Background

• Myelofibrosis is a rare and chronic bone marrow disorder characterized by the abnormal production and accumulation of fibrous tissue within the bone marrow. Myeloproliferative neoplasms (MPNs) are a group of diseases that include thrombocythemia and polycythemia vera. 
• In myelofibrosis, there is an excessive proliferation of abnormal bone marrow cells, particularly megakaryocytes (large cells that produce platelets) and hematopoietic stem cells (cells that give rise to various blood cell types). This abnormal cell growth disrupts the typical architecture of the bone marrow, leading to the replacement of healthy cells with fibrous scar tissue. As a result, bone marrow loses its ability to produce adequate blood cells, leading to various complications. 
• The exact cause of myelofibrosis is not fully understood. However, it has been linked to acquired mutations in specific genes, including Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia (MPL). These genes cause abnormal activation of signaling pathways that help cells grow and divide. This causes the body to make too many blood cells, which leads to myelofibrosis. 
• Myelofibrosis can occur either as a primary condition (primary myelofibrosis) or as a secondary condition that develops as a progression from other MPNs or bone marrow disorders. The disease primarily affects older adults, with the average age of diagnosis being around 60 to 65 years. 

Epidemiology

• Myelofibrosis is a relatively rare disorder, accounting for approximately 1 to 2 cases per 100,000 individuals in the general population. It predominantly affects adults, with the average age at diagnosis being around 60 to 65 years. Myelofibrosis incidence increases with age and is marginally more prevalent in men than women. 
• Myelofibrosis can occur as a primary condition, known as primary myelofibrosis (PMF), or as a secondary condition that develops as a progression from other myeloproliferative neoplasms (MPNs) or bone marrow disorders. PMF represents most myelofibrosis cases, accounting for about 70% to 80% of cases, while secondary myelofibrosis accounts for the remaining cases. 
• There are variations in the incidence and prevalence of myelofibrosis across different populations. For example, studies have shown that myelofibrosis is more common among Ashkenazi Jewish individuals than other populations. Additionally, the incidence of myelofibrosis may vary based on geographic location and ethnic background. 
• Several risk factors associated with myelofibrosis have been identified. The most significant risk factor is the presence of specific acquired genetic mutations, including mutations in genes such as Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia (MPL). These mutations are found in most myelofibrosis cases, with the JAK2 mutation being the most common. 

Anatomy

Pathophysiology

Myelofibrosis is a complex disorder characterized by abnormal bone marrow cell proliferation, fibrosis (formation of excessive scar tissue), and disruption of average blood cell production. The exact pathophysiology of myelofibrosis is not fully understood, but it involves several vital mechanisms. 

• Genetic Mutations: Myelofibrosis is associated with acquired mutations in specific genes, including Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia (MPL). These mutations activate signaling pathways involved in cell growth and proliferation, leading to the abnormal production of blood cells. 
• Dysregulated Signaling: The JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway plays a crucial role in regulating cell growth and differentiation. In myelofibrosis, abnormal activation of this pathway occurs due to genetic mutations, particularly the JAK2 mutation. Dysregulated JAK-STAT signaling leads to the overproduction of blood cells and contributes to the pathogenesis of myelofibrosis. 
• Abnormal Megakaryocytes: Megakaryocytes, extensive bone marrow cells responsible for platelet production, are particularly affected by myelofibrosis. These cells undergo excessive proliferation and produce abnormal amounts of platelet-derived growth factors, such as transforming growth factor-beta (TGF-β) and fibroblast growth factor (FGF). These growth factors promote fibrosis and scar tissue formation in the bone marrow. 
• Dysregulated Bone Marrow Microenvironment: The bone marrow microenvironment, including various cells and cytokines, supports average blood cell production. In myelofibrosis, the microenvironment becomes dysregulated, leading to the excessive production of fibrous tissue and disruption of the normal hematopoietic (blood cell-forming) process. Abnormal interactions between fibroblasts, endothelial cells, and hematopoietic cells contribute to the fibrotic changes in myelofibrosis. 
• Inflammatory Cytokines: Increased levels of inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), have been observed in myelofibrosis. These cytokines contribute to the inflammatory milieu within the bone marrow and further promote fibrosis. 

