Myelofibrosis

Myelofibrosis is a rare type of blood cancer that occurs when scar tissue, or fibrosis, develops within the bone marrow — the soft, spongy tissue responsible for producing blood cells. It is classified under a group of diseases known as myeloproliferative disorders. This scarring disrupts the normal production of red blood cells, white blood cells and platelets, leading to various health complications.

As the disease progresses, the bone marrow becomes less efficient at producing healthy blood cells. A decreased number of red blood cells results in anaemia, causing symptoms such as fatigue and weakness. Reduced white blood cells and platelet production increase the risk of infections and bleeding, respectively.

While some individuals may not experience any symptoms in the early stages, others may require active treatment to manage more severe complications.

How prevalent is myelofibrosis?

Myelofibrosis is a rare disease. Studies estimate that the age-standardised incidence rate (which adjusts for differences in age across populations) for primary myelofibrosis ranges from 0.3 to 0.8 cases per 100,000 people each year.

Research also suggests that men are more commonly affected than women. In Singapore, local data shows an age-standardised incidence rate of approximately 0.43 cases per 100,000 population. Myelofibrosis tends to affect people over the age of 50, though it can occur at any age.

What are the types of myelofibrosis?

There are two main types of myelofibrosis, depending on whether the condition develops on its own or as a complication of another blood disorder:

• Primary myelofibrosis: This type develops on its own, without any pre-existing blood condition. It arises when genetic mutations occur in the bone marrow stem cells, leading to uncontrolled blood cell production and subsequent scarring in the bone marrow.
• Secondary myelofibrosis: Also known as post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis, this type develops as a progression from another myeloproliferative disorder, such as polycythaemia vera or essential thrombocythaemia. These precursor conditions gradually cause damage to the bone marrow over time, leading to secondary myelofibrosis.

What are the symptoms of myelofibrosis?

Myelofibrosis symptoms can vary. In its early stages, some people may not experience any symptoms and may only be diagnosed following routine blood tests. As the condition progresses, common symptoms include:

• Fatigue and tiredness, often due to anaemia
• Shortness of breath
• Easy bruising or bleeding
• Pale skin
• Enlarged spleen (splenomegaly), leading to abdominal discomfort or pain, or early satiety (feeling full quickly after eating)
• Bone pain or joint pain
• Night sweats
• Fever
• Unintentional weight loss
• Frequent infections
• Bleeding gums or nosebleeds

When should you see a doctor?

If you experience any persistent symptoms such as fatigue, unexplained bruising or fullness under the left rib cage, it is important to consult a doctor. Early evaluation can help identify underlying conditions such as myelofibrosis, especially if abnormalities are found in routine blood tests.

Can myelofibrosis be prevented?

Currently, there are no proven strategies to prevent myelofibrosis, as the exact cause of the gene mutations remains unknown.

However, general steps to support overall blood health include:

• Avoid or minimize exposure to industrial chemicals such as benzene and toluene
• Reduce radiation exposure where possible
• Eat a balanced diet rich in fruits and vegetables
• Exercise regularly
• Limit alcohol consumption
• Avoid smoking

Regular health check-ups may aid in early detection of blood disorders.

What causes myelofibrosis?

Myelofibrosis develops due to mutations in the genes responsible for regulating blood cell production. These mutations cause the bone marrow stem cells to behave abnormally, leading to scarring and disruption in normal blood cell production.

The key gene mutations linked to myelofibrosis include:

• JAK2 mutation: The most common mutation, found in approximately 60% of individuals with myelofibrosis.
• CALR mutation: Detected in around 20-25% of individuals with myelofibrosis.
• MPL mutation: Detected in about 5-10% of individuals with myelofibrosis.

The exact cause of these genetic changes remains unclear. Most mutations are acquired during a person’s lifetime and are not inherited.

What causes myelofibrosis?

Myelofibrosis develops due to mutations in the genes responsible for regulating blood cell production. These mutations cause the bone marrow stem cells to behave abnormally, leading to scarring and disruption in normal blood cell production.

The key gene mutations linked to myelofibrosis include:

• JAK2 mutation: The most common mutation, found in approximately 60% of individuals with myelofibrosis.
• CALR mutation: Detected in around 20-25% of individuals with myelofibrosis.
• MPL mutation: Detected in about 5-10% of individuals with myelofibrosis.

The exact cause of these genetic changes remains unclear. Most mutations are acquired during a person’s lifetime and are not inherited.

What are the risk factors for myelofibrosis?

Myelofibrosis can affect anyone, but certain factors can increase the risk of developing the condition:

• Age: It is most commonly diagnosed in individuals over the age of 50.
• Other blood disorders: Conditions such as polycythaemia vera or essential thrombocythaemia can progress to secondary myelofibrosis.
• Exposure to industrial chemicals: Such as benzene or toluene.
• Exposure to radiation: Including previous medical treatments or environmental exposure.
   

What are the complications associated with myelofibrosis?

Over time, myelofibrosis can lead to several complications:

• Severe anaemia: Resulting in profound fatigue and weakness
• Enlarged spleen (splenomegaly): Causing abdominal pain and reduced appetite
• Portal hypertension: Increased pressure in the vein supplying blood to the liver, potentially leading to bleeding from oesophageal or stomach veins
• Bone pain and joint pain
• Increased risk of bleeding: Due to low platelet counts (thrombocytopenia)
• Development of tumours outside the bone marrow (extramedullary haematopoiesis): These growths can cause organ compression and other complications
• Progression to acute myeloid leukaemia (AML): Occurs in about 10-20% of cases

How is myelofibrosis diagnosed?

