Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 13-26: Primary Myelofibrosis + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Striking splenomegaly Teardrop poikilocytosis on peripheral smear Leukoerythroblastic blood picture; giant abnormal platelets Initially, hypercellular bone marrow, then hypocellular bone marrow with reticulin or collagen fibrosis +++ General Considerations ++ Primary myelofibrosis is a myeloproliferative disorder characterized by clonal hematopoiesis that is often but not always accompanied by JAK2, CALR or MPL mutations, bone marrow fibrosis, anemia, splenomegaly, and a leukoerythroblastic peripheral blood picture with teardrop poikilocytosis A myeloproliferative disorder, also known as myelofibrosis with myeloid metaplasia, agnogenic myeloid metaplasia, and idiopathic myelofibrosis Can also occur as a secondary process following other myeloproliferative disorders (see Polycythemia Vera and Essential Thrombocytosis) It is believed that bone marrow fibrosis occurs in response to increased secretion of platelet-derived growth factor (PDGF) and possibly other cytokines In response to the bone marrow fibrosis, extramedullary hematopoiesis takes place in the liver, spleen, and lymph nodes Abnormalities of JAK2 and MPL are involved in the pathogenesis + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ Onset is usually insidious Develops in adults over age 50 years Most common presentations Fatigue due to anemia Abdominal fullness related to splenomegaly Uncommon presentations Bleeding Bone pain Splenomegaly Almost invariably present Commonly massive Liver is enlarged in > 50% of cases Later in the course of the disease Splenomegaly may result in early satiety Splenic infarction may occur Progressive bone marrow failure takes place as it becomes increasingly more fibrotic Progressive thrombocytopenia leads to bleeding Patient becomes cachectic and may experience severe bone pain, especially in the upper legs Hematopoiesis in the liver leads to portal hypertension with ascites, esophageal varices, and occasionally transverse myelitis caused by myelopoiesis in the epidural space +++ Differential Diagnosis ++ Severe infection, inflammation, or infiltrative bone marrow processes Metastatic carcinoma, Hodgkin lymphoma, and hairy cell leukemia Chronic myeloid leukemia (CML) Polycythemia vera Essential thrombocytosis + Diagnosis Download Section PDF Listen +++ +++ Laboratory Findings ++ Anemia White blood count Variable—either low, normal, or elevated May be increased to 50,000/mcL Platelet count is variable Peripheral blood smear is dramatic, with significant poikilocytosis and numerous teardrop forms in the red cell line Nucleated red blood cells are present and the myeloid series is shifted, with immature forms including a small percentage of promyelocytes or myeloblasts Platelet morphology may be bizarre, and giant degranulated platelet forms (megakaryocyte fragments) may be seen The triad of teardrop poikilocytosis, leukoerythroblastic blood, and giant abnormal platelets is highly suggestive of myelofibrosis Bone marrow usually cannot be aspirated (dry tap), though early in the course of the disease it is hypercellular, with a marked increase in megakaryocytes Fibrosis at this stage is detected by a silver stain demonstrating increased reticulin fibers; later, marrow biopsy reveals more severe fibrosis, with eventual replacement of hematopoietic precursors by collagen There is no characteristic chromosomal abnormality JAK2 is mutated in ~65% of cases, and MPL and CALR are mutated in the majority of the remaining cases; 10% of cases are "triple-negative" + Treatment Download Section PDF Listen +++ +++ Medications ++ Androgens, prednisone, and thalidomide can control anemia Lenalidomide and pomalidomide result in control of anemia in 25% and thrombocytopenia in ~58% of cases, without significant reduction in splenic size Hydroxyurea Dosage: 500–1000 mg/day orally First-line therapy for primary myelofibrosis–associated splenomegaly Effective in reducing spleen size by half in about 40% of patients Both thalidomide and lenalidomide may improve splenomegaly and thrombocytopenia in some patients Lenalidomide and pomalidomide Immunomodulatory medications Result in control of anemia in 25% and thrombocytopenia in ~58% of cases However, there is no significant reduction in splenic size Ruxolitinib A JAK2 inhibitor Reduces spleen size and improves constitutional symptoms However, does not induce complete clinical or cytogenetic remissions or significantly affect JAK2/CALR/MPL mutant allele burden May lead to an overall survival benefit in patients with intermediate- or high-risk disease Can exacerbate cytopenias Fedratinib Newer selective JAK2 inhibitor Can lead to sustained reduction in spleen size and improvement in disease-associated symptoms for patients with advanced stage myelofibrosis However, it carries a significant risk of serious and fatal encephalopathy, including Wernicke encephalopathy Providers should regularly assess thiamine levels in all patients +++ Therapeutic Procedures ++ Observation with supportive care is a reasonable treatment strategy for asymptomatic patients with low or intermediate-1 Dynamic International Prognostic Scoring System (DIPSS)-plus risk disease, especially in the absence of high-risk mutations Anemic patients are supported with transfusion Splenectomy Not routinely performed Indications include drug-refractory splenic enlargement causing recurrent painful episodes, severe thrombocytopenia, or an unacceptable transfusion requirement Radiation therapy has a role for painful sites of extramedullary hematopoiesis, pulmonary hypertension, or severe bone pain Transjugular intrahepatic portosystemic shunt might also be considered to alleviate symptoms of portal hypertension The only potentially curative option is allogeneic stem cell transplantation + Outcome Download Section PDF Listen +++ +++ Complications ++ Perioperative complications can occur in 28% of the patients and include infections, abdominal vein thrombosis, and bleeding +++ Prognosis ++ Median survival from time of diagnosis is ~5 years The Dynamic International Prognostic Scoring System is associated with overall survival Therapies with biologic agents and the application of reduced-intensity allogeneic stem cell transplantation appear to offer the possibility of improving the outcome for many patients End-stage myelofibrosis is characterized by generalized asthenia, liver failure, and bleeding from thrombocytopenia, with some cases terminating in acute myeloid leukemia +++ When to Refer ++ Patients should be referred to a hematologist +++ When to Admit ++ Admission is not usually necessary + References Download Section PDF Listen +++ + +Finazzi G et al. Prefibrotic myelofibrosis: treatment algorithm 2018. Blood Cancer J. 2018 Nov 7;8(11):104. [PubMed: 30405096] + +Zimran E et al. Novel treatments to tackle myelofibrosis. Expert Rev Hematol. 2018 Nov;11(11):889–902. [PubMed: 30324817]