Etiology

The etiology of myelofibrosis is not fully understood, but genetic and environmental factors are involved. 

• Genetic Factors: Myelofibrosis is associated with acquired genetic mutations in specific genes, including Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia (MPL). These mutations are found in most myelofibrosis cases, leading to abnormal activation of signaling pathways involved in cell growth and proliferation. Genetic mutations appear to be the most significant risk factor for developing myelofibrosis. 
• Environmental Risk Factors: Exposure to several chemicals, including benzene, increases the chance of developing myelofibrosis. Viral infections and radiation exposure have been mentioned as potential environmental risk factors. 
• Other Hematological Disorders: Myelofibrosis can occur as a secondary condition that progresses from other myeloproliferative neoplasms (MPNs) or bone marrow disorders. For example, myelofibrosis may develop in patients with polycythemia vera (PV) or essential thrombocythemia (ET) who have progressed to a myelofibrosis phase of their disease. 
• Idiopathic Cases: A small percentage of myelofibrosis cases, about 5-10%, are classified as idiopathic, meaning that the cause is unknown. 
• Inherited Predisposition: There is a rare familial form of myelofibrosis known as familial myelofibrosis (FMF), inherited in an autosomal dominant manner. FMF is caused by mutations in the thrombopoietin receptor gene (MPL), leading to abnormal signaling and cell growth. 

Genetics

Prognostic Factors

Prognostic factors in myelofibrosis are used to assess the likely course and outcome of the disease. The prognosis and treatment options may be informed by several variables that have been found. These prognostic factors include: 

• Age: Advanced age at diagnosis is associated with a poorer prognosis in myelofibrosis. Patients above 65 have a greater risk of illness progression and shorter overall survival. 
• Disease Stage: The International Prognostic Scoring System (IPSS) and Dynamic International Prognostic Scoring System (DIPSS) are commonly used to assess disease stages and predict prognosis. These scoring systems consider factors such as blood cell counts, lactate dehydrogenase (LDH) levels, and constitutional symptoms (e.g., weight loss, night sweats). 
• Hemoglobin Level: Low hemoglobin levels, indicating anemia, are associated with a worse prognosis in myelofibrosis. Anemia is often a result of insufficient red blood cell production in the fibrotic bone marrow. 
• Platelet Count: Very high and low platelet counts have been associated with a poorer prognosis. Extremely high platelet counts (thrombocytosis) may indicate more aggressive disease, while very low platelet counts (thrombocytopenia) suggest bone marrow dysfunction. 
• Leukocyte Count: High white blood cell counts, particularly elevated absolute monocyte count, have been linked to unfavorable prognoses. Increased levels of circulating white blood cells are associated with disease progression and symptoms. 
• Constitutional Symptoms: The presence of constitutional symptoms, such as fatigue, weight loss, night sweats, and fever, is associated with a more advanced and aggressive disease course. 
• Cytogenetic Abnormalities: Certain chromosomal abnormalities detected through cytogenetic analysis of bone marrow cells can provide prognostic information. Abnormalities such as monosomy seven or complex karyotype have been associated with a poorer prognosis. 
• Mutational Status: Specific genetic mutations, such as the JAK2, CALR, and MPL mutations, can influence disease progression and overall survival. JAK2 mutation is associated with a worse prognosis than CALR mutation, which is generally associated with a more indolent disease course. 
• Spleen Size: Enlargement of the spleen (splenomegaly) is a common feature of myelofibrosis. Larger spleen size is associated with a higher symptom burden and poorer prognosis. 
• Bone Marrow Fibrosis Grade: The extent of fibrosis observed in a bone marrow biopsy can provide prognostic information. Higher fibrosis grades, indicating more severe fibrosis, are associated with a worse prognosis. 

