Combination therapies in Myeloproliferative Neoplasms: why do we need them and how to identify potential winners?

The myeloproliferative neoplasms (MPN) are clonal myeloid disorders characterized by proliferation of mature myeloid cells, such that in polycythaemia vera (PV), the red cell proliferation dominates, platelets in essential thrombocythaemia (ET) and in myelofibrosis (MF), there may be cytopenia or proliferation, but the characteristic feature is the strikingly abnormal bone marrow stroma. These entities have a tendency to show phenotypic mimicry and may transform from one to another, for example, 20–30% of patients with PV are likely to develop MF. The significant event in this field was the recognition that Janus Kinase-2 (JAK2) activation was highly prevalent, followed by the description of the mutation in 2005 ( which stimulated renewed interest in disease biology. Janus Kinase-2-targeted therapies have led to marked improvements for patients with this condition. However, it is obvious that the pathogenesis of these complex disorders reaches beyond this mutation; only 50–60% of patients with ET, for example, have the mutation and several additional mutations have been described, which are of relevance in both the pathogenesis and clinical phenotype of these conditions.