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Optimizing JAKi Therapy in MF
Optimizing JAK Inhibitor Therapy in Myelofibrosis: Personalizing the Path Forward for Every Patient

Released: April 11, 2025

Expiration: October 10, 2025

Pankit Vachhani
Pankit Vachhani, MD
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Key Takeaways
  • Choosing the optimal JAKi based on patient-specific cytopenias and symptom burden is critical for improving outcomes in patients with myelofibrosis. 
  • Ruxolitinib remains a standard of care for first-line therapy, and momelotinib and pacritinib are options for patients with significant anemia and thrombocytopenia, respectively. 
  • Early identification of treatment failure and a seamless transition to a second-line JAKi can preserve clinical benefits and improve survival. 

The treatment landscape for myelofibrosis (MF) has evolved significantly, with an increasing number of Janus kinase inhibitors (JAKis) that enable more personalized care. As such, healthcare professionals (HCPs) must continue to navigate the nuances of selecting the optimal JAKi for each patient and determining when it is appropriate to transition to another agent. In this commentary, I walk through how I approach initial and subsequent JAKi therapy, incorporating both clinical trial data and real-world insights to individualize a treatment plan for my patients—along with some questions from hematology/oncology teams that reflect real challenges we all face in clinical practice. 

Starting Smart: Choosing the Optimal First-line JAKi Based on Patient Profiles
When starting JAKi therapy, one size does not fit all. The choice depends heavily on the patient’s symptom burden, the presence of cytopenias, and goals of care. Ruxolitinib remains a standard of care for first-line therapy, supported by long-term data from the randomized phase III COMFORT-I/II trials. However, I increasingly find myself choosing alternative first-line agents based on patient-specific needs. 

During our live session, one audience member asked: “If a patient presents with symptomatic disease and a platelet count of 45 x 10⁹/L, what is the best frontline choice?” 

This is an excellent and practical question. In that setting, I typically favor pacritinib, which is approved by the FDA specifically for patients with intermediate- or high-risk primary or secondary MF with a platelet count below 50 x 10⁹/L. The randomized phase III PERSIST-2 trial in patients with moderate to severe thrombocytopenia at baseline (platelets ≤100 x 109/L) showed that pacritinib provides meaningful spleen volume reduction (SVR) and reduction in total symptom score with minimal myelosuppression—a crucial feature when platelets are already low. GI side effects associated with pacritinib, such as diarrhea, are manageable with early supportive care. 

Another attendee asked: “For patients with significant anemia at baseline, what first-line treatment is optimal?” 

For these patients, momelotinib may offer an advantage. The randomized phase III SIMPLIFY-1 and MOMENTUM trials demonstrated both favorable symptom and spleen volume reduction and transfusion independence. These anemia benefits, including transfusion independence and hemoglobin improvements, have been associated with improved survival. Ruxolitinib may cause or exacerbate cytopenias; however, dose modifications or interruptions, a planned dose escalation strategy (as done in the REALISE phase II study), and/or the addition of supportive care therapies for anemia can mitigate these effects. Not all patients with anemia are the same and the ability to tolerate ruxolitinib with an initial decrease in hemoglobin can differ in younger, more fit patients compared with someone who is older with multiple other comorbidities. Finally, for patients with anemia and low platelet count (≤50 x 109/L), pacritinib may be an option as well.

When to Pivot: Recognizing Suboptimal Response and Planning Next Steps
Once treatment is initiated, monitoring for inadequate response or intolerance is key. Community HCPs often ask: “What criteria do you use to define ruxolitinib failure?” 

This is a complex question. I define failure as a lack of symptom response or spleen response after at least 12 weeks at a therapeutic dose, loss of previously achieved spleen or symptom response,  unacceptable toxicity (eg, worsening cytopenias or significant weight loss), or progression to accelerated/blast phase disease state. Spleen imaging with an ultrasound or CT scan before starting a JAK inhibitor and again 4 to 6 months after a patient has started therapy should be used to detect a suboptimal response. In addition, assessing patient-reported outcomes using tools like the Myeloproliferative Neoplasm-Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) can help guide treatment decisions.

