Myelofibrosis (MF) is a rare form of bone marrow cancer where normal blood-forming tissue is replaced by scar tissue (fibrosis). This scarring disrupts the bone marrow’s ability to produce healthy blood cells, leading to various complications. MF is classified as a myeloproliferative neoplasm, which involves the overproduction of abnormal blood cells. It can arise on its own (primary myelofibrosis) or develop from other blood disorders like polycythemia vera or essential thrombocythemia.
Risk stratification is a structured process used to determine the severity and expected course of MF for each patient. Since the disease is highly variable, ranging from slow progression to rapid, aggressive illness, this assessment helps doctors predict an individual’s trajectory.
Understanding the Purpose of Risk Assessment
Risk assessment predicts two main outcomes: the patient’s overall life expectancy and the likelihood of transformation into acute myeloid leukemia. Because prognosis varies widely, a single treatment approach is not appropriate for all patients.
The stratification process guides the choice between different management strategies, from simple observation to potentially curative procedures. By objectively measuring risk, doctors can have informed discussions with patients about the likely future course of their condition. The resulting risk score determines whether a patient requires supportive care, symptom-focused medication, or intensive intervention.
Clinical and Molecular Factors Used in Assessment
Prognostic scoring systems rely on specific data points from the patient’s history, physical exam, and laboratory tests. A significant clinical risk factor is age; being over 65 years old is associated with a worse prognosis. Other clinical markers include constitutional symptoms, such as unexplained fever, night sweats, or significant unintended weight loss.
Laboratory Markers
Laboratory markers used in assessment include:
- Severe anemia (hemoglobin below 10 g/dL).
- A high white blood cell count (above 25,000 per microliter).
- The presence of circulating blast cells (immature blood cells) in the peripheral blood.
- A low platelet count or the need for red blood cell transfusions.
Molecular Factors
Genetic data is crucial for evaluating the disease at a molecular level. Most MF cases involve a mutation in one of three driver genes: JAK2, CALR, or MPL. The presence of specific high-risk unfavorable molecular mutations, such as ASXL1, SRSF2, or EZH2, independently predicts shorter survival. Genetic analysis also includes karyotyping, where certain chromosomal abnormalities are linked to a poorer outcome.
Standardized Prognostic Scoring Systems
Early models, like the International Prognostic Scoring System (IPSS), used clinical and laboratory data at the time of diagnosis. The IPSS assigns points based on factors such as advanced age, anemia, high white blood cell count, constitutional symptoms, and circulating blast cells. The Dynamic International Prognostic Scoring System (DIPSS) and DIPSS-Plus allowed risk calculation at any time during the disease course. DIPSS-Plus incorporated additional factors, including unfavorable karyotype, low platelet count, and transfusion dependence.
These systems categorize patients into four distinct risk groups: Low, Intermediate-1, Intermediate-2, and High. These groups broadly predict survival time and the likelihood of transformation to acute leukemia. The limitations of these older models became apparent as molecular testing advanced, showing that genetics play a significant role independent of clinical presentation.
The Mutation-Enhanced International Prognostic Scoring System (MIPSS70) integrated molecular information directly into the risk calculation. The current variant, MIPSS70-Plus version 2.0 (MIPSSv2), combines clinical risk factors with unfavorable genetic mutations like ASXL1 and the absence of the favorable CALR Type 1 mutation. MIPSSv2 provides a more precise prediction, classifying risk into five categories, including a “Very High” risk group. The Genetically Inspired Prognostic Scoring System (GIPSS) is another contemporary model that relies exclusively on genetic mutations and karyotype abnormalities.
Linking Risk Categories to Treatment Decisions
The final risk category determines the recommended treatment pathway. Patients classified as Low or Intermediate-1 risk who are not experiencing significant symptoms are often managed with a conservative “watch and wait” approach. Treatment in this group is supportive, focusing on managing specific symptoms like anemia or fatigue.
More aggressive therapies are considered for patients in the Intermediate-2 or High-risk categories due to the increased risk of progression. A primary drug treatment involves Janus kinase (JAK) inhibitors, such as ruxolitinib, which control constitutional symptoms and reduce an enlarged spleen. These medications are palliative; they manage symptoms and improve quality of life but do not cure the disease.
The only potentially curative treatment is an Allogeneic Hematopoietic Stem Cell Transplant (ASCT), which replaces diseased bone marrow with healthy donor cells. Because ASCT carries substantial risks, it is reserved for patients in the High or Very High-risk categories who are healthy enough to withstand the intensity of the treatment. The risk score is the determining factor in the timing and necessity of a transplant referral.