A novel application of XPO1 inhibition for the treatment of myelofibrosis.

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by constitutional symptoms, progressive cytopenias, and splenomegaly. Activating mutations in the JAK/STAT pathway and cytokine dysregulation driving bone marrow fibrosis and extramedullary hematopoiesis underlie the pathobiology of MF. Although multiple JAK inhibitors are currently approved and provide significant symptom improvement, these agents do not possess disease course modifying potential. Additionally, outcomes are poor for patients who fail JAK inhibitors, highlighting the need for novel mechanism-based therapies and innovative combination strategies. Selinexor, a novel Exportin 1 (XPO1) inhibitor that blocks nuclear export, increases nuclear localization and activity of p53 and other tumor suppressor pathways and decreases cytoplasmic activation of multiple proliferative and profibrotic pathways. Selinexor currently has approved indications in multiple myeloma and lymphoma, with broad potential applications in other malignancies, although it can be limited by toxicity in some settings. Selinexor has shown clinical activity and tolerability in MF, both as monotherapy and, particularly, in combination with ruxolitinib. The collective, early phase trial data support a phase 3 randomized, registration study of selinexor and ruxolitinib in patients with MF naïve to JAK inhibitor therapy. Further work is needed to elucidate the role of XPO1 inhibition as a potential disease-modifying strategy to improve outcomes in MF.