by Jason Wasserman MD PhD FRCPC and Kamran M. Mirza MBBS PhD
December 24, 2025
Primary myelofibrosis is a type of blood cancer called a myeloproliferative neoplasm. It starts in the bone marrow, the soft tissue inside bones where blood cells are made. In this condition, abnormal blood-forming stem cells cause excessive production of certain blood cell types, especially megakaryocytes (the cells that make platelets). Over time, these abnormal cells trigger fibrosis (scarring) of the bone marrow, which interferes with normal blood cell production.
As the bone marrow becomes less able to make blood cells, the body begins producing blood cells outside the marrow, most commonly in the spleen. This process, called extramedullary haematopoiesis, leads to enlargement of the spleen and, sometimes, other organs.
Primary myelofibrosis can be diagnosed in an early, prefibrotic stage (pre-PMF) or in a more advanced fibrotic stage.
Where does primary myelofibrosis occur?
Primary myelofibrosis always involves the blood and bone marrow. In later stages, blood cell production shifts to other organs, particularly the spleen and sometimes the liver. In advanced disease, abnormal blood-forming tissue can also appear in lymph nodes, skin, lungs, or other organs.
What are the symptoms of primary myelofibrosis?
The symptoms of primary myelofibrosis vary widely and depend on the stage of disease. About one-third of patients have no symptoms at diagnosis and are identified after routine blood tests show abnormalities such as anemia or low platelet counts.
Many patients experience symptoms caused by increased energy use and inflammation in the body. These can include fatigue, weakness, weight loss, loss of appetite, fever, and night sweats. These symptoms are important because their presence is linked to a worse prognosis.
As the spleen enlarges, patients may feel fullness or pain in the left upper abdomen and may feel full quickly when eating. Bone pain can also occur.
Bleeding and blood clots are common complications. Anemia is frequent and may worsen as the disease progresses. In advanced stages, primary myelofibrosis can transform into acute myeloid leukemia, which happens in about 20–25% of patients over time.
What causes primary myelofibrosis?
Primary myelofibrosis is caused by genetic mutations that develop in blood-forming stem cells in the bone marrow. A genetic mutation is a change in the DNA inside a cell. DNA acts like an instruction manual that tells cells how to grow, divide, and function. When a mutation occurs, those instructions change, and the cell may begin to behave abnormally.
In primary myelofibrosis, these mutations cause blood-forming stem cells to produce abnormal cells, especially megakaryocytes. These abnormal megakaryocytes release substances that stimulate the formation of scar tissue in the bone marrow. Over time, this scarring interferes with normal blood cell production.
The most common mutations affect genes involved in a signaling pathway called JAK/STAT, which normally helps regulate blood cell growth. Mutations in this pathway keep it switched on, leading to uncontrolled cell production. These mutations are acquired, meaning they develop during a person’s lifetime and are not inherited or passed on to children.
In many patients, additional genetic changes are also present. These extra mutations can affect how aggressive the disease is and how likely it is to progress or transform into leukemia.
How is the diagnosis made?
The diagnosis is based on a combination of blood tests, bone marrow examination, and molecular genetic testing.
Blood tests
Blood tests often show anemia, abnormal platelet counts, and changes in white blood cells. In more advanced disease, immature blood cells may appear in the bloodstream, along with misshapen red blood cells called teardrop cells.
Microscopic features (bone marrow biopsy)
A bone marrow biopsy is essential for diagnosis and for determining the disease stage.
Prefibrotic primary myelofibrosis (pre-PMF)
In the prefibrotic stage, the bone marrow is usually hypercellular, meaning it contains too many blood-forming cells. The marrow shows increased production of white blood cells, especially granulocytes, while red blood cell production is relatively reduced.
The most important feature is the presence of abnormal megakaryocytes. These cells are increased in number and arranged in loose clusters. They vary widely in size and shape, with large, irregular nuclei that often appear dark and bulbous with a cloud-like pattern. Megakaryocytes are often found near blood vessels and bone surfaces, which is abnormal.
Scarring of the bone marrow is minimal or absent at this stage. There is no significant increase in immature blast cells, and there is no clear dysplasia of red or white blood cell precursors.
Fibrotic primary myelofibrosis
In fibrotic primary myelofibrosis, bone marrow scarring is moderate to severe. The normal marrow space becomes progressively replaced by fibrous tissue and, later, by fat.
Megakaryocytes are markedly abnormal and often found in tight clusters. They show severe maturation defects, with irregular, hyperchromatic nuclei and abnormal nuclear-to-cytoplasmic ratios. Some appear as “naked” nuclei without visible cytoplasm.
Normal red blood cell production is reduced, while white blood cell production may remain increased. Blood vessels in the marrow become prominent and dilated, and bone formation (osteosclerosis) may occur in advanced cases.
Immunohistochemistry can help highlight megakaryocytes and immature cells, and special stains are used to grade the degree of fibrosis.
Molecular and genetic testing
Genetic testing is routinely performed and looks for mutations in JAK2, CALR, or MPL. Together, these account for most cases.
Additional mutations in genes such as ASXL1, TET2, SRSF2, and TP53 are common and help refine prognosis. The presence of specific mutations is associated with a higher risk of progression or transformation to leukemia.
Testing also confirms that the BCR::ABL1 gene rearrangement (seen in chronic myeloid leukemia) is absent.
WHO grading system for myelofibrosis
Pathologists use a standardized system developed by the World Health Organization (WHO) to grade the amount of fibrosis (scarring) in the bone marrow. This grading system is important because it helps determine the stage of disease, monitor changes over time, and assess response to treatment.
The grading is based on the amount of scar tissue present, its distribution, and whether there are changes in bone structure.
