The Ongoing Challenges of Managing Cytopenic Myelofibrosis in 2025: The Emergence of Non-JAK Inhibitor Therapies.

Abstract

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm that is felt to arise from somatic mutations with hematopoietic stem and progenitor cells (HSPC's), leading to the development of atypical megakaryocytic hyperplasia. Associated dysregulated cytokine signaling and the trafficking of fibroblasts to the marrow compartment then leads to the deposition of collagen in the marrow compartment. On a molecular level, several well-established driver mutations in JAK2, CALR or MPL activate signaling through JAK/STAT, producing the proliferative phenotype of myelofibrosis. JAK inhibition, accordingly, has been and remains a mainstay in MF-directed therapy. In patients whose disease becomes refractory to Jak inhibitors or in those who experience intolerable adverse effects, however, options from different therapeutic classes are available. Despite this broad availability that includes erythropoiesis-stimulating agents, androgens and TGF-β inhibitors, one of the major challenges in management remains the implementation and successful long-term use of agents to treat cytopenic myelofibrosis. Research into alternative drivers has now led not only to the identification of alternative signaling mechanisms in MF but also to the development and now approval of new therapies outside of Jak inhibitors.