Clinical History

• The clinical presentation of myelofibrosis can vary depending on the age group of the patient, any associated comorbidities or activity levels, and the understanding of the presentation. Here are some of the standard clinical features associated with myelofibrosis: 
• Age Group: Myelofibrosis is primarily diagnosed in individuals over 60, although it can also occur in younger patients. 

Physical Examination

• General Appearance: Patients with myelofibrosis may exhibit signs of pallor (pale skin), fatigue, and overall weakness. They may appear chronically ill, mainly if the disease is advanced or constitutional symptoms are present. 
• Splenomegaly: Enlargement of the spleen (splenomegaly) is a hallmark of myelofibrosis. It can be detected during a physical examination by palpating the left upper quadrant of the abdomen. The spleen may be significantly enlarged and extend below the left costal margin. The presence of splenomegaly can cause abdominal fullness, discomfort, or tenderness. 
• Hepatomegaly: In addition to splenomegaly, patients with myelofibrosis may have an enlarged liver (hepatomegaly). The liver may be palpable below the right costal margin. Hepatomegaly can occur due to portal hypertension or infiltration of abnormal cells in the liver. 
• Lymphadenopathy: Although less common than splenomegaly, lymphadenopathy (enlarged lymph nodes) may be present in some cases of myelofibrosis. Enlarged lymph nodes can be detected during a physical examination in various regions, such as the neck, axilla, or groin. 
• Petechiae and Ecchymoses: Myelofibrosis can be associated with platelet dysfunction and abnormalities, leading to bleeding tendencies. During the examination, the healthcare provider may look for small pinpoint-sized reddish-purple spots (petechiae) or larger bruise-like areas (ecchymoses) on the skin, mucous membranes, or conjunctiva. 
• Signs of Anemia: Myelofibrosis can cause anemia due to decreased red blood cell production. Signs of anemia that may be observed during the examination include skin and mucous membranes, conjunctival pallors, and tissue hypoxia, such as tachycardia (rapid heart rate) or dyspnea (shortness of breath). 
• Bone Tenderness: In some cases, patients with myelofibrosis may experience bone pain or tenderness. The healthcare provider may assess focal tenderness over the long bones, spine, or sternum. 
• Signs of Infection: Myelofibrosis can increase the risk of infections due to white blood cell function abnormalities. Signs of infection, such as fever, localized warmth, redness, or swelling, should be assessed during the examination. 

Age group

Associated comorbidity

• Patients with myelofibrosis may have comorbid conditions, such as hypertension, hyperlipidemia, diabetes, or coronary artery disease. The therapy of myelofibrosis may be complicated by these disorders and at increased risk for cardiovascular events. 
• Activity Level: Patients with myelofibrosis may present with fatigue, weakness, and exercise intolerance. These symptoms may be related to anemia, splenomegaly, or other disease-related factors. 

Associated activity

Acuity of presentation

• Myelofibrosis can present acutely, with rapidly progressive symptoms, or may develop slowly over time. In some cases, myelofibrosis is diagnosed incidentally, without any symptoms. 
• Constitutional Symptoms: Patients with myelofibrosis may experience a range of constitutional symptoms, including fatigue, weight loss, night sweats, and fever. 
• Splenomegaly: Enlargement of the spleen is a common feature of myelofibrosis and can cause abdominal discomfort, early satiety, and portal hypertension. 
• Anemia: Myelofibrosis can cause anemia due to the replacement of normal bone marrow with fibrous tissue. Patients with anemia may experience fatigue, weakness, and shortness of breath. 
• Thrombocytosis or Thrombocytopenia: Myelofibrosis can cause either an increase or a decrease in platelet count. Patients with thrombocytosis may experience thrombotic events, while those with thrombocytopenia may experience bleeding episodes. 
• Leukocytosis: Patients with myelofibrosis may have an elevated white blood cell count, including a higher proportion of monocytes, which may contribute to disease progression. 
• Bone Pain: Myelofibrosis can cause bone pain, particularly in the long bones, which may be related to fibrosis or bone marrow infiltration by abnormal cells. 

