<p>The clinical presentation of the patient with myelofibrosis is important when selecting a treatment regimen because there is no single therapy that is appropriate for all patients. The choice of therapy should be goal oriented and focused on cytopenias, the spleen, the symptoms involved, and individual patient characteristics.</p>

The guiding principle when treating myelofibrosis should be to know what it is that you are treating in an individual patient because there is not one treatment that is right for every single patient. For example, in someone who has anemia alone (ie, without an enlarged spleen) and a few other symptoms that are not related to the anemia, JAK inhibitor therapy may not be the right treatment choice. For this type of patient, the off-label use of an erythropoiesis-stimulating agent or an immunomodulatory drug might be the right choice.

 

For those who have spleen involvement or additional symptom burden, JAK inhibitors should enter into the treatment conversation. Now that there are multiple JAK inhibitors available, the choice of agent is more complicated than it was before, but there are certain patient characteristics that can guide us in the selection of a specific JAK inhibitor for an individual patient.

 

For example, in those who have profound thrombocytopenia (ie, platelet counts <50,000/µL), pacritinib may be a good choice because it has demonstrated efficacy. More recently, momelotinib was approved by the US Food and Drug Administration (FDA) for patients with myelofibrosis and anemia. However, it is important to distinguish between the different levels of anemia, ranging from patients with mild asymptomatic anemia to those who are transfusion dependent, to determine what the right JAK inhibitor may be for each patient. For patients with more preserved blood counts, fedratinib and ruxolitinib have both shown good efficacy as first-line therapy in clinical trials.

 

When selecting therapy for an individual patient, it is also important to consider the side-effect profiles of the various agents and the patient’s comorbidities. Overall, the choice of therapy comes down to what you are trying to treat, how you are trying to treat it, and what drug might interact best with the patient.

The treatment of myelofibrosis remains goal oriented and is focused on anemia, the spleen, and/or the patient’s clinical symptoms. Initially, treatment choices are often governed by the patient’s platelet count. Pacritinib is FDA approved for individuals with platelet counts of less than 50,000/µL, and we have a wealth of data that give us confidence that full dosing will provide clinical benefit. Momelotinib is also now FDA approved and may be another option to consider in patients with platelet counts of less than 50,000/µL based on data from the MOMENTUM and SIMPLIFY-1 studies.

 

For patients with platelet counts of greater than 50,000/µL, there are more options. Ruxolitinib is often the go-to drug for most patients in this category because we have more than a decade of experience with it. We have comfort that it will address the spleen and patient symptoms; however, it does not improve hemoglobin or platelet counts. Fedratinib can be used first line as a selective JAK2 inhibitor based on data from the JAKARTA study, although it is often reserved for second-line therapy after failure with ruxolitinib as per the JAKARTA-2 trial. Interestingly, you can use a drug from the same class and still obtain additional spleen and symptom improvements even after ruxolitinib exposure.

 

If anemia is the sole issue for a patient with myelofibrosis, you can consider following a treatment algorithm that is similar to those used for myelodysplastic syndromes: check erythropoietin levels and treat accordingly with the off-label use of either an erythropoiesis-stimulating agent or an immunomodulatory drug, depending on the degree of the anemia. For patients with anemia in the setting of ruxolitinib therapy, adjunctive, off-label therapies such as luspatercept and lenalidomide can be considered, or momelotinib can be used instead of ruxolitinib.

 

Overall, you need to tailor the approach to the patient and observe the patient to make sure that they are adequately responding from a symptom and/or spleen perspective, meaning that you need to take a very detailed review of systems to determine whether the patient is receiving optimal benefit from their therapy. There is a school of thought that the more significant the spleen or anemia response, the better the survival. But it is important to keep in mind that these drugs do not induce histopathologic remissions or complete responses. That remains a significant unmet need and is the subject of ongoing clinical trials that are studying whether we can find ways to get deeper, more durable responses and prolong progression-free and overall survival.

An ongoing question for physicians is: How do you choose the right JAK inhibitor for patients with myelofibrosis as new agents become available? We have a lot of experience with ruxolitinib, and it is helpful to have a lot of postmarketing data and a sense of safety with this drug. The various available agents have similarities, but they are not the same. They have different specificities for different proteins and pathways that they inhibit, and this has to be considered, as they relate to both the toxicity profiles and, ultimately, their efficacy. You need to look at not only what you are treating but also who we are treating and the safety profile of the drug. Some patients are relatively healthy when they come to us, but others are less so. For example, some people are on anticoagulation therapy or have a history of heart disease that could limit the use of a drug, and these patient-specific factors must be considered when selecting the best therapy for the patient.

 

There is clinical evidence that patients do not appear to have worsening anemia with momelotinib; in fact, it might even resolve anemia in some patients. However, we do not have a lot of long-term data with this therapy, and we will need to continue obtaining clinical evidence to determine whether it is as safe and well tolerated as some of the other JAK inhibitors that we have more experience with using.

 

Momelotinib and pacritinib are both fairly potent inhibitors of ACVR1, and it appears that the level of inhibition is fixed with these drugs. There are ongoing evaluations to study novel molecules, including ACVR1 inhibitors and TGF-β ligand trap molecules that are dosed independently together with JAK inhibitors, which would give you the opportunity to titrate the level of inhibition that is achieved with these molecules based on the patient whom you are treating. However, determining whether this approach can improve clinical outcomes will require long-term trials.