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Primary myelofibrosis
is a chronic, usually idiopathic disorder characterized by bone
marrow fibrosis, splenomegaly, and anemia with immature and teardrop-shaped
RBCs. Diagnosis requires bone marrow examination and exclusion of
other conditions that can cause myelofibrosis (secondary myelofibrosis).
Treatment is usually supportive.
Pathophysiology
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 2: Myeloproliferative Disorders: Conditions Associated with Myelofibrosis ).
Primary myelofibrosis (PMF) is more common than secondary 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 primary myelofibrosis 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 may actually be a true megakaryocytic leukemia.
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Table 2
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Conditions
Associated with Myelofibrosis
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Condition
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Examples
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Cancers
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Cancer with bone marrow metastases
Hodgkin lymphoma
Leukemias (particularly chronic myelocytic and hairy cell)
Multiple myeloma
Non-Hodgkin lymphoma
Polycythemia vera (15 to 30% of patients in the spent phase)
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Infections
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Osteomyelitis
TB
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Primary pulmonary hypertension
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Toxins
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Benzene
Thorium dioxide
X- or γ-radiation
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Autoimmune disorders (rarely)
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SLE
Systemic sclerosis
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Symptoms and Signs
In many patients, myelofibrosis is asymptomatic. Other patients have symptoms of anemia, splenomegaly, or, in later stages, general malaise, weight loss, fever, or splenic infarction. Hepatomegaly occurs in a significant proportion of patients. Lymphadenopathy is rare.
Diagnosis
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 2: Myeloproliferative Disorders: 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 primary myelofibrosis.
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.
Prognosis
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
Treatment is directed at symptoms and complications. Androgens, splenectomy, chemotherapy, and splenic embolization and radiation therapy have been used for palliation. For patients with low erythropoietin levels relative to the degree of anemia, erythropoietin may increase Hct sufficiently; otherwise, RBC transfusion may be necessary. For younger patients with advanced disease, allogeneic stem cell transplantation should be considered. Nonmyeloablative allogeneic stem cell transplantation has been successfully used even in older patients; however, it is usually limited to patients < 65 yr.
Inhibitors of the JAK pathway appear to have a significant effect on splenomegaly and abnormal peripheral hematologic abnormalities. These drugs are in early trials.
Last full review/revision September 2009 by Josef T. Prchal, MD; Scott Samuelson, MD
Content last modified September 2009
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