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Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, extramedullary hematopoiesis (particularly symptomatic splenomegaly), constitutional symptoms, progressive cytopenias, and, in a subset of patients, leukemic transformation. The advent of the JAK1/2 inhibitor ruxolitinib has revolutionized the management of MF, substantially improving splenomegaly, symptom burden, and, in some settings, overall survival. However, a substantial percentage of patients fail to achieve sustained benefit, are intolerant, or become refractory; real-world and clinical trial data indicate that approximately half of treated patients discontinue ruxolitinib treatment within 3 years and up to approximately 75% within 5 years, with poor outcomes after discontinuation (median survival in several series is approximately 12–14 months). In recent years, several new small molecules that act beyond the JAK-STAT axis have emerged in clinical development. These include agents targeting telomerase (imetelstat), epigenetic regulation via BET inhibition (pelabresib/CPI-0610), the MDM2-p53 axis (navtemadlin/KRT-232), erythroid maturation and the bone marrow microenvironment (luspatercept), PI3K signaling (parsaclisib), and PIM inhibitors (nuvisertib). Early clinical data show promising results for symptom and splenic control in specific settings and, importantly, suggest potential disease-modifying activity (improvements in marrow fibrosis and molecular responses) for some compounds. This review summarizes the biological rationale, key clinical data (efficacy and safety), ongoing randomized trials, and remaining knowledge gaps for these non-JAK small molecules in MF and offers practical considerations for integrating them into contemporary treatment algorithms. Full article