New strategies in myelofibrosis: the evolving paradigm of disease pathogenesis, prognostication and treatment

Abstract Myelofibrosis (MF) is the most severe among the classical Philadelphia‐negative myeloproliferative neoplasms that also include essential thrombocytemia and polycythemia vera. Myelofibrosis is characterized by numerous genetic lesions, often variously associated with each other, and by an aggressive clinical phenotype leading to severely reduced survival. Also, the inflammatory microenvironment plays a key role in disease initiation and progression. Because of the complexity of its pathogenesis and the variability of clinical features, MF is a disease that requires a personalized approach and remains orphan of curative treatments besides allogeneic transplantation. JAK2 inhibitors have marked a remarkable progress, because they alleviate systemic symptoms and reduce splenomegaly but have a limited effect on survival, on mutation load, and on marrow fibrosis. Here, we review the main contributing factors to MF pathogenesis and prognosis, focusing on how these factors relate to therapeutic choices. We discuss results from ongoing studies of JAK2 inhibitors and report on new therapeutic strategies that proved effective in early preclinical and clinical trials, including combination treatments, antifibrotic agents, and telomerase inhibitors.