Systemic Therapies for Myelofibrosis


Abdulraheem Yacoub, MD, details the systemic therapy options for myelofibrosis and his approach to treatment sequencing.

Case: A 68-Year-Old Woman with Myelofibrosis

  • A 68-year-old woman presented to her physician with symptoms of mild fatigue, moderate night sweats, and abdominal pain/fullness lasting 4 months; she also reported increased bruising and unexplained weight loss
  • Spleen was palpable 8 cm below the left costal margin
  • Genetic testing shows a JAK2 V617F mutation; CALR negative; Karyotype: 46XX
  • Bone marrow biopsy: megakaryocyte proliferation and atypia with evidence of reticulin fibrosis
  • Blood smear reveals leukoerythroblastosis
  • Diagnosis: Primary myelofibrosis
  • Risk: DIPSS: Intermediate-2; MIPSS70: Intermediate risk
  • Labs demonstrate:
    • RBC 3.40 x 1012/L
    • HGB 13.2 g/dL
    • HCT 36%
    • MCV 94 fL
    • WBC 23.0 x 109/L
    • PLT 450 x 109/L
    • PB Blasts 1%


Abdulraheem Yacoub, MD: We’ve established that the JAK-STAT pathway is the cornerstone for pathogenesis for myelofibrosis. Therapy with JAK inhibitors has become the backbone for all therapies for myelofibrosis. The first agent approved was ruxolitinib based on the COMFORT-I and COMFORT-II studies, which were presented in 2001. Ruxolitinib has been approved for the last 12 years, with consistent postapproval data that show remarkable improvement in a patient’s quality of life and symptoms, significant reduction in spleen volume in most patients on therapy, and a true improvement in overall survival for patients who received this therapy. This has become the cornerstone for therapy for myelofibrosis and will likely be the backbone for all future therapies for myelofibrosis. If anything, this has become a standard template to build on with combinations for myelofibrosis. It has become the expectation or the minimum therapy you offer patients.

After the success of ruxolitinib, we’re fortunate to have 2 additional active agents that are very helpful for many patients. Based on the JAKARTA and JAKARTA-2 studies, fedratinib was approved in 2015 for patients with myelofibrosis as a first-line [therapy]. It’s also a fair therapy for patients beyond first line. The most recent addition was pacritinib, which was approved in 2022 for patients with cytopenic myelofibrosis and platelet counts of under 50,000 per mm3, which was a specific unmet need. This is a category of patients who had no approved therapy. Both ruxolitinib and fedratinib are approved for patients with platelet counts of over 50,000 per mm3 with the goals of spleen volume reduction, symptom improvement, and overall survival advantage in the case of ruxolitinib. But both drugs are contraindicated for patients with platelet counts of under 50,000 per mm3 with the risk of bleeding and severe cytopenias.

Pacritinib is a unique JAK inhibitor that addresses the different benefits between JAK1 and JAK2 and has other targets, such as IRAK1 and activin receptor 1, that result in a different clinical benefit. It continues to provide significant spleen reduction and symptom improvement, but it doesn’t result in furthering the cytopenias. If anything, it might result in improvement in anemia. It’s a safe therapy for patients with severe thrombocytopenia, and it’s approved as a first-line therapy for that. Beyond first-line therapy, after patients have had 1 JAK inhibitor, it’s reasonable to offer 1 of the other 2 JAK inhibitors as a second-line therapy. [We do this] if they continue to have symptoms—such as big spleen or high constitutional symptoms—and the treating physician believes a JAK inhibitor would be of benefit. Second-line therapy with a JAK inhibitor is indicated and becoming a common practice in many settings.

My first-line therapy for the majority of patients is ruxolitinib based on the data that showed activity and improvement in survival. Ruxolitinib is approved for patients with platelet counts of 50,000 per mm3 or higher. We dose patients differently based on their platelet count. We use different dose levels for different thrombocytopenia levels. That remains our first-line therapy. For patients with platelet counts of under 50,000 per mm3, the approved therapy is pacritinib at a dosage of 200 mg twice a day. That’s my standard first-line therapy for patients who would benefit from a JAK inhibitor. For patients who are not having a successful therapy—because of lack of benefit or unacceptable toxicities—if I believe they would benefit from another JAK inhibitor, we often switch them. If somebody started with ruxolitinib, it’s reasonable to offer them fedratinib or pacritinib as a second-line therapy. For patients who started with pacritinib who are candidates for JAK inhibitor therapy, a reduced dose of ruxolitinib can be offered, especially if I believe they would benefit from a JAK inhibitor. This has become a standard approach for many patients. Most of our patients end up getting 1, 2, or 3 JAK inhibitors during their journey with myelofibrosis.

Transcript edited for clarity.

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