Synonym: agnogenic myeloid metaplasia

Bone marrow fibrosis is associated with the appearance of marrow stem cells in abnormal sites (myeloid metaplasia), e.g. liver and spleen. Myelofibrosis may be primary (idiopathic) or secondary to a variety of diseases, including:

• Idiopathic myelofibrosis
• Leukaemias: acute lymphocytic leukaemia, acute myelogenous leukaemia, acute megakaryocytic leukaemia, chronic myelogenous leukaemia, hairy cell leukaemia
• Lymphomas: Hodgkin's and non-Hodgkin's
• Multiple myeloma
• Metastatic carcinoma
• Polycythaemia vera
• Systemic mastocytosis
• Infection: HIV, tuberculosis
• Endocrine/metabolic: hyperparathyroidism, renal osteodystrophy, vitamin D deficiency
• Connective tissue disease: systemic lupus erythematosus
• Toxins: x-radiation, gamma radiation, benzene, thorium dioxide exposure

Epidemiology

• Uncommon disease, with an annual incidence of approximately 0.4 cases per 100,000.¹
• The median age at diagnosis is 60 years, and more than 90% of patients are diagnosed after age 40 years.² However myelofibrosis has been reported in all age groups.

Risk factors

• More common in white people than in individuals of other races.
• An increased prevalence rate has been noted in Ashkenazi Jews.
• A slight male preponderance appears to exist; however, in younger children, girls are affected twice as frequently as boys.

Presentation

• In early stages, the disease may be asymptomatic.
• Hepatosplenomegaly or abnormal blood findings (leukoerythroblastic anaemia with teardrop-shaped red blood cells) may be discovered on routine examination.

Symptoms

• In later stages, general malaise, weight loss, night sweats and low-grade fever.
• Anaemia (may occur due to ineffective erythropoiesis, erythroid hypoplasia, and hypersplenism) may cause fatigue, weakness and dyspnoea.
• Splenomegaly may result in left upper quadrant discomfort. Splenic infarcts, perisplenitis, or subcapsular haematoma may cause severe left upper-quadrant or left shoulder pain.
• Spontaneous bleeding may occur and vary from insignificant cutaneous petechiae to severe, life-threatening GI tract bleeding. Platelet dysfunction, acquired factor V deficiency, thrombocytopenia, disseminated intravascular coagulation, oesophageal varices, and peptic ulcer disease may occur.
• Extramedullary haematopoiesis may cause symptoms, depending on the organ or site of involvement. The condition may result in spinal cord compression, focal seizures, symptoms related to brain tumours, ascites, haematuria, pericardial effusion, pleural effusion, haemoptysis, and respiratory failure.

Signs

• Splenomegaly (may be massive)
• Hepatomegaly
• Pallor
• Petechiae and ecchymosis
• Neutropenia may cause opportunistic infection, e.g. oral thrush
• Lymphadenopathy
• Signs of portal hypertension
• Gout

Investigations

• Peripheral blood film: leukoerythroblastosis with teardrop poikilocytosis. Large platelets and megakaryocyte fragments may also be seen. May be anaemia and leucopenia. Thrombocytosis is more common than thrombocytopenia.
• Disseminated intravascular coagulation (15% of patients) is usually clinically silent, but may cause decreased platelets, decreased clotting factors and increased fibrin degradation products.
• Bone marrow aspiration is usually dry. A bone marrow biopsy is required to show fibrosis. Fibrosis may not be uniformly distributed and so the biopsy may need to be repeated at a different site. Cytogenetic studies of bone marrow help to exclude CML, myelodysplastic syndrome, or other chronic myeloid disorders. In patients with myelofibrosis, cytogenetic studies reveal chromosomal abnormalities in about half of all patients. The presence of an abnormal karyotype is associated with a poorer prognosis.
• Skeletal radiographs: increased bone density (may be patchy and result in a mottled appearance) and a prominence of bony trabeculae.
• MRI scan: help to assess the severity and progression of disease. Marrow patterns observed on an MRI examination of the proximal femur appear to correlate with clinical severity.
• Investigation of possible underlying cause (see above), e.g. parathyroid hormone, antinuclear antibodies.

Associated diseases

• Idiopathic myelofibrosis is a chronic myeloproliferative disorder, along with chronic myelogenous leukaemia, polycythaemia rubra vera, and essential thrombocytosis.
• Myeloproliferative diseases are a group of disorders characterised by cellular proliferation of one or more blood cell lines distinct from acute leukaemia.
• In some patients, conditions overlap and one condition may evolve into one of the other myeloproliferative conditions and/or transform to acute leukaemia.

