Emerging Therapeutic Approaches for Anemia in Myelofibrosis

In this review, we highlight conventional agents and novel emerging therapeutic strategies to treat anemia in MF.

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.

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.