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Primary Myelofibrosis

By

Jane Liesveld

, MD, James P. Wilmot Cancer Institute, University of Rochester Medical Center

Last full review/revision Feb 2019| Content last modified Feb 2019
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Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm 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 be curative.

Pathophysiology

Myelofibrosis is a reactive, reversible increase in bone marrow collagen often with extramedullary hematopoiesis (primarily in the spleen). Myelofibrosis may be

Primary myelofibrosis results from neoplastic transformation of a multipotent bone marrow stem cell. These primary myelofibrosis 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 years and predominantly in males.

Mutations of the Janus kinase 2 (JAK2) gene are responsible a high proportion of cases of primary myelofibrosis. JAK2 is a member of the tyrosine kinase family of enzymes and is involved in signal transduction for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor (G-CSF) among other entities. Mutations of the thrombopoietin receptor gene (MPL) or the calreticulin (CALR) gene also may be the cause of primary myelofibrosis. However, there are rare cases of primary myelofibrosis in which none of these three mutations are present (triple negative primary myelofibrosis).

In primary myelofibrosis, nucleated RBCs (normoblasts) and myelocytes are released into the circulation (leukoerythroblastosis) when there is extramedullary hematopoiesis (ie, non-marrow organs have taken over blood cell production because of the fibrosed marrow). 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 30% of patients.

Malignant myelofibrosis (sometimes called acute myelofibrosis), is a rare variant of myelofibrosis characterized by pancytopenia, myeloblastosis, and marrow fibrosis that has a more rapidly progressive downhill course and is generally due to a type of acute leukemia called acute megakaryoblastic leukemia.

Table
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Conditions Associated With Myelofibrosis

Condition

Examples

Malignancies

Cancer with bone marrow metastases

Leukemias (particularly chronic myeloid leukemia and hairy cell leukemia)

Myelodysplasia

Non-Hodgkin lymphoma (including hairy cell leukemia)

Polycythemia vera (15 to 30% of patients)

Hematologic disorders

Essential thrombocythemia

Polycythemia vera

Infections

Primary pulmonary hypertension

Toxins

Benzene

Thorium dioxide

X- or gamma-radiation

Autoimmune disorders (rarely)

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 some patients. Lymphadenopathy is rare. Severe extramedullary hematopoiesis can disturb the function of organs in which it occurs, including the brain.

Diagnosis

  • CBC and peripheral blood smear

  • Bone marrow examination

  • Testing for JAK2, CALR, and MPL mutations

Primary myelofibrosis should be suspected in patients with splenomegaly, splenic infarction, and anemia. If the disorder is suspected, CBC should be done and peripheral blood morphology and a bone marrow biopsy should be examined. If myelofibrosis is present on bone marrow examination (as detected by reticulin staining or trichrome staining, indicating excess collagen and osteosclerosis), other disorders associated with myelofibrosis (see table Conditions Associated With Myelofibrosis) should be excluded by appropriate clinical and laboratory evaluation. The diagnosis of primary myelofibrosis is confirmed by detecting a mutation in JAK2, CALR, or MPL.

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. In advanced stages, 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.

Prognosis

The median survival in primary myelofibrosis is 5 years from onset, but variation is wide; some patients have a rapidly progressing disorder, including development of acute myeloid leukemia, with short survival, but most have a more indolent course. Only allogeneic stem cell transplantation is curative.

Unfavorable prognostic markers include hemoglobin < 10 g/dL, a history of transfusions, leukocytosis, and a platelet count < 100,000/mcL. Patients in the least favorable risk group usually survive < 1 year, but those with low-risk disease have a median survival of several years. Several prognostic scoring systems are available to predict survival.

A number of useful risk stratification systems are available to aid prognosis and guide decisions to institute medical therapy or stem cell transplantation. The International Prognostic Scoring System (IPSS) for Myelodysplastic Syndromes is used for newly diagnosed primary myelofibrosis, and the Dynamic International Prognostic Scoring System (DIPSS) for Myelodysplastic Syndromes can be used to predict progression to chronic myeloid leukemia (1). .

Prognosis reference

Treatment

  • Symptomatic therapy

  • Sometimes allogeneic stem cell transplantation

  • Sometimes ruxolitinib

Treatment is directed at symptoms and complications. Some patients can be observed without treatment.

In early primary myelofibrosis, pegylated interferon has been shown to reduce marrow fibrosis and spleen size and can be used for low-risk patients.

Currently, for advanced primary myelofibrosis, the nonspecific JAK pathway inhibitor ruxolitinib is the therapy of choice. Ruxolitinib is effective whether or not a JAK2 mutation or splenomegaly is present. The main adverse effects of ruxolitinib are anemia and thrombocytopenia. Care must be taken when stopping ruxolitinib because a withdrawal syndrome may occur, with significant worsening of symptoms in part due to splenic enlargement and a rebound in inflammatory cytokines. Low-dose corticosteroids may be used short term for symptom control.

For patients with advanced disease, allogeneic stem cell transplantation may be beneficial. Nonmyeloablative allogeneic stem cell transplantation has been successfully used in older patients.

Androgens, erythropoietin, splenectomy, chemotherapy, thalidomide, lenalidomide, splenic embolization, and radiation therapy have been tried for palliation. Of these, low-dose thalidomide and prednisone can be effective in controlling splenomegaly, anemia, thrombocytopenia, and circulating blast cells. However, the other modalities are of limited effectiveness. Splenectomy should be avoided if possible; splenic irradiation has only a temporary effect and can cause severe neutropenia and infection.

Key Points

  • Myelofibrosis is excessive bone marrow fibrosis, often with loss of hematopoietic cells and consequent extramedullary hematopoiesis.

  • Myelofibrosis is often primary but may occur secondary to a number of hematologic, malignant, and nonmalignant disorders, including polycythemia vera and essential thrombocytosis.

  • Primary myelofibrosis is a clonal hematopoietic disorder and often involves JAK2, CALR, or MPL mutations.

  • Diagnose with blood count, examination of peripheral blood smear and bone marrow, and molecular testing for JAK2, MPL, and/or CALR mutations.

  • Some patients have an indolent course and do not require therapy immediately, but some patients have a rapidly progressive downhill course with short survival.

  • Ruxolitinib is the therapy of choice for control of symptoms; allogeneic stem cell transplantation may be beneficial in selected cases.

Drugs Mentioned In This Article

Drug Name Select Trade
REVLIMID
JAKAFI
THALOMID
RAYOS
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