<p>With 4 JAK inhibitors having US Food and Drug Administration (FDA) approval for myelofibrosis and no optimal therapeutic sequence for them, the selection of an initial and a subsequent therapy requires the consideration of each patient’s unique disease presentation and the presence or absence of cytopenias.</p>

The first question that I ask myself when seeing a new patient with myelofibrosis is: Is this someone whom I would consider for a curative approach with an allogeneic stem cell transplant, or should they receive symptom-directed treatment with a JAK inhibitor? Transplant may be reasonable for patients with higher-risk disease who are otherwise healthy and fit, but many patients are not candidates. Other questions to consider are: How is the patient’s disease presenting, and what can we hope to accomplish with treatment? Patients with myelofibrosis often present with enlarged spleens that are causing disease-related symptoms such as fevers, chills, night sweats, bone pain, or weight loss. Other patients may present with cytopenias.

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In patients with myelofibrosis presenting with symptomatic splenomegaly or constitutional symptoms, JAK inhibitors are the clear standard of care. Ruxolitinib reduces spleen size, improves disease-related symptoms, and is even associated with a survival benefit. However, it tends to exacerbate anemia and lower platelet counts, so sometimes we cannot use ruxolitinib, or we have to use it at lower doses that are less effective. Fedratinib has a similar efficacy profile to ruxolitinib and also tends to cause or worsen anemia and thrombocytopenia. Fedratinib is also associated with more gastrointestinal toxicity and has a boxed warning from the FDA regarding encephalopathy. Finally, pacritinib and momelotinib have been able to expand the benefits of JAK inhibition (ie, spleen reduction and symptom improvement) to patients with myelofibrosis who have anemia and/or thrombocytopenia.

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Instead of establishing sequencing by saying that one drug is our first-line treatment, another is our second-line treatment, and a third is our third-line treatment, it is about matching the treatment with the patient. What are the patient’s presenting disease-related features, and what can these agents do to address them? You can use all of these JAK inhibitors in the frontline setting, as their FDA approvals are treatment-line agnostic. There are not enough data to say, “Oh, you have to use this agent as a frontline therapy.” At the end of the day, we are trying to help patients feel better, and that may mean something different to each one.

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It can be a little dangerous to abruptly stop ruxolitinib therapy because some patients can develop cytokine release syndrome, where their symptoms return quite quickly and mimic an inflammatory or infectious event. So, when you switch from ruxolitinib to another agent, you may have to overlap the treatments for a few days or taper the ruxolitinib.

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If someone has been on ruxolitinib, becomes anemic, and switches to momelotinib, it is not a problem to go back to ruxolitinib if their anemia improves but they feel worse. Again, you are trying to find the drug that makes the most sense for the patient. Frequently, physicians will say, “The patient has already been on ruxolitinib, so we cannot go back to it.” However, you definitely can. In fact, you now have data on how the patient felt on ruxolitinib therapy, you know how they feel on the new agent, and you can talk with the patient and ask them what makes the most sense for them. The patient may say, “I want to try ruxolitinib, but maybe we can add a supporting agent to help with the cytopenia.”