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(Agnogenic Myeloid Metaplasia; Myelofibrosis with Myeloid Metaplasia)
Primary myelofibrosis (PMF) is a chronic, usually idiopathic disorder characterized by bone marrow fibrosis, splenomegaly, and anemia with nucleated and teardrop-shaped RBCs. Diagnosis requires bone marrow examination and exclusion of other conditions that can cause myelofibrosis (secondary myelofibrosis). Treatment is often supportive, but JAK2 inhibitors such as ruxolitinib may decrease symptoms, and stem cell transplantation may reverse fibrosis.
Myelofibrosis is excessive bone marrow fibrosis and loss of hematopoietic cells, with subsequent marked increase in extramedullary hematopoiesis (primarily in the liver and spleen, which enlarge significantly). Myelofibrosis may be primary or secondary to a number of hematologic, malignant, and nonmalignant conditions (see Table: Conditions Associated With Myelofibrosis).
PMF is more common than secondary myelofibrosis and results from neoplastic transformation of a multipotent bone marrow stem cell. These PMF progeny cells stimulate bone marrow fibroblasts (which are not part of the neoplastic transformation) to secrete excessive collagen. The peak incidence of PMF is between 50 and 70 yr.
In PMF, large numbers of nucleated RBCs (normoblasts) and granulocytes are released into the circulation (leukoerythroblastosis). Serum LDH level is often elevated. Bone marrow failure eventually occurs, with consequent anemia and thrombocytopenia. Rapidly progressive, chemotherapy-incurable acute leukemia develops in about 10% of patients.
Malignant or acute myelofibrosis, an unusual variant, has a more rapidly progressive downhill course; this variant is best classified as megakaryocytic leukemia.
Conditions Associated With Myelofibrosis
PMF should be suspected in patients with splenomegaly, splenic infarction, anemia, or unexplained elevations in LDH. If the disorder is suspected, CBC should be done and peripheral blood morphology and bone marrow should be examined, including cytogenetic testing. If myelofibrosis is detected on bone marrow examination (eg, by increased fibroblasts and collagen as detected by reticulin staining, osteosclerosis), other disorders associated with myelofibrosis (see Table: Conditions Associated With Myelofibrosis) should be excluded by appropriate clinical and laboratory evaluation.
Anemia is typically present and usually increases over time. Blood cell morphology is variable. RBCs are poikilocytic. Reticulocytosis and polychromatophilia may be present; teardrop-shaped RBCs (dacryocytes) are characteristic morphologic features. Nucleated RBCs and neutrophil precursors are typically present in peripheral blood. WBC counts are usually increased but are highly variable; a low WBC count tends to indicate a poor prognosis. Neutrophils are usually immature, and myeloblasts may be present, even in the absence of acute leukemia. Platelet counts initially may be high, normal, or decreased; however, thrombocytopenia tends to supervene as the disorder progresses.
If diagnosis is difficult, CD34+ cell count on peripheral blood can be done. Levels are much higher in patients with PMF.
Bone marrow aspiration is usually dry. Because demonstration of bone marrow fibrosis is required and fibrosis may not be uniformly distributed, biopsy should be repeated at a different site if the first biopsy is nondiagnostic. About 50% of patients have a JAK2 mutation. Some have a mutation of the calreticulin gene.
The median survival is 5 yr from onset, but variation is wide; some patients have a rapidly progressing disorder with short survival and some have a delay in initial diagnosis. Unfavorable prognostic markers include Hb < 10 g/dL, history of transfusions, leukocytosis and leukopenia, and platelet count < 100,000/μL. Patients in the least favorable risk group usually survive < 1 yr. No treatment reverses or controls the underlying process except for allogeneic stem cell transplant.
Treatment is directed at symptoms and complications. Androgens, splenectomy, chemotherapy, and splenic embolization and radiation therapy have been used for palliation. Temporary use of low-dose corticosteroids may relieve symptoms. For younger patients with advanced disease, allogeneic stem cell transplantation may be beneficial. Nonmyeloablative allogeneic stem cell transplantation has been successfully used even in older patients.
Inhibitors of the JAK pathway appear to have a significant effect on splenomegaly and symptoms; ruxolitinib is currently available and others are being tested in clinical trials. JAK inhibitors are effective whether or not a JAK2 mutation is present. Care must be taken when stopping ruxolitinib as a withdrawal syndrome has been described, and can result in significant worsening of symptoms in part due to splenomegaly.
Myelofibrosis is excessive bone marrow fibrosis and loss of hematopoietic cells, with subsequent marked increase in extramedullary hematopoiesis (primarily in the liver and spleen, which enlarge significantly).
Myelofibrosis is often primary but may be secondary to a number of hematologic, malignant, and nonmalignant conditions.
Primary myelofibrosis is caused by neoplastic transformation of a multipotent bone marrow stem cell; the progeny cells stimulate bone marrow fibroblasts to secrete excessive collagen.
Diagnose using CBC and peripheral blood smear and bone marrow evaluation.
Median survival is 5 yr from onset, but variation is wide.
Give supportive care and sometimes allogeneic stem cell transplantation or a JAK pathway inhibitor (eg, ruxolitinib).
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