Primary Myelofibrosis

Chapter: Primary Myelofibrosis
McMaster Section Editor(s): Mark Crowther
Section Editor(s) in Interna Szczeklika: Andrzej Hellmann, Bogdan Ochrem
McMaster Author(s): Christopher Hillis, 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, presence of immature forms of granulocytic lineage in peripheral blood, bone marrow fibrosis, splenomegaly, and extramedullary hematopoiesis. Etiology is unknown. Estimated incidence is 1.5/100,000 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, 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, hepatosplenomegaly, and extramedullary hematopoiesis. 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; 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 marrow is hypercellular with atypical megakaryocytes. In 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), CALR, or MPL gene mutations.

Diagnostic Criteria

A diagnosis of overt PMF requires meeting all 3 major criteria and ≥1 minor criterion:

1) Major criteria:

a) Presence of megakaryocytic proliferation and atypia accompanied by either reticulin and/or collagen fibrosis grade 2 or 3.

b) Not meeting World Health Organization criteria for essential thrombocythemia (ET), polycythemia vera (PV), BCR-ABL1 chronic myelogenous leukemia (CML), myelodysplastic syndromes, or other myeloid neoplasms.

c) Presence of JAK2, CALR, or MPL mutation or, in the absence of these mutations, presence of another clonal marker, or absence of reactive myelofibrosis.

2) Minor criteria: Presence of ≥1 of the following, confirmed on 2 consecutive determinations:

a) Anemia not attributed to a comorbid condition.

b) Leukocytosis >11 × 109/L.

c) Palpable splenomegaly.

d) Lactate dehydrogenase (LDH) increased to above the upper limit of normal.

e) Leukoerythroblastosis.

Differential Diagnosis

1. Myelofibrosis caused by malignant conditions: PV, ET, CML, acute megakaryoblastic 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

The only curative treatment for PMF is allogeneic hematopoietic stem cell transplantation (HSCT). 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) Unfavorable karyotype.

Asymptomatic patients classified as low-risk or intermediate-1-risk group (0 or 1 risk factor present) are observed. In patients with symptoms and/or splenomegaly consider conventional symptomatic treatment or JAK inhibition. Patients classified as intermediate-2-risk or high-risk group (≥2 risk factors) may be considered for allogeneic HSCT or treatment with JAK inhibitors if they are symptomatic or have splenomegaly; 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) and interferon alpha. Rarely melphalan, busulfan, or cladribine may be used.

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.

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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