Prefibrotic Myelofibrosis (Pre-MF) is an early-stage Myeloproliferative Neoplasm (MPN), a disorder originating in the bone marrow characterized by the overproduction of abnormal blood cells. Pre-MF is a distinct entity within the MPN spectrum, lying between Essential Thrombocythemia and Overt Myelofibrosis. Recognizing Pre-MF is important because it carries a specific prognosis and requires a different diagnostic and management approach than its more advanced counterpart.
Defining Prefibrotic Myelofibrosis
Pre-MF is defined by a specific pattern of cell growth in the bone marrow that precedes significant scar tissue development. The pathological characteristic is the hyperproliferation of blood-forming cells, especially megakaryocytes, which produce platelets. These megakaryocytes display abnormal (atypical) morphology, often appearing clustered with irregular nuclei.
The World Health Organization (WHO) recognizes Pre-MF as a separate disease entity. Unlike Overt Myelofibrosis, Pre-MF is characterized by the absence of significant reticulin or collagen fibrosis (less than grade 2). This lack of extensive scarring is the source of the term “prefibrotic.”
Pre-MF is differentiated from Essential Thrombocythemia (ET) by these specific bone marrow features. While both conditions may have elevated platelet counts, the megakaryocyte changes in Pre-MF are more pronounced and distinctively abnormal, guiding the correct diagnosis.
How Prefibrotic Myelofibrosis Is Diagnosed
Diagnosing Prefibrotic Myelofibrosis requires a comprehensive approach integrating clinical findings, blood counts, molecular testing, and a bone marrow biopsy, following specific WHO criteria. Diagnosis starts with a complete blood count, which may show variable results, often including an elevated platelet count (thrombocytosis) and a high white blood cell count (leukocytosis).
A bone marrow biopsy is the most informative step, allowing microscopic examination of tissue architecture. Pathologists look for megakaryocytic proliferation and atypia without significant fibrosis (reticulin fibrosis grade 0 or 1). The megakaryocytes are often large and immature, forming clusters within a hypercellular marrow.
Molecular testing for specific driver mutations is a major diagnostic criterion. These mutations are typically found in the JAK2, CALR, or MPL genes, confirming the clonal nature of the disorder. If these common mutations are absent, another clonal marker is required to establish the diagnosis.
In addition to these major criteria (histology, mutation status, and exclusion of other MPNs), at least one minor criterion must be present:
- Anemia not related to another condition.
- White blood cell count above 11,000 cells per cubic millimeter.
- Palpable enlargement of the spleen (splenomegaly).
- Elevated level of lactate dehydrogenase (LDH) in the blood.
Determining Disease Progression and Risk
Determining the potential for disease progression is a central component of patient care after diagnosis. Risk assessment focuses on the likelihood of advancing to Overt Myelofibrosis (significant scarring) or transforming into Acute Myeloid Leukemia (AML). This stratification informs the management strategy.
Clinicians use prognostic scoring systems, such as the Mutation-Enhanced International Prognostic Scoring System (MIPSS70) or the Dynamic International Prognostic Scoring System Plus (DIPSS-plus), to categorize patients. These systems assign weighted points to clinical and molecular factors to predict overall survival and transformation risk. High-risk features include advanced age, specific low or high blood cell counts, and constitutional symptoms.
Molecular profiling identifies high-risk non-driver gene mutations, which significantly influence prognosis. Mutations in genes like ASXL1, EZH2, SRSF2, and IDH1/2 are known as high-molecular-risk (HMR) mutations. The presence of HMR mutations is associated with shorter survival and a higher chance of progression to AML. Incorporating these genetic details allows for a more personalized and precise risk categorization for each patient.
Treatment and Long-Term Monitoring
Management of Pre-MF is guided by risk stratification. For low-risk patients, the primary approach is “active surveillance,” involving regular monitoring of blood counts and symptoms without immediate drug intervention.
Symptomatic management is introduced to address specific patient issues. For instance, low-dose aspirin may be used to reduce the risk of blood clots in patients with thrombocytosis. For those with high white blood cell or platelet counts, cytoreductive therapies, such as hydroxyurea, may be prescribed.
Patients with significant constitutional symptoms or bothersome splenomegaly may benefit from targeted therapies, such as Janus Kinase (JAK) inhibitors like Ruxolitinib.
For the small subset of high-risk patients, or those whose disease has progressed, the only potentially curative treatment is allogeneic stem cell transplantation. This procedure carries substantial risks and is generally reserved for younger, fitter patients.
Long-term monitoring involves regular blood work and periodic physician visits to track cell counts and symptom burden. Follow-up bone marrow assessments may also be performed to monitor for increasing fibrosis or transformation to a more aggressive phase.