JAK inhibitor selection in challenging scenarios of myelofibrosis: a review

Myelofibrosis is a progressive myeloproliferative neoplasm characterized by dysregulated Janus kinase (JAK)/signal transducer and activator of transcription signaling. Common clinical manifestations include constitutional symptoms, splenomegaly, and anemia, which can significantly impact quality of life and survival. Although hematopoietic stem cell transplant is the only curative treatment modality in myelofibrosis, JAK inhibitors have transformed management by providing symptom relief and reducing spleen size in many patients; newer JAK inhibitors also offer anemia-related benefits. Four JAK inhibitors - ruxolitinib, fedratinib, pacritinib, and momelotinib - are now available for the treatment of myelofibrosis, each with distinct profiles and safety considerations that may inform selection. However, head-to-head trial comparisons are limited, and real-world experience with most of these JAK inhibitors is only just emerging; therefore, first-line selection and optimal sequencing in particular patients can be challenging. This review summarizes the current data surrounding available JAK inhibitors for the treatment of patients with myelofibrosis and examines how individual patients' characteristics can help guide selection among them. To illustrate the diverse clinical factors and key considerations associated with JAK inhibitor selection in practice, we discuss these data in the context of four hypothetical cases representing possible real-world scenarios, offering treatment recommendations based on our collective expertise in the field. As the myelofibrosis therapeutic landscape continues to evolve, a thorough understanding of the strengths and limitations of each JAK inhibitor relative to a given patient's presentation will support individualized treatment decisions for optimal long-term outcomes.