Management

• Allogeneic stem cell transplantation represents the only treatment modality with curative potential.^3,4
• Asymptomatic patients may be observed without intervention.
• Therapy is directed at management of complications and no treatment has been shown to consistently prolong survival.
• Androgens, corticosteroids and erythropoietin are useful for the treatment of anaemia. Symptomatic splenomegaly is best managed by chemotherapy (e.g. hydroxyurea) therapy or splenectomy.
• Transfusion of packed red cells and/or platelets may be required. Patients with haemolysis should take folic acid supplements.
• Allopurinol for hyperuricaemia.
• Bone marrow transplantation should be considered for younger patients with advanced disease.
• Management of any underlying cause, e.g. vitamin D deficiency, HIV infection, leukaemia.

Drugs

• Hydroxyurea has traditionally been the preferred and most commonly used agent. Moderately effective at improving splenomegaly, leucocytosis and thrombocytosis.²
• Interferon alfa is a viable alternative to hydroxyurea therapy, especially in patients under 45 years of age. Response rates of 50% have been observed, with improvement in splenomegaly and blood cell counts.⁵
• Androgens and corticosteroids: used to treat patients with severe anaemia and may improve symptoms and decrease transfusion requirements.
• Thalidomide: small studies have reported some improvement in anaemia, thrombocytopenia, and splenomegaly. Improvements were associated with significant adverse effects, resulting in high drop-out rates. Low-dose thalidomide and prednisolone in more recent studies has been better tolerated.⁶
• The combination of low-dose thalidomide and prednisone is better tolerated and more effective than thalidomide alone.⁷
• Even with aggressive chemotherapy, remissions are rare and there is no effect on the overall course of the disease.
• High-dose chemotherapy: This modality combined with autologous transplantation has been shown to slow disease progression. A small study found evidence of improvement in fibrosis.
• Several new drugs are being studied, including farnesyl transferase inhibitors, tyrosine kinase inhibitors and vascular endothelial growth factor inhibitors.⁸

Radiotherapy

• May be used to treat symptomatic extramedullary haematopoiesis and for bone pain resulting from tumours or periostitis.
• Splenic irradiation may be considered for patients in whom splenectomy is contraindicated.⁹ Splenic irradiation is beneficial to patients with symptomatic splenomegaly or splenic infarction but the effects are usually temporary. Prolonged pancytopenia may occur after splenic irradiation.

Surgical

• Splenectomy:
  • Considered for patients with portal hypertension, progressive anaemia requiring transfusions or symptomatic splenomegaly refractory to hydroxyurea.
  • Has been associated with a significant operative mortality and morbidity from infections, haemorrhage, and thrombosis.
  • Marked hepatomegaly and thrombocytosis may develop after splenectomy.
  • Splenectomy is thought to be an independent risk factor for transformation to acute myeloblastic leukaemia.
• Allogeneic stem cell transplantation:
  • Potentially curative therapy and long-lasting, complete remissions have been reported.¹⁰ Requires high dose chemotherapy to destroy the bone marrow before stem cell transplant. The high dose chemotherapy may have severe adverse effects. Studies are currently focused on ways to avoid the need for such high dose chemotherapy.
  • Patients with low haemoglobin, karyotypic abnormalities, osteomyelosclerosis and older age appear to have poorer outcomes. The 1-year mortality rate for persons receiving HLA-identical sibling transplants is approximately 30%.

Complications

• Portal hypertension may result in variceal bleeding, ascites and hepatic encephalopathy. Hepatic or portal vein thrombosis may also occur.
• Splenic infarction: usually self-limited and treated with fluids and opiate analgesics. Refractory cases may require splenectomy or splenic irradiation.
• Osteosclerosis, hypertrophic osteoarthropathy and periostitis: may cause severe joint and bone pain.
• Abnormalities of humoral immunity: variety of autoantibodies and circulating immune complexes may be detected and amyloidosis may develop. Infections, commonly pneumonia, may occur as a result of immune deficiency.
• Leukaemic transformation occurs in approximately 20% of patients within the first 10 years.
• Extramedullary hematopoiesis may involve any organ and may result in GI tract bleeding, spinal cord compression, seizures, haemoptysis, and/or effusions. These are easily controlled with low-dose radiation.
• Gout or urate renal calculi due to uric acid overproduction.

Prognosis

• The overall median survival is 5 years although it might range from 2 to 15 years depending on the presence or absence of clinically defined prognostic factors.¹¹
• Death is often due to leukaemic transformation, portal hypertension or infection.
• Other poor prognostic factors include older age, anaemia, leucocytosis, leucopenia, circulating blasts, increased numbers of granulocyte precursors, thrombocytopenia and karyotype abnormalities.¹²
• Leukocytosis and abnormal karyotype are associated with increased risk of transformation to acute myeloblastic leukaemia.