Elena Torre

Purpose of Review In this review, we highlight conventional agents and novel emerging therapeutic strategies to treat anemia in MF. Recent Findings Anemia is a common and challenging feature of myelofibrosis (MF). The pathobiology of anemia is multifactorial, including progressive bone marrow fibrosis, decreased erythropoiesis due to high hepcidin levels leading to iron sequestration in the reticuloendothelial system, hypersplenism, erythropoiesis inhibition by myelosuppressive JAK inhibitors (ruxolitinib, fedratinib), and others. MF-associated anemia has a negative impact on survival. Conventional agents to manage anemia include erythropoiesis-stimulating agents, danazol, corticosteroids, and immunomodulatory agents, but responses are infrequent and lack durability. Notable advancements have emerged in developing novel treatments for anemia in MF, including the regulatory approval of momelotinib (ACVR1/JAK1/2 inhibitor) in 2023 and development of novel promising agents targeting hemojuvelin and activins. Momelotinib and pacritinib (ACVR1/JAK2 inhibitor) are the preferred JAK inhibitors for patients with cytopenias (anemia, thrombocytopenia). Luspatercept and elritercept are activin receptor ligand traps, promoting erythroid maturation and late-stage erythropoiesis. Currently, luspatercept is being evaluated in a phase 3 trial (INDEPENDENCE™) for anemia in MF patients who are on a JAK2 inhibitor and require transfusions, and in a phase 2 trial (ODYSSEY) in combination with momelotinib in MF patients who are transfusion dependent, whether or not on a JAK inhibitor. Interim results of the RESTORE trial demonstrated that elritercept significantly decreased transfusions in MF patients. DISC-0974 is a first-in-class anti-hemojuvelin (positive hepcidin regulator) monoclonal antibody that decreased hepcidin expression, increased serum iron, and enhanced erythropoiesis in anemic patients with MF in a phase 1b/2 study. Burgeoning studies of novel anemia-targeted agents and combinations are significantly improving the quality of life and outcomes of patients with MF. Summary The recent approval of momelotinib to treat MF with anemia and the emerging novel anemia-directed strategies in early and advanced clinical development have ushered in a new era in the treatment of MF-related anemia.

Myeloproliferative neoplasms (MPNs) are the leading causes of unusual site thrombosis, affecting nearly 40% of individuals with conditions like Budd–Chiari syndrome or portal vein thrombosis. Diagnosing MPNs in these cases is challenging because common indicators, such as spleen enlargement and elevated blood cell counts, can be obscured by portal hypertension or bleeding issues. Recent advancements in diagnostic tools have enhanced the accuracy of MPN diagnosis and classification. While bone marrow biopsies remain significant diagnostic criteria, molecular markers now play a pivotal role in both diagnosis and prognosis assessment. Hence, it is essential to initiate the diagnostic process for splanchnic vein thrombosis with a JAK2 V617F mutation screening, but a comprehensive approach is necessary. A multidisciplinary strategy is vital to accurately determine the specific subtype of MPNs, recommend additional tests, and propose the most effective treatment plan. Establishing specialized care pathways for patients with splanchnic vein thrombosis and underlying MPNs is crucial to tailor management approaches that reduce the risk of hematological outcomes and hepatic complications.

Despite distinct clinical entities, the myeloproliferative neoplasms (MPN) share morphological similarities, propensity to thrombotic events and leukemic evolution, and a complex molecular pathogenesis. Well-known driver mutations, JAK2, MPL and CALR, determining constitutive activation of JAK-STAT signaling pathway are the hallmark of MPN pathogenesis. Recent data in MPN patients identified the presence of co-occurrence somatic mutations associated with epigenetic regulation, messenger RNA splicing, transcriptional mechanism, signal transduction, and DNA repair mechanism. The integration of genetic information within clinical setting is already improving patient management in terms of disease monitoring and prognostic information on disease progression. Even the current therapeutic approaches are limited in disease-modifying activity, the expanding insight into the genetic basis of MPN poses novel candidates for targeted therapeutic approaches. This review aims to explore the molecular landscape of MPN, providing a comprehensive overview of the role of drive mutations and additional mutations, their impact on pathogenesis as well as their prognostic value, and how they may have future implications in therapeutic management.