Myelofibrosis Treatment Algorithm in 2025
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Key Points
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Bone marrow evaluation and next-generation sequencing are necessary components of initial workup for a myelofibrosis (MF) diagnosis.
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Upfront treatment for many patients is JAK inhibitor therapy with one of the four approved options: ruxolitinib, fedratinib, pacritinib, and momelotinib.
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Stem cell transplant remains the only curative option for MF, and starting the process early is recommended.
MF Treatment Paradigm
Raajit Rampal, MD, PhD, of Memorial Sloan Kettering Cancer Center, joined the cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, to discuss the current treatment landscape for patients with MF, a type of myeloproliferative neoplasm.
Diagnosis and Risk Stratification
A bone marrow biopsy is necessary to confirm a diagnosis of MF, and bone marrow sampling alongside next-generation sequencing is another primary component of the initial workup. Molecular testing supports a diagnosis as the majority of patients with MF carry common driver mutations in JAK2, CALR, or MPL, but different mutational profiles can also yield prognostic information, Dr. Rampal said.
Alongside marrow evaluation and sequencing, radiographic spleen examination, particularly spleen volume, can support a MF diagnosis and inform the starting point for therapy. Lactate dehydrogenase levels are also a minor diagnostic criterion, but are valuable to track over time as a prognostic marker.
Once a diagnosis of MF has been confirmed, patients are scored for risk based on International Prognostic Scoring System (IPSS) or Dynamic IPSS criteria. Relevant risk factors include leukocytosis, older age (over 65 years), presence of constitutional symptoms, and anemia, the last of which data suggest is a major driver of prognosis, Dr. Rampal said.
In addition to IPSS score, other risk scoring systems exist based on mutations associated with a higher risk of disease progression in primary MF (IDH1, IDH2, EZH2, ASXL1, and SRSF2). However, more recent data has challenged this profile, and the relevant mutations may be revised in the near future, according to Dr. Rampal.
Primary MF Treatment Algorithm
Risk score and symptom burden are main drivers in selecting upfront MF treatment. For lower-risk or asymptomatic patients, observation alone may be a viable approach. In symptomatic patients with splenomegaly, the standard upfront treatment is JAK inhibitor therapy with one of four approved agents: ruxolitinib, fedratinib, pacritinib, and momelotinib.
Ruxolitinib is the oldest FDA approved JAK inhibitor, and it remains an excellent choice for many patients. However, ruxolitinib dosing is attenuated based on platelet count, and doses under 10 mg twice-daily are not as effective for spleen and symptom response, Dr. Rampal said. In this setting, pacritinib may be an effective choice, as the full intensity dose is approved for patients with platelet counts under 50Ă—109/L.
Momelotinib is approved for patients with MF and anemia, and was associated with improved outcomes in ruxolitinib-exposed patients in the SIMPLIFY-2 trial. Fedratinib can also be used, but it carries a black box warning for Wernicke’s encephalopathy and tends to involve more gastrointestinal side effects, Dr. Rampal said.
While JAK inhibitor therapies have continued to evolve over time, the doctors stressed the only curative option for MF remains stem cell transplantation. “I think early referral for transplant is the right thing to do for patients with intermediate or higher risk disease to start the donor search,” Dr. Rampal said. He added that starting the transplant conversation early is key, as it can be hard to convince a patient to consider transplant after they have responded well to therapy.
When JAK Inhibitors Fail
Patients who do not respond to initial JAK inhibitor therapy and are otherwise ineligible for transplant should be referred to a clinical trial, Dr. Rampal said. Recent clinical trials explore the addition of agents alongside JAK inhibitors or evaluate novel agents with separate mechanisms of action to treat MF.
If enrollment in a clinical trial is not possible, there are data on switching from one JAK inhibitor to another. The most robust data exist for switching from ruxolitinib to fedratinib, where about 30% of patients met trial-defined criteria for spleen volume and symptom burden reduction. Most patients showed some benefit even if they did not meet response criteria, Dr. Rampal said.
Another potential approach that was more common before alternative JAK inhibitors were available is to taper a patient off of a JAK inhibitor and then reintroduce it. However, this method requires very careful tapering to avoid the serious toxicities associated with JAK inhibitor withdrawal.
Dr. Rampal stressed the value of community oncologists partnering with transplant centers, and staying abreast of clinical trial options if they are feasible for a patient with MF.