Primary Myelofibrosis

Primary Myelofibrosis

Overview

Primary myelofibrosis (PMF) is a rare bone marrow disorder that is characterized by abnormalities in blood cell production (hematopoiesis, the process by which the body makes new blood cells) and scarring (formation of fibrous tissue, the buildup of stiff scar-like tissue) within the bone marrow.1-5  

Bone marrow is the soft, spongy tissue that fills the center of most bones, and it contains specialized cells called hematopoietic stem cells (early “parent” cells that can develop into all types of blood cells). These stem cells grow and eventually develop into one of the three main types of blood cells: red blood cells (erythrocytes), which carry oxygen throughout the body; white blood cells (leukocytes), which help fight infection; or platelets (thrombocytes), which help the blood clot to stop bleeding.1, 2  

The symptoms associated with primary myelofibrosis vary from person to person and are related to the abnormalities affecting blood cell production.1, 3 Affected people may not have symptoms at the time of diagnosis (asymptomatic, no noticeable symptoms) and may remain symptom-free for many years.3, 5  

Eventually, people with PMF may develop fatigue, fever, frequent infections, pale skin, night sweats, and unexplained weight loss.1, 3, 5, 6 An enlarged spleen (splenomegaly, swelling of the spleen), an organ involved in filtering blood and supporting immune function, is a common finding.1, 3, 5 An enlarged liver (hepatomegaly) may also occur.1, 3 

In primary myelofibrosis, a change (variant) in the DNA of a single hematopoietic stem cell causes the abnormal cell to continually reproduce itself. 3, 6, 7 This change is not inherited as it does not affect the reproductive cells (egg or sperm). 3 Eventually, these abnormal cells crowd out normal, healthy cells in the bone marrow and, along with scarring within the marrow, disrupt the production of red blood cells, white blood cells, and platelets.3  

In more than half of the people with PMF, a variant in the JAK2 gene (a gene involved in signaling the bone marrow to make blood cells) is identified. Variants in the CALR gene are detected in about 20-25% of cases, while MPL gene variants are present in about 6-7% of the people with PMF. 8, 9, 10 The exact role these genetic abnormalities play in the development of the disorder is not fully understood. 6, 8 

Treatment includes several medications and, in some cases, a procedure to replace the bone marrow (stem cell or bone marrow transplant, which replaces diseased bone marrow with healthy blood-forming cells).  

Primary myelofibrosis belongs to a group of diseases known as the myeloproliferative neoplasms (MPNs).1, 3, 6 This group of disorders is characterized by the overproduction (proliferation: excessive growth and division) of one or more of the three main blood cell lines – red blood cells, white blood cell, or platelets.1, 3, 6 Because MPNs are characterized by uncontrolled cell growth, they may also be classified as blood cancers.1, 6  

The term “myelofibrosis” is usually reserved for bone marrow fibrosis related to myeloid neoplasm. Fibrosis means scarring, and bone marrow fibrosis refers to the replacement of normal bone marrow with stiff scar tissue that occurs in the setting of myeloid neoplasm. A myeloid neoplasm is a cancer that begins in the myeloid cells, which are precursor cells that normally develop into red blood cells, certain white blood cells, and platelets.  

Myeloproliferative neoplasms include: 

chronic myeloid leukemia 

polycythemia vera 

essential thrombocythemia 

primary myelofibrosis (also called chronic idiopathic myelofibrosis) 

chronic neutrophilic leukemia 

chronic eosinophilic leukemia 

Unclassifiable myeloproliferative neoplasms  

Symptoms

Most of the symptoms of primary myelofibrosis are related to abnormalities affecting the production of the three main types of blood cells – red blood cells, white blood cells, and platelets.1, 2, 4 Most blood cells are produced in the bone marrow (the soft tissue inside bones where blood cells are made) and released into the bloodstream to travel throughout the body performing their specific functions. Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections, and platelets allow the body to form clots to stop bleeding.1, 2  

In primary myelofibrosis there are often low levels of circulating red blood cells, a condition known as anemia. 1, 3 Red blood cells may also be misshapen (i.e., shaped like teardrops) and underdeveloped (immature). White blood cells and platelets are also misshapen and immature. However, there are often too many white blood cells produced. There may be abnormally low or high levels of platelets.1, 3  

