The treatment paradigm for myelofibrosis has undergone significant transformation over the past decade, evolving from a single therapeutic option to a personalized approach utilizing four distinct JAK inhibitors. This evolution enables clinicians to tailor treatment strategies based on individual patient presentations, addressing the heterogeneous nature of this rare chronic myeloproliferative neoplasm.
Current JAK Inhibitor Arsenal
The FDA has approved four JAK inhibitors for myelofibrosis treatment, each with distinct clinical advantages. Ruxolitinib (Jakafi), the pioneering agent approved in 2011, remains a cornerstone therapy with demonstrated survival benefits. However, optimal efficacy requires appropriate dosing, with experts emphasizing that doses below 15 mg twice daily—and potentially below 20 mg twice daily—may not provide optimal therapeutic benefit.
"Ruxolitinib, we must remember, has a survival benefit. It is a great drug that has a survival benefit, but it has to be dosed appropriately," explained Dr. Prithviraj Bose from the University of Texas MD Anderson Cancer Center during the Society of Hematological Oncology 2025 Annual Meeting.
The newer agents address specific clinical challenges. Momelotinib (Ojjaara) demonstrates particular utility in anemia-predominant presentations, while pacritinib (Vonjo) offers benefits for patients with severe thrombocytopenia, though to a lesser degree than momelotinib regarding anemia management. Fedratinib (Inrebic) serves as an effective second-line option for patients who have progressed on ruxolitinib, particularly those with significant splenomegaly and preserved blood counts.
Addressing Disease Complexity
Myelofibrosis presents unique therapeutic challenges due to its heterogeneous nature. The disease is characterized by abnormal hematopoietic stem cell proliferation in bone marrow, leading to fibrosis that impairs healthy blood cell production and results in cytopenias, particularly anemia and thrombocytopenia. Compensatory blood cell production shifts to the spleen and liver, causing splenomegaly and hepatomegaly.
"The biggest problem with myelofibrosis—this constellation of symptoms that patients can experience, which can really decrease the quality of life for these patients," noted Jessica Lewis-Gonzalez, PharmD, BCOP. These symptoms include fatigue, night sweats, fever, and weight loss, driven by inflammatory processes from bone marrow scarring.
Personalized Treatment Selection
The expansion of therapeutic options has enabled a more nuanced approach to treatment selection. For anemia-predominant cases, momelotinib and pacritinib offer advantages over ruxolitinib, as they can be dosed at full strength regardless of blood counts, whereas ruxolitinib dosing may be constrained by cytopenia.
"I go to momelotinib when it is an anemia-predominant picture. Although pacritinib also has some anemia benefit, I think momelotinib has more of a benefit in that regard," Dr. Bose explained.
For second-line therapy, fedratinib provides an effective option for patients with preserved blood counts who have progressed on ruxolitinib. "Fedratinib in the second line—I don't use it in the first line—is a really good drug for spleen and symptoms when you have blood counts that are relatively robust," Dr. Bose noted.
Emerging Therapeutic Horizons
Beyond JAK inhibitors, the treatment landscape continues to evolve with emerging therapies targeting specific aspects of myelofibrosis. For anemia management, drugs including DISC-0974, elritercept, and luspatercept-aamt (Reblozyl) are showing promise. Additionally, interferons are generating excitement for early-stage disease, including pre-fibrotic and clinically early overt myelofibrosis, though data remains preliminary.
The evolution from a single therapeutic option to multiple targeted approaches represents a significant advancement in myelofibrosis management, allowing clinicians to address the disease's heterogeneous presentations more effectively while optimizing patient outcomes through personalized treatment strategies.
