Myelofibrosis: Symptoms, Types, Causes and Treatment

Myelofibrosis is a rare and complex blood cancer that often goes unrecognized in its early stages. It belongs to a group of diseases known as myeloproliferative neoplasms (MPNs) and is marked by scarring (fibrosis) of the bone marrow, leading to a range of symptoms, complications, and variable outcomes. This article offers a comprehensive, evidence-based overview of myelofibrosis: exploring its symptoms, the different types, underlying causes, and the latest approaches to treatment. Whether you are a patient, caregiver, or simply interested in hematology, this guide will help clarify the multifaceted nature of myelofibrosis.

Symptoms of Myelofibrosis

Myelofibrosis can manifest with a broad spectrum of symptoms, from subtle early signs to severe complications as the disease progresses. Understanding these symptoms is vital for early detection and effective management.

Symptom	Description	Prevalence/Severity	Source(s)
Fatigue	Persistent tiredness, exhaustion	Very common, often severe	1 5 4
Splenomegaly	Enlarged spleen, abdominal fullness/pain	Common, progressive	4 6 8
Anemia	Low red blood cell count, pallor, weakness	Frequent, worsens over time	5 8 4
Bruising/Bleeding	Easy bruising, prolonged bleeding	Due to low platelets	5 9 4
Infections	Increased susceptibility	Due to low white cells	5 9
Night sweats	Excessive sweating during sleep	Constitutional symptom	4 1
Weight loss	Unintentional, often significant	Advanced disease	4 2 3

Table 1: Key Symptoms

Fatigue and Quality of Life

Fatigue is reported as the most frequent and severe symptom among patients with myelofibrosis, significantly impacting their daily function and quality of life—even in those with lower disease risk or symptom burden. This tiredness is often profound, not relieved by rest, and may be accompanied by weakness and a general sense of malaise. Fatigue, along with other constitutional symptoms (like night sweats and weight loss), can affect work ability and overall activity levels, underlining the importance of symptom management for maintaining patient well-being 1 4.

Splenomegaly and Abdominal Discomfort

As bone marrow function deteriorates, the body attempts to produce blood cells in other organs, most notably the spleen and liver—a process called extramedullary hematopoiesis. This leads to splenomegaly (enlargement of the spleen), which may cause a sensation of abdominal fullness, early satiety, pain, or even complications like portal hypertension and variceal bleeding 4 6 8. Hepatomegaly (enlarged liver) can also occur.

Blood Cell Abnormalities: Anemia, Bleeding, and Infections

The scarring of the bone marrow impairs its ability to produce blood cells, leading to:

• Anemia: Responsible for pallor, shortness of breath, and worsening fatigue. Progressive anemia is a hallmark of advancing disease 5 8.
• Thrombocytopenia (low platelets): Increases the risk of easy bruising and bleeding 5 9.
• Leukopenia (low white cells): Heightens susceptibility to infections, sometimes severe or recurrent 5 9.

Additional Constitutional and Systemic Symptoms

Other general symptoms include night sweats, fever, bone pain, and weight loss. These are driven by the overproduction of inflammatory cytokines and are often grouped as "constitutional symptoms" 4 2 3. Pruritus (itching) and cachexia (wasting) may also be present.

Complications

Advanced myelofibrosis can lead to serious complications, such as transformation to acute leukemia, severe infections, organ failure, and thrombohemorrhagic events (clotting or bleeding) 4.

Types of Myelofibrosis

Myelofibrosis is not a single uniform disease but exists in several distinct forms, each with unique features and prognostic implications.

Type	Key Characteristics	Clinical Course/Prognosis	Source(s)
Primary MF (PMF)	Arises de novo, classic form	Heterogeneous, often severe	2 3 8
Secondary MF (post-PV/ET MF)	Evolves from PV or ET	Often less aggressive, better prognosis	7 8
Myeloproliferative phenotype	High blood counts, large spleen	Better survival, milder anemia	6 8
Myelodepletive/cytopenic phenotype	Low blood counts, severe cytopenias	Worse prognosis, higher complications	6 8 9

Table 2: Types and Phenotypes

Primary vs. Secondary Myelofibrosis

Primary Myelofibrosis (PMF):

• Develops spontaneously, without a preceding blood disorder.
• Characterized by clonal proliferation of abnormal stem cells, leading to bone marrow fibrosis, abnormal blood counts, and systemic symptoms 2 3 8.

