Current treatment concepts of Philadelphia-negative MPN

Since William Dameshek has described the concept of "myeloproliferative disorders (MPD)" by identifying common clinical characteristics (i.e. hemorrhage, thrombosis and leukemic transformation) of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), the advent of molecular biology has provided substantial molecular insight into the pathobiology of myeloproliferative neoplasia (MPN). Recently, the description of the gain-of-function mutation of JAK2 (JAK2V617F) has been identified in classical Philadelphia (Ph)-negative MPN, thus providing a rational target for novel innovative treatment strategies. In addition, molecular characterization of atypical Ph-negative MPN (e.g. the KITD816V mutation in mastocytosis and PDGF-receptor rearrangements in hypereosinophilic syndromes/chronic eosinophilic leukemia) complement the molecular knowledge of this heterogeneous disease family. Currently, clinical studies testing various JAK2-inhibitors in PV, ET as well as in primary and secondary myelofibrosis (MF) are under way. Interestingly, first data indicate that despite marked clinical activity in terms of spleen size reduction and improvement of constitutional symptoms, these inhibitors might not sufficiently reduce disease burden. Thus, alternative and well established treatment strategies, such as inhibition of thrombocyte aggregation by low dose aspirin, cytotoxics (e.g. hydroxyurea), immuno- and stroma-modifying therapy with interferon, tyrosine kinase inhibitors and, in selected cases, allogeneic stem cell transplantation are still important treatment options for patients suffering from MPN, which will be discussed in detail in this review.