Prefibrotic myelofibrosis is a rare blood cancer and an early stage of primary myelofibrosis. It is a type of myeloproliferative neoplasm, where the bone marrow overproduces certain blood cells. The term “prefibrotic” indicates this is the initial phase of the disease, before significant scar tissue forms in the bone marrow. Recognizing this condition can be complex, as its presentation often overlaps with other blood disorders.
Defining Prefibrotic Myelofibrosis
Prefibrotic myelofibrosis (pre-PMF) begins in the bone marrow, the spongy tissue inside bones where blood cells develop. In pre-PMF, the bone marrow becomes hypercellular, meaning it is packed with an abnormally high number of cells. This is driven by the excessive production of platelets and granulocytes, a type of white blood cell.
The cause of this uncontrolled cell growth lies in specific genetic mutations acquired during a person’s lifetime, meaning they are not inherited. The most common is a mutation in the Janus kinase 2 (JAK2) gene. The JAK2 protein is part of a signaling pathway that tells stem cells when to produce blood cells, and a mutation can cause this signal to be stuck in the “on” position.
Other genetic drivers include mutations in the calreticulin (CALR) and myeloproliferative leukemia (MPL) genes. These changes also disrupt the normal regulation of blood cell development, causing the bone marrow to produce cells in an uncontrolled manner.
Diagnostic Criteria and Distinctions
Diagnosing prefibrotic myelofibrosis requires a detailed evaluation centered on a bone marrow biopsy. Pathologists look for features outlined by the World Health Organization (WHO), including a proliferation of atypical megakaryocytes, the cells that produce platelets. A diagnostic marker is the amount of reticulin fibrosis (connective tissue); in pre-PMF, this scarring is graded as 0 or 1, indicating it is minimal or absent.
A correct diagnosis involves distinguishing pre-PMF from similar myeloproliferative neoplasms. It is commonly confused with essential thrombocythemia (ET), as both conditions can present with high platelet counts. The bone marrow biopsy is necessary to differentiate them, as pre-PMF shows a distinct proliferation and atypical appearance of megakaryocytes not seen in ET.
The other distinction is with overt primary myelofibrosis (overt PMF), the more advanced stage where the bone marrow has developed significant scar tissue (graded as 2 or 3). This scarring disrupts the bone marrow’s ability to produce blood cells effectively. In contrast, pre-PMF is defined by the absence of this significant fibrosis.
Signs and Symptoms
Many individuals with prefibrotic myelofibrosis are asymptomatic for extended periods and the condition is discovered incidentally through routine blood tests. When symptoms do appear, they can be varied and develop slowly.
An enlarged spleen (splenomegaly) can occur as it takes over blood cell production from the struggling bone marrow. This can cause a feeling of fullness or pain in the upper left abdomen. Other symptoms may include:
- Profound fatigue not relieved by rest
- Unexplained weight loss
- Low-grade fevers
- Drenching night sweats
- Bone pain
- Itchy skin (pruritus)
Disease Progression and Risk Assessment
Prefibrotic myelofibrosis is a chronic disease, and its course can differ significantly from person to person. A primary concern is the potential for the disease to advance to overt myelofibrosis, which involves significant bone marrow scarring. This progression is not inevitable, with studies suggesting the 10-year incidence ranges from 10% to 31.5%. The median survival for patients with pre-PMF is notably longer than for those with overt PMF, estimated at around 17.6 years.
To predict the disease course, physicians use risk stratification models to classify patients into lower or higher-risk categories. This assessment helps guide decisions about monitoring frequency and treatment timing. Factors considered include:
- The patient’s age
- White blood cell count
- Hemoglobin levels
- The presence of constitutional symptoms like fever or weight loss
- The specific type of genetic mutation
Management and Treatment Approaches
Management of prefibrotic myelofibrosis is tailored to the individual, based on their risk category and symptoms. For many low-risk, asymptomatic patients, the recommended approach is active surveillance, sometimes called “watch and wait.” This involves regular check-ups and blood tests to monitor the condition without initiating active treatment.
For patients who require intervention, treatment focuses on managing symptoms and reducing risks like blood clots (thrombosis) from high platelet counts. To mitigate this, low-dose aspirin is often prescribed to help prevent platelets from sticking together.
In cases where blood cell counts are extremely high or the spleen is significantly enlarged, cytoreductive therapy may be used. Medications such as hydroxyurea can help lower elevated blood cell counts and reduce spleen size. For patients with a substantial symptom burden, targeted therapies known as JAK inhibitors, like ruxolitinib, may be considered. These drugs work by blocking the activity of the mutated JAK protein, addressing an underlying driver of the disease.