Primary myelofibrosis (PMF) is a chronic blood cancer belonging to a group of diseases called myeloproliferative neoplasms (MPNs), defined by the overproduction of blood cells. Prefibrotic primary myelofibrosis (pre-PMF) is recognized by the World Health Organization (WHO) as a distinct, early phase of this disease. It is a stage where the disease process has begun but has not yet led to the significant scar tissue in the bone marrow that defines the more advanced, overt stage of PMF.
Understanding Prefibrotic Primary Myelofibrosis
Prefibrotic primary myelofibrosis originates from a genetic change in a hematopoietic stem cell, the cell that produces all blood cells in the bone marrow. This mutation causes the cell to reproduce uncontrollably, leading to a surplus of abnormal cells that crowd out healthy ones. This disrupts normal blood production. The defining characteristic of the prefibrotic stage is minimal to no scar tissue, known as reticulin fibrosis, within the bone marrow.
Pathologists grade this fibrosis on a scale from 0 to 3, with a pre-PMF diagnosis corresponding to a grade of 0 or 1. This lack of significant scarring distinguishes it from overt PMF, where more extensive fibrosis (grade 2 or 3) impairs bone marrow function. This distinction is important because their prognoses and management can differ.
The condition can mimic other MPNs like essential thrombocythemia (ET), which also involves overproducing platelets and can present with high platelet counts. This creates diagnostic challenges. However, a detailed examination of bone marrow morphology helps clinicians confirm that pre-PMF is a unique disease.
Recognizing the Symptoms
The symptoms of pre-PMF are highly variable, and many individuals are asymptomatic when diagnosed. The condition is often discovered incidentally during routine blood tests. When symptoms appear, they reflect the underlying disruption in blood cell production.
Constitutional symptoms, which affect the entire body, are common. These are driven by the release of inflammatory proteins called cytokines and include:
- A persistent sense of fatigue and weakness, often related to anemia
- Unexplained weight loss
- Drenching night sweats
- A persistent low-grade fever
An enlarged spleen (splenomegaly) can also cause symptoms. As bone marrow becomes less efficient, the spleen may compensate by producing blood cells, causing it to grow. This can lead to fullness or discomfort in the upper left abdomen, causing a person to feel full after eating only a small amount. Abnormal blood counts can also cause symptoms like shortness of breath from anemia or easy bruising from low platelet counts.
The Diagnostic Pathway
Confirming a pre-PMF diagnosis relies on World Health Organization (WHO) criteria, beginning with a complete blood count (CBC). A CBC may reveal abnormalities like anemia and variable white blood cell and platelet counts. Blood tests may also show an elevated level of lactate dehydrogenase (LDH), an enzyme indicating cell turnover.
A bone marrow biopsy and aspirate is the definitive diagnostic procedure. A pathologist examines a small sample of bone marrow tissue for an overabundance of cells, a proliferation of granulocytes, and abnormal megakaryocytes—the cells that produce platelets. In pre-PMF, these megakaryocytes often appear in clusters and have atypical shapes.
Genetic testing is the final component. Analysis looks for specific acquired gene mutations that drive the disease, most commonly in the JAK2, CALR, or MPL genes. Finding one of these mutations is a major criterion for diagnosis. Patients without these mutations are called “triple-negative,” requiring other markers for confirmation.
Treatment and Management Approaches
The management strategy for pre-PMF is personalized and may not involve immediate treatment. The first step is determining a patient’s risk of disease progression. Clinicians use prognostic scoring systems, like MIPSS70+, which incorporate clinical factors, plus genetic information, to categorize patients into risk groups.
For many asymptomatic, low-risk individuals, the recommended approach is active surveillance, or “watch and wait.” This involves regular monitoring with physical exams and blood tests to track the disease’s stability. This approach avoids medication side effects when there is no clear benefit from early intervention.
When treatment is needed, it is directed at managing symptoms or reducing health risks. Low-dose aspirin is often recommended for patients with a JAK2 mutation to lower the chance of blood clots. If anemia becomes significant, medications may be used to stimulate red blood cell production.
For patients with a higher symptom burden or in higher-risk categories, targeted therapies may be used. JAK inhibitors, such as ruxolitinib, can reduce spleen size and alleviate symptoms like fatigue and night sweats. Cytoreductive therapies like hydroxyurea may also be used to lower elevated blood cell counts.
Prognosis and Disease Progression
The long-term outlook for pre-PMF is more favorable than for overt PMF, though it is a progressive condition. A primary concern is the potential for the disease to advance to overt primary myelofibrosis, which further impairs blood production. This progression occurs in approximately 10% to 20% of patients over a 10-to-15-year period.
A less frequent but more serious risk is the transformation into acute myeloid leukemia (AML), a rapidly progressing blood cancer. The 10-year incidence of this transformation is estimated between 5% and 12%. This outcome is associated with a poorer prognosis and requires more aggressive treatment.
Overall survival is influenced by the patient’s risk score at diagnosis. The median survival for patients with pre-PMF is significantly longer than for those with overt PMF, with some studies reporting a median survival of over 17 years. This highlights the value of distinguishing between the two stages to predict the disease course and guide management.