Differential Diagnoses

• Essential Thrombocythemia (ET): ET is a hematologic disorder characterized by increased platelet counts, and it can share some clinical features with myelofibrosis, such as splenomegaly and thrombosis. 
• Polycythemia Vera (PV): A hematologic disorder characterized by increased red blood cell production. It can also present with splenomegaly, thrombosis, and other similar symptoms as myelofibrosis. 
• Chronic Myeloid Leukemia (CML): CML is a type of leukemia that can also present with splenomegaly and leukocytosis. However, the presence of the Philadelphia chromosome is a key diagnostic feature of CML, which distinguishes it from myelofibrosis. 
• Lymphoma: In addition to lymphadenopathy and other nonspecific symptoms that are like myelofibrosis, lymphoma, a kind of malignancy that impacts the lymphatic system, may also be present with these symptoms. 
• Hepatic or Portal Vein Thrombosis: These conditions can present abdominal pain, hepatomegaly, and splenomegaly, also seen in myelofibrosis. 
• Chronic Liver Disease: Liver cirrhosis or other chronic liver diseases can present with splenomegaly, thrombocytopenia, and fatigue, which can mimic the symptoms of myelofibrosis. 
• Rheumatologic Diseases: Certain rheumatologic diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), can present with constitutional symptoms, fatigue, and arthralgia, which can overlap with the symptoms of myelofibrosis. 
• Infections: Chronic infections such as tuberculosis, hepatitis, or HIV can present with nonspecific constitutional symptoms, fatigue, and lymphadenopathy, which can mimic the symptoms of myelofibrosis. 
• Myelodysplastic Syndrome (MDS): MDS is a group of disorders characterized by ineffective blood cell production and can present with similar clinical features as myelofibrosis. 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

• The management of myelofibrosis is typically divided into three phases: early, intermediate, and advanced. 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

• Patient Education: Providing information about the disease, its symptoms, and potential complications can help patients better manage their condition and make informed decisions. 
• Lifestyle Modifications: Encouraging a healthy lifestyle, including regular exercise, a balanced diet, and adequate rest, can help manage symptoms and improve overall well-being. 

• Disease-Modifying Therapies: Medications such as JAK inhibitors (e.g., ruxolitinib) target the dysregulated JAK-STAT signaling pathway and can help reduce spleen size, alleviate symptoms, and improve quality of life. 
• Supportive Therapies: Blood transfusions, erythropoiesis-stimulating agents (ESAs), and androgen therapy may be used to manage anemia. Platelet transfusions or medications like hydroxyurea may be employed to control thrombocytopenia or thrombocytosis. 
• Immunomodulatory Agents: Drugs such as thalidomide or lenalidomide may be considered in select cases to manage symptoms and splenomegaly. 

• Splenic Radiation: For patients with severe symptomatic splenomegaly, splenic irradiation may be considered to reduce spleen size and improve symptoms. 
• Splenectomy: Surgical removal of the spleen (splenectomy) may be an option for patients with massive splenomegaly, symptomatic splenomegaly, or severe cytopenia that are not adequately controlled with medical therapy. 
• Stem Cell Transplantation: Allogeneic stem cell transplantation (bone marrow transplant) may be considered for eligible patients, significantly younger individuals with suitable donors and high-risk features. 

The management of myelofibrosis is typically divided into three phases: 

• Early Phase: Patients with low-risk diseases and minimal symptoms may be managed with watchful waiting and regular monitoring. 
• Intermediate Phase: Patients with intermediate-risk disease or moderate symptoms may be candidates for disease-modifying therapies or other targeted agents to control symptoms and prevent disease progression. 
• Advanced Phase: More aggressive interventions, such as stem cell transplantation or palliative measures, may be considered for patients with high-risk diseases or severe symptoms. 

Medication

Future Trends

Media Gallary

References

• https://emedicine.medscape.com/article/197954-treatment 
• https://www.ncbi.nlm.nih.gov/books/NBK531464/ 
• https://www.ncbi.nlm.nih.gov/books/NBK531464/