Diagnosing myelofibrosis requires a comprehensive approach, as its symptoms can resemble other bone marrow disorders. Healthcare professionals use a combination of physical examinations, blood tests, bone marrow analysis and genetic testing to confirm the diagnosis and assess the severity of the disease.

Physical examination

The doctor will check for signs such as an enlarged spleen or liver, pale skin (a sign of anaemia) or other physical clues. These examinations also help identify potential complications.

Blood tests

• Complete blood count (CBC): This fundamental test evaluates red blood cells, white blood cells and platelets. In myelofibrosis, patients typically have a low red blood cell count (anaemia), abnormal levels of white blood cells (these can be elevated, normal or reduced) and platelet counts that may be either high or low, depending on disease progression.
• Peripheral blood smear: This allows a closer look at blood cell shapes and sizes. In myelofibrosis, tear-drop shaped red blood cells (dacrocytes) are commonly seen.
• Blood chemistry tests: Elevated levels of substances such as uric acid or lactate dehydrogenase (LDH) can indicate high cell turnover, common in myeloproliferative disorders.

Bone marrow aspiration and biopsy
This is a critical step in confirming myelofibrosis. A small sample of bone marrow tissue and liquid is taken, usually from the pelvic bone, and examined under a microscope. Pathologists assess the degree of fibrosis (scarring), the number and type of abnormal cells and the presence of immature blood cells or “blasts”, which may signal disease progression.

Genetic testing
Identifying mutations in genes such as JAK2, CALR and MPL helps to confirm the diagnosis, determine prognosis and guide treatment decisions, as certain therapies target specific genetic mutations.

Imaging tests
Ultrasound or MRI scans help assess the size of the spleen and liver, and detect extramedullary haematopoiesis (blood cell production outside the bone marrow).

Risk scoring systems
Doctors may also use tools such as the Dynamic International Prognostic Scoring System (DIPSS) or the Mutation-Enhanced International Prognostic Scoring System (MIPSS) to categorise disease severity and estimate prognosis.

How is myelofibrosis treated?

Treatment decisions for myelofibrosis are best made collaboratively between the patient and healthcare team. These decisions should be tailored to the individual, taking into account the severity of symptoms, disease progression, genetic profile and overall health. While some patients may not require immediate treatment, others may need prompt intervention to manage complications, improve quality of life, and even prolong survival.
 

Observation (watchful waiting)
For patients without significant symptoms or complications, careful monitoring with regular check-ups is recommended. Some individuals may remain stable for years without needing active treatment.
 

Managing anaemia
Anaemia is one of the most common and debilitating features of myelofibrosis. Treatment optiions may include:

• Blood transfusions: These can quickly raise red blood cell counts and relieve anaemia-related symptoms.
• Androgen therapy: Male hormones, such as danazol, may stimulate red blood cell production, although they can have side effects like liver toxicity.
• Erythropoiesis-stimulating agents (ESAs): These injectable medications encourage the bone marrow to produce more red blood cells.
• Immunomodulatory drugs: Thalidomide, lenalidomide and pomalidomide - sometimes combined with steroids - may help improve anaemia and reduce spleen size in certain patients.
• Corticosteroids: These may be used selectively to manage anaemia, especially if autoimmune destruction of red blood cells is suspected.
   

Treating high blood counts
In some patients, myelofibrosis is associated with elevated blood cell counts, particularly early in the disease course or in cases that evolve from polycythaemia vera or essential thrombocythaemia. Treatment options may include:

• Hydroxyurea: An oral chemotherapy drug that helps control high white blood cell and platelet levels.
• Anagrelide: This can lower elevated platelet counts and reduce the risk of clotting complications.
• PEGylated interferon: A modified form of interferon that can help regulate blood cell production with a longer duration of action and improved tolerability.
  
  

Treating spleen enlargement
The spleen often becomes enlarged due to overwork in filtering abnormal blood cells. Treatment options may include:

• JAK inhibitors: Targeted therapies such as ruxolitinib, fedratinib, momelotinib and pacritinib are indicated for patients with intermediate- or high-risk myelofibrosis. They effectively reduce spleen size and control myelofibrosis-related symptoms such as night sweats, itch and bone or muscle pain.
• Radiotherapy: This can be applied to the spleen when drug treatments are insufficient or surgery is not an option.
• Splenectomy (surgical removal of the spleen): This may be considered for patients with severely enlarged spleens unresponsive to other treatments. However, there are risks, such as infection and blood clot formation.
   

Allogeneic stem cell transplant
Currently, this remains the only treatment with curative potential. The procedure involves replacing diseased bone marrow with healthy stem cells from a compatible donor. Prior to transplantation, high-dose chemotherapy and/or radiation is used to clear the patient’s bone marrow.

Transplant is best suited for younger patients with high-risk disease and good overall health, as it carries significant risks such as graft-versus-host disease and infection.

Supportive (palliative) care
Supportive care plays an essential role in the management of myelofibrosis, especially in advanced stages. It includes pain management, nutritional support, psychological support and symptom relief strategies tailored to individual needs.

Engaging palliative care teams early can significantly enhance quality of life, even while pursuing disease-modifying treatments.

References

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