Clinical and laboratory features of myelofibrosis and limitations of current therapies.

Myelofibrosis (MF) is a life-threatening clonal stem cell malignancy characterized by progressive bone marrow fibrosis and ineffective hematopoiesis. The term "MF" encompasses primary myelofibrosis (PMF) as well as 2 other phenotypically similar malignancies: post-polycythemia vera (PV) MF (PPV-MF) and post-essential thrombocythemia (ET) MF (PET-MF). The World Health Organization classification system for myeloid malignancies recognizes PMF, PV, ET, and chronic myeloid leukemia (CML) as the "classic" myeloproliferative neoplasms (MPNs). Patients with low- or intermediate-1-risk disease have a median survival of 6-15 years, in contrast to those with intermediate-2- or high-risk disease, which is associated with a considerably worse prognosis. Following transformation into (secondary) acute myeloid leukemia (AML), the prognosis of MF is even worse, with a median survival of 3 months or less. Due to the heterogeneous nature of MF, the diagnosis and treatment of this malignancy can be challenging. At present, the only treatment that can be applied with curative intent is allogeneic stem cell transplantation (SCT), whereas no other specific therapies exist that are approved by the US Food and Drug Administration (FDA) for MF. Since most patients with MF appear not to be eligible for allogeneic SCT, patients are often treated by conventional "older" drugs such as androgens and hydroxyurea (HU; hydroxycarbamide), with the principal objective being palliation. Following the establishment of a causal role of a specific mutation in the Janus kinase type 2 (JAK2) gene, namely JAK2V617F, in the molecular pathogenesis of MPNs in 2005, many efforts have been directed towards the development of novel JAK2 (including JAK1/JAK2) inhibitors. Other investigative approaches include immunomodulatory agents, histone deacetylase inhibitors, hedgehog inhibitors, and others. Recently, the positive results of the first in class of the JAK1/JAK2 inhibitors, ruxolitinib (formerly INCB18242), from 2 large phase III studies were presented and are discussed herein.