MF-0 (no fibrosis)
MF-0 represents normal or near-normal bone marrow. Only very thin fibers are seen, similar to what is found in healthy marrow. There is no significant scarring, no abnormal collagen network, and the bone structure remains normal. This level may be seen in very early disease.
MF-1 (mild fibrosis)
MF-1 shows a loose network of fine fibers with multiple intersections, especially around blood vessels. Small areas of collagen may be present, but there is no widespread scarring. Early changes in bone formation may be seen near the edges of bone trabeculae. This grade is commonly seen in prefibrotic primary myelofibrosis.
MF-2 (moderate fibrosis)
MF-2 represents a clear progression of scarring. The fibrous network becomes dense and widespread, and thicker fibers consistent with collagen begin to form. Areas of bone thickening and new bone formation become more obvious. This grade indicates established fibrotic disease.
MF-3 (severe fibrosis)
MF-3 is the most advanced stage. The bone marrow is extensively replaced by dense scar tissue and collagen, often accompanied by marked new bone formation. Normal marrow spaces are largely lost. At this stage, normal blood cell production in the marrow is severely impaired.
When scarring is uneven, the final grade is determined by the highest grade present in at least 30% of the bone marrow. Special stains are used to assess fibrosis and collagen at higher grades accurately.
The WHO fibrosis grade correlates with important clinical features such as:
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Severity of anemia.
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Degree of spleen enlargement.
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Risk of disease progression.
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Prognostic scores such as DIPSS and MIPSS.
Extramedullary disease
In advanced disease, blood cell production shifts outside the bone marrow, most commonly to the spleen. The spleen may show diffuse or nodular infiltration by abnormal blood-forming cells. In rare cases, the disease can progress to a blast phase, which resembles acute leukemia and requires urgent correlation with bone marrow findings.
Accelerated phase and blast phase primary myelofibrosis
In some patients, primary myelofibrosis can evolve into more aggressive forms of the disease called accelerated phase or blast phase. These phases represent the progression of the original condition and require close medical attention.
Accelerated phase
Accelerated phase primary myelofibrosis is an intermediate stage between chronic disease and acute leukemia. It is defined by an increase in immature blood cells called blasts, typically making up 10 to 19% of cells in either the bone marrow or blood. Patients in the accelerated phase may experience worsening symptoms, such as increasing fatigue, infections, bleeding, or a rapidly enlarging spleen. Blood counts often become more unstable, with worsening anemia or low platelets. Although this stage is not leukemia, it signals a higher risk of progression and usually prompts a change in treatment strategy and closer monitoring.
Blast phase (leukemic transformation)
Blast phase primary myelofibrosis occurs when blasts make up 20% or more of cells in the blood or bone marrow. At this point, the disease behaves like an acute leukemia, most commonly acute myeloid leukemia. This transformation happens in a minority of patients over time and is more likely in advanced disease or in patients with certain high-risk genetic mutations. Symptoms may progress quickly and can include severe fatigue, frequent infections, bleeding, fevers, and weight loss. Blast phase myelofibrosis is a serious condition that requires urgent evaluation by a hematology team. Treatment often involves intensive chemotherapy, targeted therapies, or consideration of stem cell transplantation when appropriate.
Recognizing accelerated or blast phase disease is important because it significantly affects prognosis and treatment decisions. Regular monitoring with blood tests, bone marrow examinations when needed, and genetic testing helps detect disease progression early and guides timely treatment adjustments.
What is the difference between primary myelofibrosis and myelofibrosis associated with essential thrombocythemia or polycythemia vera?
Myelofibrosis can develop in different ways, and understanding the difference helps guide prognosis and treatment.
Primary myelofibrosis starts as myelofibrosis from the beginning. The bone marrow scarring develops early in the disease, either gradually (prefibrotic stage) or more extensively (fibrotic stage). The abnormal megakaryocytes and bone marrow fibrosis are part of the original disease process.
In contrast, myelofibrosis associated with essential thrombocythemia (ET) or polycythemia vera (PV) develops later. In these cases, the patient is first diagnosed with ET or PV, conditions where the bone marrow initially produces too many platelets or red blood cells. After many years, some patients with ET or PV develop progressive bone marrow scarring. This is called post-ET myelofibrosis or post-PV myelofibrosis.
Although the bone marrow scarring may look similar under the microscope, these conditions behave differently. Patients with post-ET or post-PV myelofibrosis often have less severe anemia and different risk patterns compared with primary myelofibrosis. For this reason, doctors use different prognostic scoring systems depending on how the myelofibrosis developed.
What is the prognosis for primary myelofibrosis?
Prognosis varies widely. Some patients live for decades with mild disease, while others progress rapidly.
Patients with pre-PMF generally have a better outlook than those with fibrotic PMF, but pre-PMF often progresses over time. Median survival is shorter in fibrotic PMF, and the risk of leukemia transformation is higher.
Doctors use prognostic scoring systems that combine clinical features, blood counts, bone marrow findings, and genetic results to estimate risk and guide treatment decisions. These scores are critical when considering stem cell transplantation, the only potentially curative treatment.
What happens after the diagnosis?
After diagnosis, further testing is done to determine disease risk and guide treatment. Management focuses on controlling symptoms, improving blood counts, reducing spleen size, and monitoring for progression.
Some patients are treated with medications that target the JAK/STAT pathway. Others may be monitored closely without immediate treatment. Patients with higher-risk disease may be referred for stem cell transplant evaluation.
Questions to ask your doctor
- Do I have prefibrotic or fibrotic primary myelofibrosis?
- What mutations were found in my testing, and what do they mean?
- What is my risk category based on prognostic scoring?
- Am I at risk for progression to leukemia?
- What treatment options are appropriate for me now?
- Should I be evaluated for stem cell transplantation?
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