The specific symptoms and progression of primary myelofibrosis vary from person to person.1, 3 Some individuals may not exhibit symptoms for many years (asymptomatic, meaning without symptoms).3 Reported signs and symptoms may include:1, 3, 4 

Anemia (having fewer health red blood cells), which may cause:  

Tiredness 

Weakness 

Shortness of breath 

Lightheadedness 

Headaches 

Irritability 

Pale skin color 

Fever and drenching night sweat may also occur, along with weight loss 

Increased susceptibility to bacterial and fungal infections, because, although white blood cell counts may be elevated, these cells are abnormal and do not function properly  

Abnormal platelet production which may result in easy bruising, spontaneous bleeding from the gums or nose, and small, flat red spots under the skin caused by bleeding (petechiae). 

Other common signs and symptoms include: 1, 3-5  

Abnormally enlarged spleen (splenomegaly), which may cause pain or a feeling of fullness below the ribs on the left side or referred pain to the upper left shoulder. 

Abnormal enlargement of the liver (hepatomegaly), which occurs in approximately two-thirds of affected people.  

These findings are partly due to extramedullary hematopoiesis, an abnormal process in which blood cells are produced outside the bone marrow, such as in the spleen or liver. 1, 7, 11  

Extramedullary hematopoiesis may also lead to the formation of fibrohematopoietic tumors (masses made up of fibrous tissue and blood-forming cells) in the gastrointestinal (GI) tract, lungs, skin, liver, spleen, brain, or near the spine.1, 7, 11 Symptoms depend on tumor location and may result from compression of nearby structures or impaired organ function, including gastrointestinal bleeding, neurological complications, or spinal cord compression.1, 7 Bone or joint pain may develop later in the course of disease.1, 10  

Additional complications may include: 1, 3  

Increased blood pressure in the main vein supplying the liver (portal hypertension) due to excess blood flow from an enlarged spleen 1, 3  

This can cause blood to be diverted into smaller veins in the stomach or esophagus, which may enlarge and rupture, leading to bleeding (esophageal or gastric varices) 

Increased blood pressure in the main artery of the lungs (pulmonary hypertension) 

In about 10-20% of the affected people, there is a 10-year risk of leukemic transformation, in which primary myelofibrosis progresses to acute myelogenous leukemia (AML), a fast-growing cancer of immature white blood cells. 1, 3, 5  

Causes

The underlying cause of primary myelofibrosis is unknown (idiopathic, meaning no identifiable cause).1, 3 More than 80% of people with primary myelofibrosis have changes in certain genes that play a role in the disease. The most common change affects the JAK2 gene and is found in about 50-60% of people with PMF. Changes in the CALR gene occur in about 20-25% of affected people, and changes in the MPL gene are found in about 6-7% of the affected people. About 10-15% of people with primary myelofibrosis do not have any of these gene changes. This group is often referred to as having “triple-negative” primary myelofibrosis.10, 12 

The exact role that JAK2, CALR or MPL gene variants play in the development of primary myelofibrosis is not fully understood.6, 8  

Many of the symptoms of primary myelofibrosis occur because abnormalities affect the formation of blood cells.1, 7 The disorder begins with an acquired change in the DNA (a change that develops during life and is not inherited) of one hematopoietic stem cell (a blood-forming parent cell).1, 3, 6 This defective cell produces copies of itself that also carry the same DNA changes.1, 6 These abnormal cells eventually outnumber healthy cells in the marrow.1, 3 In response, scar (fibrous) tissue forms within the bone marrow (fibrosis), further affecting blood cell production.  

In primary myelofibrosis, there is overproduction of megakaryocytes, which are cells that eventually become platelets.1, 7 These megakaryocytes release substances called cytokines (chemical signaling molecules), which may stimulate the formation of fibrous (scar) tissue within the marrow. Additional changes may affect the marrow including abnormal density or hardening of bone or marrow (osteosclerosis) and the development of too many small blood vessels (angiogenesis).1,7  

PMF often causes an enlarged spleen because the body produces too many white blood cells and begins making blood cells outside the bone marrow. Many affected people also experience general symptoms such as fatigue, weight loss, fever, or night sweats. These symptoms occur because inflammation increases metabolism and energy use in the body.  

