IDIOPATHIC MYELOFIBROSIS - PATHOGENESIS, NATURAL-HISTORY AND MANAGEMENT

Idiopathic myelofibrosis is a chronic myeloproliferative disorder char acterized by bone marrow fibrosis, extramedullary haematopoiesis and a leucoerythroblastic blood picture. The marrow fibrosis results from a n increased deposition of various interstitial and basement membrane g lycoproteins, including collagen types I, III, IV, V and VI, fibronect in, vitronectin, laminin and tenascin. In addition, a marked neovascul arization is present, even in the early proliferative phase of the dis ease. In contrast to the clonal haematopoiesis, the increased bone mar row stromal tissue is thought to be a reactive phenomenon, resulting f rom the inappropriate release of megakaryocyte/platelet-derived growth factors, including PDGF, TGF-beta, EGF, bFGF and calmodulin. Recent c ytogenetic studies have highlighted three defects, namely del(13q), de l(20q) and partial trisomy 1q, that account for nearly 70% of all abno rmalities at diagnosis, and suggests that in many patients gene loss a nd/or inactivation may be an important pathogenetic mechanism. The med ian survival is approximately 4 years, although individual survival va ries greatly. Prognostic schema enable the identification of patients with a limited life expectancy, for whom bone marrow transplantation s hould be considered. However, for the majority of patients therapy is supportive and consists of blood transfusions, androgens to sustain er ythropoiesis, cytoreductive agents to prevent thrombocythaemia and, in carefully selected cases, splenectomy. The role for a number of exper imental therapies, such as vitamin D-3 analogues, alpha and gamma inte rferons and erythropoietin has yet to be defined.