Chapter 86: Primary Myelofibrosis

SUMMARY

Primary myelofibrosis 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 several somatic mutations. It is one of the eight neoplasms, including polycythemia vera and essential thrombocythemia, classified as a myeloproliferative disease by the World Health Organization. Approximately 90 percent of cases have a mutation in the Janus kinase 2 (JAK2) gene (~50 percent), the calreticulin (CALR) gene (~35 percent), or the thrombopoietin receptor (MPL) gene (~4 percent). The disease is characterized, classically, by anemia, mild neutrophilia, thrombocytosis, and splenomegaly. Occasional cases may present with bi- or tricytopenias (~15 percent). 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 (e.g., transforming growth factor-β) released locally by the numerous neoplastic megakaryocytes. Osteosclerosis, also, may be present. The disease may be complicated by (1) portal hypertension and gastroesophageal varices as a result of a very large splenic blood flow and loss of compliance of hepatic vessels, (2) extramedullary fibrohematopoietic tumors that can develop in any tissue and lead to symptoms by compression of vital structures, and (3) abdominal vein thrombosis (Budd-Chiari syndrome). Newly developed JAK2 inhibitors are now first-line therapy for splenomegaly and constitutional symptoms (fever, night sweats, and weight loss). Other treatment has 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. 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; FISH, fluorescence in situ hybridization; G6PD, glucose-6-phosphate dehydrogenase; G-CSF, granulocyte colony-stimulating factor; IL, interleukin; JAK2, Janus kinase 2 gene; MPL, thrombopoietin receptor gene; MRI, magnetic resonance imaging; PDGF, platelet-derived growth factor; TGF, transforming growth factor; TNFR, tumor necrosis factor receptor.