Myelofibrosis with myeloid metaplasia: the advanced phase of an untreated disseminated hematological cancer. Time to change our therapeutic attitude with early upfront treatment?

Myelofibrosis with myeloid metaplasia (MMM) is the end stage of the Philadelphia-negative chronic myeloproliferative disorders, the classical clinical phenotype being featured by leukoerythroblastic anemia, bone marrow fibrosis and enlargement of the spleen and liver. In the early prefibrotic phase a proportion of the patients may be wrongly classified as having essential thrombocythemia (ET). Some patients with ET may also develop polycythemia vera (PV) and without a history of phlebotomies patients with primary myelofibrosis (PMF) are indistinguishable from those patients developing myelofibrosis during the course of polycythemia vera. Studies of the JAK2-mutational burden have yielded solid support to the concept of a biological continuum from JAK2-positive "ET" to JAK2-positive PMF. The statement is presented that MMM is the advanced stage of an untreated disseminated hematological cancer which accordingly should be treated upfront when the disease presents in the very early stage as ET and PV, and when the cancer stem cells - the clonal CD34+ cells - have still not egressed from the bone marrow ("carcinoma in situ"). Based upon most recent studies showing that alpha-interferon is able to induce complete and sustained molecular remissions in patients with PV it is argued that we have to change our therapeutic attitude from a "wait and watch strategy" to early upfront treatment of ET and PV. In the "metabolic syndrome" normalisation of elevated blood glucose levels has been a very important therapeutic strategy to decrease the risk of thrombotic complications consequent to in vivo platelet-, granulocyte and endothelial cell activation, which are also considered of utmost importance for the development of thrombosis in ET and PV patients. Normalisation of elevated blood cell counts in the early phase of the "chronic myeloproliferative syndromes" - ET and PV - should be the therapeutic target in the future using alpha-interferon as monotherapy or in combination with conventional (hydroxyurea and anagrelide) and novel agents (JAK2-inhibitors). By this strategy preliminary reports in PV patients of minimal residual disease with normalisation of the bone marrow during long-term alpha-interferon treatment may be further substantiated in larger series of patients, hopefully being followed by a reduction in the risk of thrombohemorrhagic complications and ultimately the development of severe bone marrow fibrosis and myeloid metaplasia.