Secondary Myelofibrosis in the Naturel History of JAK2, MPL and CALR Mutated Myeloproliferative Neoplasms

The term “myeloproliferative disorder” (MPD) is used to refer to those conditions in which there is a primary clonal stimulation of bone marrow hematopoietic stem cells producing erythroblasts, granulocytes and megakaryocytes The clonal evolution of MPD leads to hypercellularity of hematopoietic progenitor cells in the bone marrow either trilinear in classic PV, “unilinear” megakaryocytic in “true” ET or bilinear in MPD presenting with a dual chronic or primary megakaryocytic and granulocytic myeloproliferation (CMGM/PMGM) . Such intrinsic stimulation or autonomous growth of clonal hematopoietic cells in the bone marrow as well as in the extramedullary sites-in particular the spleen-begins long before increase of reticulin and collagen fibers (myelofibrosis) does occur.

The resultant initial clinical picture begins with the appearance of enlarged megakaryocytes ranging from mature, pleiomorphic in ET and PV with increasing cellularity of erythropoiesis and/or granulopoiesis in the bone marrow and progressive hematopoietic neoplasia in the spleen. The trilinear MPDs labeled as myeloproliferative neoplasms (MPNs) in the 2008 WHO classification are associated with various degrees of thrombocytosis, erythrocytosis and granulopcytosis in the prefibrotic stages. Over a period of years splenic myeloid neoplasia preceeds and myelofibrosis supervenes as two independent but related and different serious complications in various MPN, CML and MPN/MDS .