Myelofibrosis: Symptoms, Causes, Risk Factors, Diagnosis, and Treatments

Myelofibrosis (MF) is a rare, life-altering disorder of the bone marrow that disrupts the normal production of blood cells. Classified under myeloproliferative neoplasms (MPNs), it results in extensive scarring of the bone marrow, anemia, weakness, splenomegaly (enlarged spleen), and a higher risk of progression to acute myeloid leukemia (AML). Although considered a rare disease, this disease demands awareness, early detection, and innovative treatment approaches for better patient outcomes.

In this comprehensive guide, we will cover everything you need to know about myelofibrosis—from symptoms and causes to diagnosis, risk factors, treatment options, and the latest research—all carefully crafted for medical readers, patients, and caregivers alike.

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What is Myelofibrosis?

Myelofibrosis is a type of bone marrow cancer that disrupts the body’s ability to produce normal blood cells. As the disease progresses, it causes bone marrow scarring (fibrosis), impairing its function and leading to blood cell abnormalities. Due to the fibrosis, the body begins producing blood cells outside of the bone marrow, such as in the spleen and liver, leading to organ enlargement.

There are two main forms of the disease:

• Primary myelofibrosis (PMF): Occurs without any preceding blood disorders.
• Secondary myelofibrosis: Evolves from other MPNs like polycythemia vera (PV) or essential thrombocythemia (ET).

According to estimates, 1.5 out of every 100,000 people are diagnosed with this disease annually, with a higher prevalence among individuals over the age of 50.

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Symptoms of Myelofibrosis

Symptoms in myelofibrosis often develop gradually and may initially go unnoticed. Over time, however, they become increasingly debilitating.

1. Fatigue

Chronic, overwhelming fatigue is one of the most common complaints, affecting about 80–90% of patients.

2. Anemia

Severe anemia leads to weakness, dizziness, shortness of breath, and pallor.

3. Splenomegaly

The spleen enlarges significantly in more than 80% of cases, causing:

• Left-sided abdominal pain
• Early satiety (feeling full quickly)
• Weight loss due to pressure on the stomach

4. Bone and Joint Pain

Fibrotic marrow causes deep-seated bone pain, particularly in long bones and ribs.

5. Night Sweats and Fever

Unexplained fevers and drenching night sweats are signs of systemic inflammation.

6. Easy Bruising and Bleeding

Thrombocytopenia (low platelet count) can lead to:

• Prolonged bleeding
• Frequent bruises
• Nosebleeds or gum bleeding

7. Itching

Pruritus affects many patients and can be worsened by warm showers.

8. Infections

Decreased immune surveillance results in frequent or severe infections.

9. Gout

High turnover of blood cells elevates uric acid levels, leading to gout attacks.

Some patients may also develop portal hypertension due to liver involvement or rarely experience skin lesions called leukemia cutis if the disease transforms into acute leukemia.

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Causes of Myelofibrosis

Although the direct cause remains elusive, most cases are linked to acquired genetic mutations.

Genetic Mutations

1. JAK2 V617F Mutation:
   • Found in approximately 50–60% of myelofibrosis patients.
   • Leads to uncontrolled cell signaling and proliferation.
2. CALR Mutation:
   • Present in about 20–25% of patients.
   • Typically associated with a better overall prognosis.
3. MPL Mutation:
   • Detected in 5–10% of cases.
   • Affects the thrombopoietin receptor involved in platelet production.
4. Triple-Negative Myelofibrosis:
   • Patients with no detectable JAK2, CALR, or MPL mutations.
   • Generally associated with worse outcomes.
5. Other Mutations:
   • TET2, ASXL1, SRSF2, EZH2 mutations influence prognosis and disease aggressiveness.

Interestingly, this is not inherited. The mutations occur after birth and are acquired rather than passed through families.

Environmental Factors

• Radiation exposure
• Toxin exposure (e.g., benzene)
• Prior chemotherapy for other cancers may rarely trigger secondary myelofibrosis.

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Risk Factors

Several factors increase the likelihood of developing myelofibrosis:

1. Age

The median age at diagnosis is 65–70 years. However, younger adults can also be affected.

2. Gender

Men and women are almost equally affected, although some data suggest a slight male predominance.

3. Prior Blood Disorders

Having a history of essential thrombocythemia or polycythemia vera increases the risk of evolving to myelofibrosis.

4. Genetic Mutations

The presence of JAK2, CALR, or MPL mutations elevates disease risk and influences prognosis.

5. Environmental Exposures

Prolonged exposure to industrial chemicals or radiation may contribute, although such links are rare.

6. Autoimmune Conditions

Conditions like systemic lupus erythematosus (SLE) have occasionally been linked to secondary myelofibrosis.

