Primary myelofibrosis

What is Primary myelofibrosis?

Primary myelofibrosis (also called chronic idiopathic myelofibrosis, agnogenic myeloid metaplasia) is a disorder in which normal bone marrow tissue is gradually replaced with a fibrous scar-like material. Over time, this leads to progressive bone marrow failure.

Under normal conditions, the bone marrow provides a fine network of fibres on which the stem cells can divide and grow. Specialised cells in the bone marrow known as fibroblasts make these fibres.

In primary myelofibrosis, chemicals released by high numbers of platelets and abnormal megakaryocytes (platelet forming cells) over-stimulate the fibroblasts. This results in the overgrowth of thick coarse fibres in the bone marrow, which gradually replace normal bone marrow tissue. Over time this destroys the normal bone marrow environment, preventing the production of adequate numbers of red cells, white cells and platelets. This results in anaemia, low platelet counts and the production of blood cells in areas outside the bone marrow for example in the spleen and liver, which become enlarged as a result.

Primary myelofibrosis is a rare chronic disorder diagnosed in an estimated 1 per 100,000 population. It can occur at any age but is usually diagnosed later in life, between the ages of 60 and 70 years. The cause of primary myelofibrosis remains largely unknown. It can be classified as either JAK2 mutation positive (having the JAK2 mutation) or negative (not having the JAK2 mutation).

Long-term exposure to high levels of benzene or very high doses of ionising radiation may increase the risk of primary myelofibrosis in a small number of cases. Around one third of people with myelofibrosis have been previously diagnosed with polycythaemia (post-polycythaemic myelofibrosis) or essential thrombocythaemia (post-ET myelofibrosis).

Symptoms and complications of primary myelofibrosis

Around 20 per cent of people have no symptoms of primary myelofibrosis when they are first diagnosed and the disorder is picked up incidentally as a result of a routine blood test. For others, symptoms develop gradually over time. Symptoms of anaemia are common and include unexplained tiredness, weakness, shortness of breath and palpitations. Other nonspecific symptoms include fever, unintended weight loss, pruritus (generalised itching) and excess sweating, especially at night.

Virtually all patients with primary myelofibrosis have an enlarged spleen (splenomegaly) when they are first diagnosed. In around a third of cases the spleen is very enlarged. Common symptoms include feelings of discomfort, pain or fullness in the upper left-side of the abdomen. An enlarged spleen may also cause pressure on your stomach causing a feeling of fullness, indigestion and a loss of appetite. Abdominal discomfort can also result from an enlarged liver (hepatomegaly), which occurs in around two-thirds of cases.

Other less common symptoms include bone and joint pain, and bleeding problems.

How is myelofibrosis diagnosed?

Primary myelofibrosis is diagnosed using a combination of a physical examination showing the presence of an enlarged spleen, blood tests and a bone marrow examination. Primary myelofibrosis is only diagnosed when other causes of marrow fibrosis (including leukaemia, lymphoma, other types of cancer that have spread to the bone marrow) have been ruled out.

Full blood count

People with primary myelofibrosis commonly present with varying degrees of anaemia. When examined under the microscope the red cells are often described as being ‘teardrop-shaped’. Higher than normal numbers of white cells and platelets may be found in the early stages of this disorder, but low white cell and platelet counts are common in more advanced disease.

Bone marrow examination

It is frequently impossible to obtain any samples of bone marrow fluid using a needle and syringe (bone marrow aspiration) due to marrow fibrosis. This is known as a ‘dry tap’. The bone marrow trephine biopsy typically shows abnormal fibrosis of the marrow cavity.

Cytogenetic and molecular analysis of blood and bone marrow cells is also carried out to help confirm the diagnosis and may help with prognosis. A mutation in JAK2 is found in about 50% of people with primary myelofibrosis. It is unclear at present why some patients with mutations in JAK2 develop myelofibrosis and others don’t.

How is myelofibrosis treated?

Some people have no symptoms when they are first diagnosed with primary myelofibrosis and do not require treatment straight away, apart from regular check-ups with their doctor to carefully monitor their disease.

For others treatment is largely supportive and is aimed at preventing complications due to low blood counts and an enlarged spleen (splenomegaly). This involves making every effort to improve your quality of life, by relieving any symptoms of anaemia or an enlarged spleen, and preventing and treating any complications that might arise from your disease or its treatment. This may include periodic blood transfusions, biotherapy or chemotherapy. Antibiotics may be needed to prevent and treat any infections.

Biotherapy may be used to reduce an enlarged spleen. In some cases, the surgical removal of the spleen (splenectomy) may be considered, especially when your spleen has enlarged so much that it is causing severe symptoms. A splenectomy may also be considered if you have an increased need for blood transfusions. This sometimes happens because the spleen is destroying blood cells, particularly platelets, at a very fast rate. Small doses of radiation to the spleen can also be given to reduce its size. This usually provides temporary relief for about 3 to 6 months.

Some younger patients who have a suitably matched donor may be offered an allogeneic (donor) stem cell transplant. This is a medical procedure that offers the only chance of cure for patients with myelofibrosis. It involves the use of very high doses of chemotherapy, with or without radiotherapy, followed by infusion of blood stem cells, which have been donated by a suitably matched donor. Stem cell transplants carry significant risks and are only suitable for a small minority of younger patients (usually under 60 years of age).

JAK2 inhibitors

JAK2 inhibitors work by blocking the activity of the JAK2 protein, which may lead to a reduction in splenomegaly and decreased symptoms. They also work in patients with myelofibrosis without the JAK2 mutation. Side effects may include worsening anaemia or a low platelet count. A number of JAK2 inhibitors may be available in clinical trials or may become available in the near future.

Prognosis

Primary myelofibrosis is generally regarded as an incurable disease but with treatment many people can remain comfortable and symptom-free for some time.

The natural course of the disease can vary considerably between individuals. In some people their disease remains stable for long periods and they are free to live a normal life with minimal interruptions from their disease or its treatment. For others,  myelofibrosis progresses more quickly and people require treatment to help relieve symptoms of their disease. Transformation to a type of leukaemia called acute myeloid leukaemia occurs in between 10 and 20 per cent of cases.

Your doctor is the best person to give you an accurate prognosis regarding your disease as he or she has all the necessary information to make this assessment.