If failure is confirmed, there are good options for second-line therapy, including switching to another JAKi mentioned above (eg, from ruxolitinib to pacritinib or momelotinib) as well as the JAKi fedratinib. Fedratinib is approved for adults with intermediate-2 or high-risk primary or secondary MF, based on the phase III JAKARTA trial. Its use in second-line therapy for patients who have progressed on or were intolerant of ruxolitinib was confirmed in the phase III FREEDOM-2 trial, which showed improvement in SVR vs best available therapy.

One HCP asked: “Do you worry about Wernicke’s encephalopathy with fedratinib in the second line?” 

The development of fedratinib was put on hold by the FDA as a result of neurological symptoms, suggestive of Wernicke's encephalopathy, in 8 of 670 subjects exposed to fedratinib. Additional analysis showed that most had other explanations or circumstances that explained their symptoms. Nevertheless,I take this seriously. Before beginning therapy with fedratinib, thiamine levels should be assessed and supplemented as needed. Alternatively, as was done in the FREEDOM-2 trial, prophylactic thiamine supplementation (100 mg daily) can be considered. During therapy, monitoring should continue. With proper precautions, this risk is manageable and should not deter use in patients for whom this agent is appropriate. 

Another practical question we received was: “How do you choose between momelotinib and pacritinib in the second-line setting after previous ruxolitinib therapy?” 

I use various disease and patient characteristics when deciding on optimal second-line therapy, including the presence of any cytopenias. Similar to the first-line setting, if thrombocytopenia is a main concern, pacritinib is preferred; however, if anemia is the main concern, momelotinib may be preferred. In patients with both, the choice depends on which cytopenia is more limiting and what side effect profile the patient can better tolerate. Momelotinib may be preferred in patients with GI sensitivity (such as a history of irritable bowel syndrome).

Transitions and Sequencing: A Practical Framework for Community Teams
Sequencing JAKis and the transition from one JAKi to another requires attention to detail. I am often asked: “How do you safely switch from ruxolitinib to another JAKi without causing a flare?” 

Ruxolitinib discontinuation syndrome, a critical issue that should be taken into account, can manifest as cytokine rebound, with fevers, symptomatology, and splenomegaly, and sometimes results in considerable clinical deterioration. I usually recommend 1 of 3 approaches—direct switch, overlap, or cross-taper—depending on the patient’s status and which JAKi is being used. For patients on ruxolitinib who are switching to momelotinib, I may opt for a direct switch. In others, especially those with prior flares, I prefer a taper with corticosteroid support during the transition. For patients switching from ruxolitinib to either pacritinib or fedratinib, a treatment overlap of 3-5 days along with ruxolitinib taper could be considered due to the longer half-lives of these agents.  

Final Thoughts: Partnering With Patients to Individualize Care
The science behind JAKi therapy is continuing to evolve, but the art of treatment remains in how we engage patients. Every treatment plan should begin with a good understanding of the patient's goals, concerns, daily activities, and social determinants of health. I prioritize shared decision-making, set realistic expectations, and work to address socioeconomic or psychosocial factors that could impact adherence. Members of community oncology teams are in the best position to monitor symptoms closely, identify toxicity early, and support patients through transitions.

With more JAKi options and growing real-world experience, we are no longer bound to a one-size-fits-all approach. We can tailor therapy to not only disease risk but also to the individual journey of each patient with MF which results in meaningful, personalized care. 

Your Thoughts
How do you approach sequencing JAKis in your practice? What strategies have helped you optimize care for patients with anemia or thrombocytopenia? Share your insights and challenges—we’d love to hear how you’re personalizing JAKi therapy for your patients. 

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In your practice, for which of the following reasons do you most often switch patients from a first-line JAKi to a second-line JAKi?

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