Primary or idiopathic myelofibrosis is a condition in which bone marrow is replaced by fibrotic tissue with consequent diminished haematopoiesis. It comes under the category of myeloproliferative neoplasms, which also include polycythemia vera and essential thrombocythemia, both of which can transform into myelofibrosis.
The excessive bone marrow fibrosis in myelofibrosis is secondary to increased activity of fibrogenic growth factors. Due to the replacement of bone marrow by fibrous tissue, compensatory haematopoiesis begins at extra-medullary sites, predominantly the spleen.
Myelofibrosis is a rare disease seen mainly in men over 50 years of age. More than 70% of cases are diagnosed in the over-60s, while fewer than 10% of patients are aged below 45.
It is a heterogeneous disease with wide variability in survival. Disease in asymptomatic patients may remain quiescent for over ten years, while those with progressive disease can die within a year of diagnosis.
Symptoms can be arbitrarily divided into those arising from an enlarged spleen, those due to decreased haematopoiesis and those due to increased cell turnover or hyper-catabolism.
Splenomegaly is found in almost all patients at diagnosis; more than a third of these individuals develop marked splenomegaly. This can cause early satiety due to compression of the stomach, which may occasionally be the presenting symptom.
Splenomegaly can also lead to portal hypertension and hepatomegaly. Splenic infarcts may complicate the clinical picture and are suspected if a patient presents with left upper quadrant pain radiating to the shoulder, without any evidence of left-sided pneumonia or abdominal perforation.
Decreased blood production can present as anaemia or thrombocytopenia, but leukopenia is uncommon. The anaemia may be multifactorial – in addition to decreased synthesis there may be increased incidence of GI haemorrhage, and hypersplenism may cause pooling of red cells.
Up to 70% of patients are anaemic at presentation with a quarter having Hb levels <8g/dL. Thrombocytopenia, secondary to bone marrow failure or splenic pooling, can be observed in about 40% of cases.
Increased cell turnover
In the so-called proliferative phase of myelofibrosis, a high white cell count and platelet count may be seen. To compensate for the marrow underproduction, extra-medullary haematopoiesis can develop in any organ, causing symptoms related to the specific site.
For example, extra-medullary haematopoiesis in the liver, lungs or vertebral column can cause hepatomegaly, pulmonary hypertension or cord compression, respectively.
Severe fatigue is the most common symptom in myelofibrosis. Fatigue and fever, night sweats and severe weight loss are the signs of hyper-catabolism. Hyperuricaemia can also arise secondary to high cell turnover leading to gout or renal complications.
As mentioned above, other myeloproliferative disorders can transform into myelofibrosis. In some patients these disorders can overlap and/or can transform to acute leukaemia.
1. What are the commonest symptoms and signs of myelofibrosis?
2. How do you diagnose myelofibrosis?
3. What complications can a patient with myelofibrosis develop?
The diagnosis of myelofibrosis is suspected in cases of splenomegaly and weight loss in association with anaemia. Occasionally, a routine blood check shows unexplained anaemia which leads to further investigations.
FBC can show anaemia and thrombocytopenia. Both high (9%) and low white cell count (7%) may be observed at different stages of the disease.
Peripheral blood smear examination is a useful and simple test, which can provide clues to the diagnosis of myelofibrosis. Characteristic findings on the blood film include teardrop-shaped RBC and a leucoerythroblastic picture (early forms of white and red cells which have been released from the bone marrow).
To confirm the diagnosis, a bone marrow examination is essential; this can in certain cases be difficult to obtain due to the extensive fibrosis, the so-called ‘dry tap’. Special stains for fibrous tissue (reticulin) will enable the histopathologist to grade the severity of the fibrosis.
Recently, the JAK2V617F mutation has been noted in approximately 50% of patients with myelofibrosis, although this mutation is not specific for myelofibrosis and can be found in patients with some other myeloproliferative disorders.
Bone marrow changes of increased reticulin fibrosis can also be seen in patients with other haematological malignancies and autoimmune disorders – this is termed ‘secondary myelofibrosis’.
Treatment and referral
The only curative treatment for myelofibrosis is allogeneic bone marrow transplant, which is reserved for younger patients due to a very high risk of complications in the presence of co-morbidities.
Treatment can be delayed in older individuals who are asymptomatic at presentation. If treatment is considered, it is guided by the specific symptoms and disease-related complications (see box below).
|Treating symptoms and complications|
Specific treatment for myelofibrosis has been considered recently in the form of thalidomide due to its anti-angiogenic properties, which help reduce marrow fibrosis. A low dose of 50mg per day in combination with prednisolone has been noted as beneficial in some patients with anaemia and thrombocytopenia.
Side-effects include increased somnolence, constipation, peripheral neuropathy and risk of thrombosis.
Regarding when to refer, anaemia that is not explained by haematinic (iron, folate or B12) deficiencies requires further evaluation; a peripheral blood film may be requested if myelofibrosis is suspected in such cases. Splenomegaly and marked weight loss may suggest myelofibrosis.
In a patient already on haematological follow-up for myelofibrosis, new development of upper or lower limb neurological symptoms (cord compression), acute drop in blood count (haemorrhage or transformation into acute leukaemia), and breathlessness (pulmonary hypertension) need fairly urgent evaluation.
- Dr Thachil is consultant haematologist at the Roald Dahl Haemostasis and Thrombosis Centre, Royal Liverpool University Hospital