FDA-Approved JAK Inhibitors in Myelofibrosis: Mechanisms, Indications, and Clinical Impact

Four JAK inhibitors—ruxolitinib, fedratinib, pacritinib, and momelotinib—are FDA-approved for the treatment of myelofibrosis, each with nuanced differences in clinical indications. Ruxolitinib and fedratinib primarily address symptomatic splenomegaly and disease-related symptoms, whereas pacritinib is indicated for patients with severe thrombocytopenia. Momelotinib is unique in its dual mechanism, targeting both JAK1/2 and ACVR1, which can help alleviate anemia in addition to symptom control. Ruxolitinib’s approval was based on pivotal clinical trials demonstrating significant reductions in splenomegaly, improvement in symptom burden, and overall tolerability, establishing it as the first disease-modifying therapy in myelofibrosis. Its introduction fundamentally shifted treatment sequencing, positioning JAK inhibitors as first-line therapy for symptomatic patients and redefining the therapeutic landscape, while also highlighting the importance of personalized selection based on cytopenias, comorbidities, and patient-specific treatment goals.