Secondary Myelofibrosis:

• Occurs as a progression from other myeloproliferative neoplasms—namely, polycythemia vera (PV) or essential thrombocythemia (ET) 7 8.
• The transformation is often signaled by increasing symptom burden, worsening anemia, or new-onset splenomegaly.

Clinical Phenotypes: Myeloproliferative vs. Myelodepletive

Recent research has revealed two main phenotypic extremes that shape the course and treatment of myelofibrosis 6 8 9:

• Myeloproliferative phenotype:

  • Patients have normal or even elevated blood cell counts.
  • Marked by significant splenomegaly and constitutional symptoms.
  • Typically associated with secondary MF and a higher JAK2 mutation burden.
  • Prognosis is generally better, with longer survival.

• Myelodepletive (cytopenic) phenotype:

  • Characterized by one or more low blood cell counts (anemia, thrombocytopenia, leukopenia).
  • Splenomegaly is often less pronounced.
  • More common in primary MF, associated with more complex genetic mutations.
  • Prognosis is worse, with higher risk of complications like bleeding, infections, and transfusion dependence.

Heterogeneity and Risk Stratification

The disease exhibits considerable clinical heterogeneity, with some patients remaining asymptomatic for years (about 30% at diagnosis), while others progress rapidly 12. Prognostic scoring systems now incorporate genetic and molecular data to better guide treatment decisions 13.

Causes of Myelofibrosis

Myelofibrosis is fundamentally a genetic disease, but its development is influenced by a complex interplay of molecular mutations and inflammatory processes.

Cause	Mechanism/Role	Key Features	Source(s)
JAK2, CALR, MPL mutations	Drive abnormal cell signaling and proliferation	Present in ~90% cases	2 12 13 14
Inflammatory cytokines	Promote fibrosis, constitutional symptoms	TNF, TGF-β, IL-8, etc.	10 11 13
Epigenetic/splicing mutations	Worsen prognosis, drive progression	ASXL1, SRSF2, etc.	7 8 13
Chronic inflammation	Sustains disease and fibrosis	NFκB pathway, others	10 11 13

Table 3: Underlying Causes

Genetic Mutations: The Core Drivers

• JAK2 V617F Mutation: Present in about 60% of myelofibrosis cases, this mutation leads to continuous activation of the JAK-STAT pathway, causing uncontrolled proliferation of blood-forming cells 2 12 13 14.
• CALR and MPL Mutations: Found in many of the remaining cases, these mutations also activate JAK-STAT signaling via different mechanisms 2 12 13 14.
• Other Genetic Lesions: Mutations in genes regulating epigenetics (e.g., ASXL1, DNMT3A, EZH2), splicing (e.g., SRSF2), and metabolism (e.g., IDH1/2) often co-exist, especially in the myelodepletive phenotype, and are associated with worse prognosis and disease progression 7 8 13.

Role of Inflammatory Cytokines and the Bone Marrow Microenvironment

• Overproduction of proinflammatory cytokines—such as TNF, TGF-β, IL-8—drives many of the hallmark features of myelofibrosis, including bone marrow fibrosis, constitutional symptoms, and cachexia 10 11 13.
• Disrupted interactions between abnormal megakaryocytes (a type of bone marrow cell), stromal cells, and other components of the bone marrow niche further fuel fibrosis and disease progression 13.

Chronic Inflammation and Disease Progression

Chronic inflammation, partly due to persistent overproduction of cytokines and immune dysregulation, contributes to both the development and progression of myelofibrosis. This inflammatory state not only sustains the malignant clone but also remodels the bone marrow environment to favor disease persistence and resistance to therapy 11.

Disease Evolution and Transformation

• Myelofibrosis can evolve from earlier, less severe forms of MPNs (ET, PV), often triggered by additional genetic or inflammatory hits 7 11.
• Subclinical progression can be detected by increasing fibrosis, changes in blood counts, or new genetic abnormalities before symptoms worsen 7.

