Chapter 85: Primary Myelofibrosis

SUMMARY

Primary myelofibrosis (PMF) is one of several disorders in the spectrum of clonal myeloid diseases, malignant diseases that originate in the clonal expansion of a single hematopoietic multipotential cell, reprogrammed by any of several somatic mutations. It is one of the eight neoplasms, including polycythemia vera (PV), and essential thrombocythemia (ET), classified as a myeloproliferative disease by the World Health Organization and, more conventionally, one of the three classical myeloproliferative neoplasms (MPNs) with which it shares clinical features and common somatic mutations: PV, ET, and PMF. Approximately 90% of cases of PMF have a mutation in either (1) the Janus kinase 2 (JAK2) gene (~50%), (2) the calreticulin (CALR) gene (~35%), or (3) the thrombopoietin receptor (MPL) gene (~5%). The disease is characterized, classically, by anemia, mild neutrophilia, thrombocytosis, and splenomegaly. Occasional cases may present with bi- or tricytopenias (~15%). Immature myeloid and nucleated red cells, teardrop-shaped erythrocytes, and large platelets (megakaryocyte cytoplasmic fragments) are characteristic features of the blood film. The marrow contains an increased number of neoplastic dysmorphic megakaryocytes and increased reticulin fibers and, often later, collagen fibrosis. This reactive, polyclonal, fibroplasia is the result of cytokines (eg, transforming growth factor [TGF]-β) released locally by the numerous neoplastic megakaryocytes. Osteosclerosis may also be present. The disease may be complicated by (a) portal hypertension and gastroesophageal varices as a result of a very large splenic blood flow and loss of compliance of hepatic vessels, (b) extramedullary fibrohematopoietic tumors that can develop in any tissue and lead to symptoms by compression of vital structures, and (c) hepatic vein thrombosis (Budd-Chiari syndrome). JAK2 inhibitors are now first-line therapy for splenomegaly and constitutional symptoms (fever, night sweats, and weight loss). Other treatments have included hydroxyurea for thrombocytosis and massive splenomegaly; androgens, erythropoietin, or red cell transfusions for severe anemia; local irradiation of fibrohematopoietic tumors or of a massive, symptomatic spleen; or splenectomy for severe cytopenias, if splenic effects are not controlled by JAK2 inhibitors. Transjugular intrahepatic portosystemic shunt surgery may be required for gastroesophageal variceal bleeding. In younger patients, allogeneic hematopoietic stem cell transplantation can be curative, and nonmyeloablative transplantation has been successful at least up to age 60 years. The disease may remain indolent for years or may progress rapidly by further deterioration in hematopoiesis, by massive splenic enlargement and its sequelae, or by transformation to acute myelogenous leukemia.

Acronyms and Abbreviations

AML, acute myelogenous leukemia; bFGF, basic fibroblast growth factor; bp, base pair; CALR, calreticulin gene; CD, cluster of differentiation; CML, chronic myelogenous leukemia; C-MPL; the thrombopoietin receptor gene; ET, essential thrombocythemia; FISH, fluorescence in situ hybridization; G6PD, glucose-6-phosphate dehydrogenase; G-CSF, granulocyte colony-stimulating factor; IL, interleukin; JAK2, Janus kinase 2 gene; MRI, magnetic resonance imaging; MPN, myeloproliferative neoplasm PDGF, platelet-derived growth factor; PV, polycythemia vera; PMF, primary myelofibrosis; TGF, transforming growth factor; TNFR, tumor necrosis factor receptor.