Managing myelofibrosis in the frailty era: the expanding role of JAK inhibitors

Myelofibrosis (MF) is a clonal myeloproliferative neoplasm that predominantly affects older adults and is frequently complicated by anemia, thrombocytopenia, and multimorbidity. In this setting, therapeutic goals extend beyond disease control to include symptom relief, preservation of functional status, transfusion avoidance, and minimization of treatment-related toxicity. Janus kinase (JAK) inhibitors are the cornerstone of therapy for symptomatic intermediate- and high-risk MF, with four oral agents approved: ruxolitinib, fedratinib, pacritinib, and momelotinib. We performed a narrative review of phase II/III randomized and prospective trials evaluating these agents in primary and post-polycythemia vera/essential thrombocythemia MF, including eight pivotal studies. While all JAK inhibitors reduce splenomegaly and symptom burden, their distinct safety and hematologic profiles define different clinical niches: ruxolitinib and fedratinib are limited by myelosuppression, pacritinib is effective in severe thrombocytopenia, and momelotinib improves anemia and transfusion independence. Overall, JAK inhibitor therapy should be individualized using age-, cytopenia-, and frailty-adapted strategies to optimize benefit in real-world practice.