Treatment of Myelofibrosis

While myelofibrosis remains difficult to cure, significant advances have been made in symptom management and disease control. Treatment is increasingly tailored to disease risk, symptoms, and phenotype.

Therapy/Approach	Indication/Role	Key Points/Limitations	Source(s)
Ruxolitinib (JAK1/2 inhibitor)	First-line for splenomegaly and symptoms	Improves QoL, not curative, can worsen anemia	4 12 17
Fedratinib (JAK2 inhibitor)	Alternative to ruxolitinib	Effective post-ruxolitinib, GI side effects	18 19
Pacritinib, Momelotinib	For cytopenic/myelodepletive phenotype	Useful for severe anemia/thrombocytopenia	8 15 16 19
Supportive care (transfusions, ESAs)	Manage anemia, cytopenias	Non-curative, symptom relief only	17 6 9
Allogeneic stem cell transplant	Only curative therapy	High risk, for selected patients	4 12 17
Experimental/combination therapies	For refractory or advanced cases	Clinical trials ongoing	14 13 17

Table 4: Main Treatment Options

JAK Inhibitors: The Modern Backbone

• Ruxolitinib is the first and most widely used JAK1/2 inhibitor; it reduces spleen size, alleviates symptoms, and improves quality of life, but does not cure the disease or reverse fibrosis. It can worsen anemia and thrombocytopenia, making it less suitable for patients with severe cytopenias 4 12 17.
• Fedratinib is a newer JAK2 inhibitor, effective even in patients who have failed ruxolitinib. Its unique activity profile and oral dosing make it a valuable option, though gastrointestinal side effects and rare risk of Wernicke’s encephalopathy require monitoring 18 19.
• Pacritinib and Momelotinib are emerging as essential options for patients with the myelodepletive/cytopenic phenotype. They can be used in those with severe anemia or low platelets, where other JAK inhibitors are contraindicated or poorly tolerated 8 15 16 19.

Supportive and Symptom-Targeted Therapies

• Blood transfusions and erythropoiesis-stimulating agents (ESAs): Used to manage anemia and maintain quality of life, though they do not treat the underlying disease 17 6 9.
• Cytoreductive therapies (e.g., hydroxyurea): Occasionally used for symptom control, particularly in proliferative cases 17.
• Splenectomy or radiotherapy: Reserved for refractory cases with massive splenomegaly not controlled by medications 17.

Allogeneic Stem Cell Transplant: The Only Curative Option

• Transplantation offers a chance for cure but is limited to younger, fitter patients with high-risk disease due to its significant risks of morbidity and mortality 4 12 17.
• Careful selection and pre-transplant management are critical.

Emerging and Experimental Treatments

• Newer JAK inhibitors, combination therapies (such as JAK inhibitors with BRD4 inhibitors or interferons), and drugs targeting the inflammatory milieu or specific genetic mutations are under investigation 14 13 17.
• Clinical trials are crucial for advancing care and offering hope to patients with refractory or advanced myelofibrosis.

Personalized and Phenotype-Driven Approaches

• Treatment selection is increasingly based on the myeloproliferative vs. myelodepletive phenotype, genetic risk, and patient preferences 8 9.
• Improved patient-physician communication, standardized symptom monitoring, and shared decision-making are key to optimizing outcomes 1.

Conclusion

Myelofibrosis is a heterogeneous and challenging disease, but advances in our understanding of its biology and treatment continue to improve patient outcomes. Early recognition of symptoms, precise classification, and tailored therapy are essential for optimal care.

Key Takeaways:

• Myelofibrosis presents with a wide range of symptoms, with fatigue, splenomegaly, anemia, and constitutional symptoms being most common.
• The disease exists in several forms, notably primary and secondary myelofibrosis, and can manifest as myeloproliferative or myelodepletive phenotypes.
• It is driven by mutations in JAK2, CALR, or MPL, with inflammation and additional genetic changes contributing to disease progression and heterogeneity.
• Treatment is highly individualized, with JAK inhibitors (ruxolitinib, fedratinib, pacritinib, momelotinib) as mainstays for symptom control and splenomegaly, and stem cell transplantation as the only curative option.
• Ongoing research and a personalized, patient-centered approach are paving the way for better outcomes and improved quality of life for those living with myelofibrosis.