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Diagnosis of Myelofibrosis

Diagnosing this disease involves integrating clinical, laboratory, pathological, and genetic information.

1. Physical Examination

• Palpable spleen below the ribcage.
• Signs of anemia like pale skin or fast heartbeat.

2. Blood Tests

• CBC: Shows anemia, leukocytosis, or thrombocytopenia.
• Peripheral Blood Smear: Reveals teardrop-shaped red blood cells (dacrocytes) and nucleated red blood cells.

3. Bone Marrow Biopsy

A definitive diagnosis requires:

• Hypercellular marrow with fibrosis.
• Atypical megakaryocytes (large, irregular bone marrow cells).

4. Genetic Testing

• Identifying JAK2, CALR, MPL mutations.
• Next-generation sequencing panels are increasingly used for a broader genetic profile.

5. Imaging

• Ultrasound or MRI to evaluate spleen and liver enlargement.
• PET-CT scans in cases suspicious for leukemic transformation.

6. Risk Stratification

Scoring systems like DIPSS-Plus help assess prognosis based on variables such as age, hemoglobin level, symptoms, and mutations.

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Treatments for Myelofibrosis

Treatment is tailored based on symptom severity, disease risk category, age, and overall health.

1. Observation

Patients with low-risk disease and minimal symptoms may only require regular monitoring without immediate intervention.

2. Drug Therapy

a) JAK Inhibitors

• Ruxolitinib (Jakafi): Reduces spleen size and improves symptoms.
• Fedratinib (Inrebic): An alternative for patients intolerant to Ruxolitinib.
• Pacritinib: Effective for patients with low platelet counts.

b) Anemia Management

• Erythropoiesis-stimulating agents (ESAs).
• Androgens such as danazol.
• Luspatercept, a novel agent for anemia treatment in MPNs.

c) Immunomodulators

• Thalidomide, lenalidomide, and pomalidomide are occasionally used for anemia and thrombocytopenia.

d) Corticosteroids

Short courses of prednisone can help manage severe anemia or constitutional symptoms.

3. Allogeneic Stem Cell Transplantation

The only curative treatment but associated with high morbidity and mortality. Best suited for:

• Patients under 70 years old.
• High-risk disease.
• Good performance status.

4. Supportive Therapies

• Blood transfusions for anemia.
• Iron chelation therapy in case of iron overload from multiple transfusions.
• Antibiotics and vaccinations to prevent infections.

5. Splenectomy

Surgical removal of the spleen is considered when:

• Severe splenomegaly causes symptoms unmanageable by drugs.
• Risk of complications like splenic infarcts or hypersplenism.

6. Radiation Therapy

Low-dose radiation can be used for spleen reduction or bone pain.

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Living with Myelofibrosis

Living with myelofibrosis requires a holistic approach involving:

Diet

• Iron-rich foods (unless iron overload is present).
• Hydration to manage uric acid levels.

Exercise

• Gentle aerobic exercises improve stamina and prevent muscle wasting.

Mental Health

• Psychological counseling and support groups reduce anxiety and depression.
• Cognitive behavioral therapy (CBT) may help manage the psychological impact.

Routine Monitoring

• Frequent blood counts.
• Imaging studies to monitor spleen size.
• Bone marrow biopsies when clinically indicated.

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Prognosis

Prognosis varies widely:

• Low-risk patients may live for decades.
• High-risk patients may survive for a few years without transplantation.

Median survival ranges from 2 years (high-risk) to more than 15 years (low-risk) depending on multiple factors, including genetic mutations, blood counts, and symptom burden.

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Latest Research and Future Directions

Research into this disease is vibrant and promising. Ongoing studies include:

• Bomedemstat (LSD1 Inhibitor): Shows promise in early trials.
• Navitoclax (BCL-2 Inhibitor): Being studied in combination with ruxolitinib.
• BET Inhibitors: Targeting gene expression abnormalities.
• Gene Editing: CRISPR-based therapies are in experimental stages.
• CAR-T Cell Therapy: Customized immune treatments targeting specific antigens in the bone marrow.

As of 2025, several phase III clinical trials are underway, aiming to redefine treatment strategies for myelofibrosis patients globally.

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Conclusion

Myelofibrosis is a complex and evolving disease that challenges both patients and clinicians. Thanks to advances in genetics, targeted therapies, and supportive care, outcomes are improving year by year. Early diagnosis, personalized treatment, and participation in clinical trials offer patients the best chance for longer survival and better quality of life.

If you suspect symptoms or have a family history of blood cancers, don’t hesitate to seek evaluation by a hematologist. Staying informed is your best weapon against this disease.

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