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Primary Myelofibrosis

(Agnogenic Myeloid Metaplasia; Myelofibrosis with Myeloid Metaplasia)

By Jane Liesveld, MD, University of Rochester ; Patrick Reagan, MD, University of Rochester Medical Center

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Primary myelofibrosis (PMF) is a chronic myeloproliferative 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 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 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 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.

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 or acute myelofibrosis, has a more rapidly progressive downhill course and is generally due to an acute leukemia.

Conditions Associated With Myelofibrosis

Condition

Examples

Malignancies

Cancer with bone marrow metastases

Leukemias (particularly chronic myelogenous leukemia and hairy cell leukemia)

Polycythemia vera (15 to 30% of patients)

Hematologic disorders

Essential thrombocythemia

Polycythemia vera

Infections

TB

Primary pulmonary hypertension

Toxins

Benzene

Thorium dioxide

X- or γ-radiation

Autoimmune disorders (rarely)

SLE

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

PMF 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 PMF 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 yr from onset, but variation is wide; some patients have a rapidly progressing disorder, including development of acute myelogenous leukemia, with short survival, but most have a more indolent course. Only allogeneic stem cell transplantation is curative.

Unfavorable prognostic markers include Hb <10 g/dL, a history of transfusions, leukocytosis, and a platelet count < 100,000/μL. Patients in the least favorable risk group usually survive < 1 yr. Several prognostic scoring systems are available to predict survival.

Treatment

  • Symptomatic therapy

  • Sometimes allogeneic stem cell transplantation

  • Sometimes a JAK2 inhibitor, ruxolitinib

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

In early primary myelofibrosis, interferon has been shown to reduce marrow fibrosis and spleen size.

Currently, for advanced primary myelofibrosis, the nonspecific JAK pathway inhibitor ruxolitinib is the therapy of choice. It can also be combined with thalidomide for maintaining the platelet count, which often falls with ruxolitinib. Ruxolitinib is effective whether or not a JAK2 mutation or splenomegaly is present. 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 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.

Androgens, erythropoietin, splenectomy, chemotherapy, thalidomide, lenalidomide, and splenic embolization and radiation therapy have been tried for palliation. However, these 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 c-Mpl mutations.

  • Diagnose with blood count, examination of peripheral blood smear and bone marrow, and molecular testing for JAK2, c-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.

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