A novel application of XPO1 inhibition for the treatment of myelofibrosis

• DOI: 10.1016/j.bneo.2024.100010
• Publication Date: 2024-04-12T16:13:51Z
• Authors: Megan Metzger; Zachary M. Avigan; Pankit Vachhani; Julian Waksal; John Mascarenhas
• Keywords: Ruxolitinib; Myeloproliferative neoplasm; Tolerability; Pomalidomide; Constitutional symptoms

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