Recent updates of the 5th edition of the World Health Organization (WHO) Classification of Hematolymphoid Tumors (WHO-HAEM5)  and the International Consensus Classification (ICC) distinguish two stages of PMF, prefibrotic (also called early) PMF and overt fibrotic PMF. 12 

Affected populations

Primary myelofibrosis is a rare condition with an estimated prevalence of about 4-6 per 100,000 people in the United States.13, 14 Based on the current (2026) U.S. population of approximately 335 million, this translates to roughly 13,400-20,100 people living with the disease. However, this estimate is based on data from 2008-2010 data and relied on two large health plans14 rather than a comprehensive national registry.  

The most comprehensive U.S. data come from the SEER database (2002-2016), which documented 4,214 cases of primary myelofibrosis over a 14-year study period with an overall incidence rate of 0.44 per 100,000 person-years. This translates to approximately 1,470 new diagnoses annually based on the current U.S. population.15 Prevalence is higher than the annual incidence because people with primary myelofibrosis can live for several years after diagnosis. The SEER data showed a 5-year mortality of 51.0% for primary myelofibrosis, meaning approximately half of patients survive beyond 5 years.15 

Primary myelofibrosis can occur at any age, but it most often affects individuals older than 50 years, with a median age at diagnosis of approximately 65 years.1, 3  

Disorders with Similar Symptoms

Primary myelofibrosis needs to be differentiated from other conditions in which marrow fibrosis (scarring of the bone marrow) develops as a secondary process because myelofibrosis can also occur secondarily rather than as a primary disease. For example, some people with myelofibrosis may have been exposed to infections such as tuberculosis or to toxic substances such as benzene, fluoride or phosphorus. Myelofibrosis may also occur as a result of the spread of cancer (metastasis, meaning cancer cells spreading from another part of the body) to the bone marrow from a primary tumor.1, 2 These tumors most often originate in the breast, prostate, kidney, lung, or adrenal or thyroid gland.1, 2  

Myelofibrosis may occur as a secondary feature of another bone marrow disorder such as polycythemia vera, multiple myeloma, certain metabolic disorders, and/or chronic myeloid leukemia.1, 6  

Diagnosis

Diagnosis of primary myelofibrosis may be made based upon a thorough clinical evaluation, detailed patient history, and specialized tests. In many people, the first signs are enlarged spleen (splenomegaly) or anemia (low red blood cell count).1, 3 A complete blood count (CBC) test may demonstrate abnormalities in red blood cells, white blood cells or platelets.1, 3 A bone marrow biopsy (removal of a small sample of bone marrow for examination) is often used to confirm the diagnosis.1, 3, 4  

The World Health Organization (WHO) uses specific criteria to diagnose primary myelofibrosis (PMF). These include three major criteria and five minor criteria, with some differences between early (pre-fibrotic) and advanced (overt fibrotic) stages of the disease. A diagnosis requires all three major criteria and at least one minor criterion, confirmed on two separate evaluations.15,16 

Major criteria: 

Bone marrow changes: Abnormal megakaryocytes (large bone marrow cells that normally produce platelets) and increased marrow activity.  

Early PMF shows little or no scarring, while overt PMF includes moderate to severe bone marrow fibrosis. 

Evidence of a clonal blood disorder: Presence of a JAK2, CALR, or MPL gene variant (genetic changes showing the disease started from a single abnormal cell), another clonal marker, or exclusion of non-cancer-related bone marrow scarring. 

Exclusion of other blood diseases: Findings do not meet criteria for other myeloid disorders such as chronic myeloid leukemia or polycythemia vera. 

 Minor criteria: 

Unexplained anemia (low red blood cell count) 

Immature blood cells in the circulation (especially in overt PMF, meaning early-stage blood cells appear in the bloodstream) 

Enlarged spleen 

Elevated white blood cell count 

Elevated lactate dehydrogenase (LDH) level (a blood marker that can reflect increased cell turnover or tissue damage) 

 Standard Therapies

Treatment

Treatment plans for primary myelofibrosis are individualized based on symptoms, disease severity, blood counts, overall health, and risk category.  

