is some nuance in making these treatment decisions that may go beyond simple levels of anemia.

What are best practices in transitioning from ruxolitinib to other treatments after ruxolitinib failure? How do you define ruxolitinib failure and suboptimal response?

Raajit K. Rampal, MD, PhD: There are different ways to think about this, but one thing I would advocate for is spleen imaging during this process. In our practice, we always get an ultrasound before we start a JAK inhibitor, and I usually get one 4 to 6 months after a patient has started therapy. Spleen imaging can often reveal a suboptimal response. Patients may feel a little bit better during treatment but, if you look volumetrically, their spleen size hasn’t improved much. Patients have better outcomes when spleen volume is reduced. It is often more obvious when patients are not getting enough of a symptom response. In these situations, switching to another JAK inhibitor is reasonable, as is thinking about clinical trials.

Lucia Masarova, MD: It comes down to the needs of the patient. Is it spleen size or symptom reduction? Is it cytopenias?

Prithviraj Bose, MD​: Considering transitioning from ruxolitinib, in my view, the transition to momelotinib is the easiest because both agents have short half-lives. You don't have to taper the ruxolitinib or overlap treatments. In SIMPLIFY-1, when patients crossed over from ruxolitinib to momelotinib after 24 weeks, they just started momelotinib the next day. With fedratinib and pacritinib, I would overlap treatments and taper ruxolitinib because fedratinib and pacritinib have longer half-lives; if you don’t overlap and taper, you may run into ruxolitinib discontinuation syndrome.

Raajit K. Rampal, MD, PhD: To add to that, it is also important to prepare the patient when switching to specific JAK inhibitors. For example, if the patient will be switching to pacritinib, which will take some time to onset of action, it is important to let patients know there may be sort of a short rebound in symptoms while pacritinib is taking effect.

Lucia Masarova, MD: To extend the previous conversation, can the RR6 model be used to define suboptimal response?

Prithviraj Bose, MD​: I find that very intriguing. To preface this, a recent observational study assessed potential predictors of survival in patients with intermediate-1‒risk or higher MF who had received ruxolitinib for 6 or more months. Based on multivariate analyses, 4 factors were associated with shorter survival with ruxolitinib treatment: ruxolitinib dosing of <20 mg twice daily at baseline, Month 3, and Month 6; palpable spleen length reduction of ≤30% from baseline at Months 3 and 6; RBC transfusion requirement at Month 3 and/or 6; and RBC transfusion requirement at all time points (baseline, Month 3, and Month 6). The resulting model—Response to Ruxolitinib After 6 Months (RR6)—integrates the clinical parameters of dose, spleen response, and transfusion requirement into a prognostic tool that categorizes patients as low, intermediate, or high risk, with each category having increasingly worse survival.

Defining suboptimal response was perhaps not the purpose of the RR6 model; however, with numerous agents being investigated in suboptimal response settings and no clear definition for this, RR6 may provide a good framework.

Raajit K. Rampal, MD, PhD: I agree; there is currently debate about what treatment failure is, but the RR6 has objective data that say, “These are the things that tell you that the patient is not going to do well.”

Lucia Masarova, MD: I agree. It is somewhat intuitive: the presence of anemia, lack of spleen response, and requirement of a lower dose of ruxolitinib suggest worse outcomes. I would certainly consider RR6 as guidance.

With regard to emerging investigational ruxolitinib combination therapy for MF, do you think that, once approved, most practitioners will use combination therapy in the first-line setting vs using ruxolitinib monotherapy and waiting until there's a suboptimal response and then adding the novel agent on?

Raajit K. Rampal, MD, PhD: This would refer to combinations like pelabresib plus ruxolitinib, which was associated with improved spleen response over ruxolitinib alone as first-line therapy for higher-risk MF in the phase III MANIFEST-2 trial. 

Prithviraj Bose, MD​: I think I would strongly consider reserving the novel agent to add to ruxolitinib if a suboptimal response was observed.

Lucia Masarova, MD: I think this would be my approach as well.

Raajit K. Rampal, MD, PhD: Do you think there is room for subtlety here? For example, we know that the presence of certain mutations (eg, ASXL1, DNMT3A) can be predictive of earlier time to treatment failure with ruxolitinib. Do you think something like this would influence your decision to use combination therapy, or do you think that's too subtle a point?

Prithviraj Bose, MD​: I agree that in the presence of high molecular risk , the recommendation will likely be combination therapy from the outset.

Raajit K. Rampal, MD, PhD: What about spleen size? For example, a patient with a spleen volume of 1000 mL vs a patient with a spleen volume of 3000 mL; a 35% reduction isn't likely to have a great impact with a 3000 mL spleen. Does that also factor in here?

Lucia Masarova, MD: Absolutely. I would certainly prefer the combination for patients with very large spleens.

Raajit K. Rampal, MD, PhD: It sounds like we need more data to determine who the best patients are for upfront combination therapy, but it sounds like there's abundant room for second-line add-on therapy.

Your Thoughts

How do you approach patients with anemia and splenomegaly and symptomatic MF? What has been your experience with transitioning from one JAK inhibitor to another? Please answer the polling question or leave a comment to join the conversation.

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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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