Primary Myelofibrosis

Chapter: Primary Myelofibrosis
McMaster Section Editor(s): Mark Crowther
Section Editor(s) in Interna Szczeklika: Andrzej Hellmann, Bogdan Ochrem
McMaster Author(s): Mark Crowther
Author(s) in Interna Szczeklika: Irena Frydecka
Additional Information

Definition, Etiology, Pathogenesis Top

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by anemia, the presence of immature forms of granulocytic lineage, bone marrow fibrosis, splenomegaly, and extramedullary hematopoiesis. The etiology is unknown. The estimated incidence is around 1.5 cases/100,000 population per year.

Clinical Features And Natural History Top

1. General symptoms: Fatigue (in 50%-70% of patients), anorexia (<20%), weight loss, low-grade fever, dyspnea, tachycardia, night sweats, pruritus, muscle and joint pain (particularly of the lower extremities), cachexia.

2. Symptoms of bone marrow fibrosis and extramedullary hematopoiesis: Splenomegaly (observed at presentation in >90% of patients; severe in two-thirds of patients), pain due to splenic infarcts; hepatomegaly (in 40%-70% of patients), portal hypertension; thrombocytopenia, features of anemia; symptoms of mass effect due to extramedullary hematopoiesis.

3. Natural history: Asymptomatic PMF is followed by progression with worsening symptoms of anemia, thrombocytopenia, and extramedullary hematopoiesis. Pain due to splenic infarction may be severe. In patients with advanced disease, symptoms of anemia and hepatic failure predominate. The median survival is ~5 years. Transformation to acute myelogenous leukemia occurs in 20% of patients.

Diagnosis Top

Diagnostic Tests

1. Complete blood count (CBC): Normocytic anemia; a variable white blood cell (WBC) count including marked leukocytosis; thrombocytosis may be seen in early disease but advanced patients demonstrate thrombocytopenia due to splenomegaly; morphologic and functional abnormalities of the platelets. Differential blood counts reveal anisocytosis, poikilocytosis, teardrop-shaped red blood cells (RBCs), erythroblasts, and immature granulocyte forms (leukoerythroblastosis).

2. Bone marrow examination: In early PMF, the marrow is hypercellular with atypical megakaryocytes. In the later stages of the disease, marrow fibrosis and osteosclerosis make aspiration infeasible and trephine biopsy must be performed. The results reveal fibrosis (increased marrow reticulin and collagen fibers) with reduced or absent hematopoiesis.

3. Molecular studies reveal JAK2 V617F mutation (in ~50% of patients) or CALR and MPL gene mutations.

Diagnostic Criteria

All major and 2 minor criteria must be fulfilled to diagnose PMF.

1. Major criteria:

1) Typical features on histologic examination of trephine biopsy specimens.

2) Exclusion of polycythemia vera (PV), chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), and myeloid neoplasms.

3) Demonstration of JAK2 V617F mutation or other clonal markers (eg, MPL mutation). If these are absent, confirm that marrow fibrosis is not caused by another malignant or inflammatory condition (reactive fibrosis).

2. Minor criteria:

1) Leukoerythroblastosis of peripheral blood.

2) Elevated serum lactate dehydrogenase levels.

3) Anemia.

4) Splenomegaly.

Differential Diagnosis

1. Myelofibrosis caused by malignant conditions: PV, essential thrombocytosis (ET), CML, acute megakaryocytic leukemia, acute panmyelosis with myelofibrosis, MDS, chronic myelomonocytic leukemia (CMML), hairy cell leukemia, multiple myeloma (MM), Hodgkin lymphoma, and some metastatic solid tumors (breast cancer, prostate cancer, non–small cell lung cancer). In early disease, it may be difficult or impossible to differentiate myelofibrosis from PV, CML, or especially ET when the only presenting observation is thrombocytosis.

2. Myelofibrosis caused by nonneoplastic conditions: Paget disease, secondary hyperparathyroidism in patients with vitamin D deficiency, renal osteodystrophy, systemic lupus erythematosus; less frequently, other systemic connective tissue diseases, tuberculosis, syphilis, chronic benzene poisoning; thrombopoietin-receptor agonists; radiation exposure.

Treatment Top

Except for allogeneic hematopoietic stem cell transplantation (HSCT), all treatments of PMF are palliative and do not improve survival. The choice of treatment depends on the patient’s predicted survival based on the Dynamic International Prognostic Scoring System (DIPSS) Plus score. The score is used both at the time of diagnosis and in the course of treatment and includes 8 risk factors:

1) Age >65 years.

2) Constitutional symptoms.

3) Hemoglobin (Hb) <10 g/dL.

4) WBC count >25,000/microL.

5) Peripheral blood blasts ≥1%.

6) Packed red blood cell-transfusion dependence.

7) Thrombocytopenia <100,000/microL.

8) An unfavorable karyotype.

Asymptomatic patients classified as low-risk or intermediate-1-risk group (0 or 1 risk factor present) may receive no treatment. In patients with symptoms, consider conventional symptomatic treatment. Patients classified as intermediate-2-risk or high-risk group (≥2 risk factors) may be considered for allogeneic HSCT or treatment with experimental agents evaluated in clinical studies (Janus kinase [JAK] inhibitors); if this is not feasible, patients receive conventional treatment.

Types of treatment: 

1) Allogeneic HSCT: The only potentially curative treatment, which could be considered in suitable patients who have predicted survival <5 years (high-risk or intermediate-2-risk group), are transfusion-dependent, or have an unfavorable karyotype. The 5-year survival rates in highly selected patients treated with myeloablative allogeneic HSCT regimens are 45% to 50%.

2) Cytoreductive treatment (using doses lower than in other myeloproliferative neoplasms) is indicated in patients with high WBC counts, symptomatic thrombocytopenia, severe splenomegaly, and severe general symptoms. The agents used include hydroxyurea (INN hydroxycarbamide), melphalan, busulfan, cladribine, and interferon alpha.

3) Treatment of anemia (Hb <10 g/dL): Transfusion, erythropoiesis-stimulating agents (ESAs), androgens (danazol, testosterone enanthate, fluoxymesterone), glucocorticoids (prednisone), thalidomide, lenalidomide (in patients with 5q- deletion).

4) Splenectomy is indicated in patients with severe or painful splenomegaly refractory to cytoreductive treatment, radiation, or both; selected patients with transfusion-dependent anemia; and patients with severe symptomatic portal hypertension. Perioperative mortality is 5% to 10%.

5) Splenic irradiation: Indications are the same as in splenectomy.

6) Irradiation of symptomatic foci of extramedullary hematopoiesis.

7) JAK inhibitors (eg, ruxolitinib) may be of benefit in patients with symptomatic splenomegaly and severe general symptoms refractory to cytoreductive treatment.

Follow-Up Top

CBC and clinical evaluation should be performed based on the stage of the disease and manifest complications. In early disease, follow-up can be infrequent. Patients may require acute assessments at the time of splenic infarcts to differentiate surgical causes of abdominal pain from complications of the disease.

Prognosis Top

PMF has the least favorable prognosis of myeloproliferative neoplasms. Mean survival varies from 15.4 years in the low-risk group to 1.3 years in the high-risk group. Most patients die of infection, hemorrhage, or transformation to leukemia.

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