Some people have no symptoms at diagnosis, and in these cases, physicians may recommend careful monitoring without immediate treatment, often referred to as a “watch-and-wait” approach. Regular follow-up is used to detect disease progression, and some people may remain symptom-free for many years.3, 4  

Anemia (low red blood cell count) is a common complication of primary myelofibrosis. Blood transfusions may be prescribed for people with severe anemia, although several medications may help improve red blood cell production and reduce the need for transfusions. In some patients, androgens (male hormones) and/or corticosteroids (anti-inflammatory medications) have shown moderate success in increasing red blood cell production or reducing red blood cell destruction.1, 3 Additional treatments for anemia may include erythropoiesis-stimulating agents (drugs that stimulate red blood cell production), luspatercept, danazol, and momelotinib, which have been shown to improve both anemia and disease-related symptoms 3  

Medications that suppress abnormal bone marrow activity, known as myelosuppressive agents (drugs that reduce blood cell production), have been used. Hydroxyurea may help control high white blood cell counts, high platelet counts, and enlarged organs. Busulfan may be considered for people who do not respond to hydroxyurea. These medications may improve symptoms such as leukocytosis (high white blood cell count), thrombocytosis (high platelet count), and organ enlargement, but they do not reverse the underlying disease.1, 3, 18, 19 

In some individuals, an enlarged spleen (splenomegaly) can cause severe pain, anemia, low platelet counts, or portal hypertension (increased blood pressure in the vein supplying the liver). When these symptoms do not respond to medication, surgical removal of the spleen (splenectomy) or radiation treatment to the spleen (splenic irradiation) may be considered. These approaches can provide temporary improvement but carry significant risks, which must be carefully weighed against potential benefits.1, 3, 18 

Bone pain may be treated with bisphosphonates (a group of medications that help protect and strengthen bones) such as zoledronic acid, which can help relieve pain and may also improve blood cell production in some individuals. 

Interferon-alfa, an immune-modeling medication (a drug that works by changing how the immune system signals and responds, rather than directly killing cancer cells), has also been used in the treatment of primary myelofibrosis. Pegylated interferon alfa-2a may be particularly useful in earlier-stage disease. This therapy can reduce abnormal blood cell production and has been shown to delay bone marrow fibrosis in some individuals treated early, although further research is needed to better define its long-term safety and effectiveness. 

Some affected individuals may be treated with allogeneic stem cell transplantation, in which healthy blood-forming stem cells from a donor replace the person’s diseased bone marrow. This approach offers the only curative option, but it carries a high risk of serious and potentially life-threatening complications. As a result, it is typically reserved for younger individuals or those with high-risk disease who have limited alternative treatment options.20-22  

JAK inhibitor medications have significantly changed the treatment of myelofibrosis by targeting abnormal signaling pathways involved in the disease.23- 25 

Ruxolitinib (Jakafi) was approved by the U.S. Food and Drug Administration (FDA) on November 16, 2011, for treatment of patients with intermediate or high-risk myelofibrosis. 

Fedratinib (Inrebic) was approved in 2019 for patients with intermediate-2 or high-risk primary or secondary myelofibrosis both as initial treatment and for patients who have stopped responding to ruxolitinib. 

Pacritinib (Vonjo) was approved in 2022, particularly for patients with low platelet counts.  

Momelotinib (Ojjaara) was approved in 2023 for adults with intermediate- or high-risk primary or secondary myelofibrosis, including for those with anemia.21 

These medications can reduce spleen size, improve symptoms such as fatigue and night sweats, and enhance quality of life.23- 25 

Other medications have also been studied in primary myelofibrosis. Thalidomide (a medication that affects the immune system, inflammation, and blood vessel growth) has shown promise in improving certain symptoms but may cause significant side effects, including increased white blood cell and platelet counts. Lenalidomide, a related but more potent drug with generally fewer side effects, has shown effectiveness in improving blood and bone marrow abnormalities in selected people, either alone or combined with corticosteroids.3 Additional therapies are under investigation.23-25 

Because primary myelofibrosis varies widely among individuals, treatment decisions are best made through close collaboration with a healthcare team. Ongoing monitoring is essential to evaluate treatment response, manage side effects, and adjust care as the disease evolves. 

Type of Doctor Department : A hematologist or a hematologist-oncologist