Idiopathic myelofibrosis: pathogenesis, natural history and management.

Idiopathic myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, extramedullary haematopoiesis and a leucoerythroblastic blood picture. The marrow fibrosis results from an increased deposition of various interstitial and basement membrane glycoproteins, including collagen types I, III, IV, V and VI, fibronectin, vitronectin, laminin and tenascin. In addition, a marked neovascularization is present, even in the early proliferative phase of the disease. In contrast to the clonal haematopoiesis, the increased bone marrow stromal tissue is thought to be a reactive phenomenon, resulting from the inappropriate release of megakaryocyte/platelet-derived growth factors, including PDGF, TGF-beta, EGF, bFGF and calmodulin. Recent cytogenetic studies have highlighted three defects, namely del(13q), del(20q) and partial trisomy 1q, that account for nearly 70% of all abnormalities at diagnosis, and suggests that in many patients gene loss and/or inactivation may be an important pathogenetic mechanism. The median survival is approximately 4 years, although individual survival varies greatly. Prognostic schema enable the identification of patients with a limited life expectancy, for whom bone marrow transplantation should be considered. However, for the majority of patients therapy is supportive and consists of blood transfusions, androgens to sustain erythropoiesis, cytoreductive agents to prevent thrombocythaemia and, in carefully selected cases, splenectomy. The role for a number of experimental therapies, such as vitamin D3 analogues, alpha and gamma interferons and erythropoietin has yet to be defined.