Myelofibrosis

Overview

Myelofibrosis (MF) is a myeloproliferative cancer characterised by the proliferation of abnormal haematopoietic stem cells in the bone marrow leading to fibrosis and the replacement of haematopoietic tissue in the bone marrow with scar tissue.

MF can be primary or arise secondary to another myeloproliferative neoplasm such as polycythaemia vera or essential thrombocytosis.

MF is associated with mutations in the JAK2 gene.

Epidemiology

• MF is rare, its incidence is 0.4 cases per 100,000 per year
• The peak age of incidence is >40 years of age
• The median age at diagnosis is 60 years 

Risk Factors

• Exposure to mutagenic agents e.g. ionising radiation
• People of Caucasian ethnicity
• Male sex – except in children where females are affected more

Example History

A 70-year-old man has had fatigue, weight loss, and abdominal discomfort over the last 4 months. On examination, he has massive splenomegaly.

Investigations:

Presentation

Patients usually present with anaemia and fatigue and may have splenomegaly as other sites start to carry out haematopoiesis to compensate. Features are:

• Features of anaemia – due to a failure to produce new red blood cells:
  • Dyspnoea
  • Pallor
  • Fatigue
• Constitutional symptoms:
  • Weight loss
  • Night sweats
  • Low-grade fever
  • Pruritus
• Massive splenomegaly with/without hepatomegaly:
  • This occurs due to extramedullary haematopoiesis in the liver and spleen
  • This may cause abdominal discomfort and early satiety
  • Splenomegaly can also contribute to anaemia and thrombocytopenia due to the increased sequestration of cells

Differential Diagnoses

Polycythaemia vera

• Patients often have plethora – appear ‘tanned’ or ‘ruddy’
• There may be aquagenic pruritus – itching after showers/baths

Essential thrombocytosis

• Venous thromboembolism may be seen
• Patients feel a burning sensation in the hands (erythromelalgia)

Chronic myeloid leukaemia (CML)

• Signs and symptoms may be the same
• Blood film shows tear-drop poikilocytes in MF but not CML
• Bone marrow biopsy and flow cytometry can help distinguish the two

Myelodysplastic syndrome

• No splenomegaly seen
• Bone marrow biopsy can distinguish the two

Investigations

All patients

• Full blood count (FBC) and white cell differential:
  • Anaemia may be present
  • White cell counts may be low, normal, or high
  • Thrombocytosis is often seen, but thrombocytopenia can be present
• Blood film:
  • Tear-drop poikilocytes are seen
    • This is thought to occur due to red blood cells being ‘squeezed’ out of fibrotic bone marrow, leaving behind a tailed end
• Uric acid:
  • Increased due to increased cell turnover
• Lactate dehydrogenase (LDH):
  • Increased due to increased cell turnover
• Bone marrow aspiration and biopsy:
  • Bone marrow aspiration would not be possible due to fibrosis – known as a ‘dry tap’
    • If this occurs, a trephine biopsy is performed
  • Bone marrow biopsy shows fibrosis and is diagnostic
• Gene mutation analysis:
  • JAK2 mutation may be positive

Management

Overview

Patients are managed through observation and monitoring, allogeneic stem cell transplantation, and consideration of hydroxyurea and JAK2 inhibitors

Complications

• Anaemia
• Thrombocytopenia and bruising/bleeding
• Recurrent and severe infections due to low white cells
• Portal hypertension due to splenomegaly
• Splenic infarction due to splenomegaly
• Transformation to acute myeloid leukaemia (AML)
• Myeloid metaplasia due to extramedullary haematopoiesis
• Uric acid renal stones – due to increased uric acid
• Gout – due to increased uric acid
• Gout or urate renal stones due to hyperuricaemia

Prognosis

• MF is incurable without allogeneic stem cell transplantation
• Survival varies from 2-11 years