Date: 28 Sep 2010

Conventional and Investigational Therapy for Primary Myelofibrosis

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Primary myelofibrosis (PMF), also known as myelofibrosis with myeloid metaplasia or agnogenic myeloid metaplasia, is a clonal myeloproliferative neoplasm that, in patients with fully expressed disease, is characterized by profound remodeling of bone marrow architecture and derangement of hematopoiesis. Bone marrow appears with almost constant expanded population of megakaryocytes and clusters of dystrophic and dysmature elements, deposition of excessive amounts of collagen, and other extracellular matrix proteins resulting in marrow reticulin or collagen fibrosis, increase in microvessel density, and osteosclerosis. Specific hallmarks of hematopoiesis derangement consist in the aberrantly decreased expression of disease-associated surface receptors on hematopoietic stem cell, such as SDF-1 receptor CXCR4, TGF-β (beta) receptor, and TPO receptor MPL, associated with high levels of stromal molecules, like SDF-1, elastase, and metalloproteinases. These stem cell and microenvironmental alterations bring to disruption of bone marrow niches with ensuing mobilization and homing of neoplastic hematopoietic stem cells in new or reinitialized niches in the spleen and liver. These features result in extramedullary hematopoiesis (EMH) with splenomegaly, anemia with a leukoerythroblastic blood picture, and possible neutropenia and thrombocytopenia.