NORD gratefully acknowledges Ayalew Tefferi, MD, Division of Hematology, Mayo Clinic, College of Medicine, for assistance in the preparation of this report.
Primary myelofibrosis is a rare bone marrow disorder that is characterized by abnormalities in blood cell production (hematopoiesis) and scarring (formation of fibrous tissue) within the bone marrow. Bone marrow is the soft, spongy tissue that fills the center of most bones. Bone marrow contains specialized cells called hematopoietic stem cells that grow and eventually develop into one of the three main types of blood cells: red blood cells, white blood cells or platelets. In primary myelofibrosis, a change in the DNA of a single hematopoietic stem cell causes the abnormal cell to continually reproduce itself. Eventually, these abnormal cells crowd out normal, healthy cells in the marrow and, along with scarring within the marrow, disrupt the production of red and white blood cells and platelets.
The symptoms associated with primary myelofibrosis vary and are related to the abnormalities affecting blood cell production. Affected individuals may not have symptoms at the time of diagnosis (asymptomatic) may remain symptom-free for many years. Eventually, affected individuals may develop fatigue, fever, frequent infections, pale skin, night sweats and unexplained weight loss. An enlarged (spleen) is a common finding. An enlarged liver (hepatomegaly) may also occur.
In approximately 50 percent of cases, a mutation of the JAK2 gene has been detected. The exact role this abnormal gene plays in the development of the disorder is unknown.
Primary myelofibrosis belongs to a group of diseases known as the myeloproliferative neoplasms (MPNs). This group of disorders is characterized by the overproduction (proliferation) of one or more of the three main blood cell lines - red or white blood cells or platelets. Three other disorders are commonly classified as MPNs: chronic myeloid leukemia, essential thrombocythemia and polycythemia vera. Myelofibrosis may occur as a secondary characteristic of polycythemia vera or essential thrombocytyemia. Because the MPNs are characterized by uncontrolled cell growth, they may also be classified as blood cancers.
Most of the symptoms of primary myelofibrosis are related to abnormalities affecting the production of the three main types of blood cells: red and white cells and platelets. Most blood cells are produced in the bone marrow 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.
In primary myelofibrosis there are often low levels of circulating red blood cells, a condition known as anemia. 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.
The specific symptoms and progression of primary myelofibrosis vary from case to case. Some individuals may not exhibit symptoms for many years (asymptomatic). Eventually, individuals with anemia may experience tiredness, shortness of breath, weakness, lightheadedness, irritability, headaches, and pale skin color. Fever and excessive sweating at night (night sweats) may also occur. Although there may be too many white blood cells, these abnormal cells do not function properly and fail to properly fight off infection. Therefore, affected individuals may have an increased risk of contracting bacterial and fungal infections. Abnormalities in platelet production may make individuals more susceptible to excessive bruising following minimal injury and to spontaneous bleeding from the mucous membranes, especially those of the gums and nose.
An abnormally enlarged spleen is a common finding in individuals with primary myelofibrosis. Splenomegaly may cause pain or a feeling of fullness in the upper left portion of the stomach. Splenomegaly can also cause severe pain in the upper left shoulder (referred pain). Abnormal enlargement of the liver (hepatomegaly) occurs in approximately two-thirds of cases. Abnormal enlargement of the spleen or liver may occur, in part, due to extramedullary hematopoiesis, an abnormal process where blood cells develop outside of the bone marrow.
Extramedullary hematopoiesis may also cause masses (fibrohematopoietic tumors) to form in the gastrointestinal tract, lungs, skin, liver, spleen and other areas of the body. Symptoms associated with these tumors occur due to compression of nearby structures or impaired function of an affected organ. Fibrohematopoietic tumors in the gastrointestinal tract may lead to excessive bleeding, tumors in the brain can cause neurological complications, and tumors near the spine can compress the spinal cord.
Bone or joint pain may develop later in the course of the disease. Additional complications may occur in some cases of primary myelofibrosis including increased blood pressure of the main artery delivering blood to the liver (portal hypertension) due to excess blood flow from the spleen. The liver cannot absorb the excess blood flow, which may be forced into small veins within the stomach or esophagus. These veins may expand and eventually rupture causing bleeding (esophageal or gastric varices). Increased blood pressure of the main artery of lungs (pulmonary hypertension) may also occur.
In approximately 20 percent of cases, primary myelofibrosis will progress to acute myelogenous leukemia, a specific type of blood cancer.
The underlying cause of primary myelofibrosis is unknown (idiopathic). Approximately, 50 percent of cases are associated with a mutation of the JAK2 gene. This gene is also mutated in essential thrombocythemia and polycythemia vera. Approximately 10 percent of cases of primary myelofibrosis are associated with mutations of the MPL gene. The exact role that JAK2 or MPL gene mutations play in the development of primary myelofibrosis is unknown.
Many of the symptoms of primary myelofibrosis occur because abnormalities affecting the formation of blood cells. The disorder begins with an acquired, change in the DNA of one hematopoietic stem cell. This defective cell produces copies of itself that also carry the same mutated DNA. These abnormal cells eventually outnumber healthy cells in the marrow. In response to this process, 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.
These megakaryocytes release certain substances called cytokine, which some researchers believe may stimulate the formation of fibrous 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) within the marrow.
Some cases of myelofibrosis may be associated with tuberculosis and with exposure to toxic substances, such as benzene, fluoride or phosphorus. Myelofibrosis may occur as a result of the spread of cancer (metastasis) to bone marrow from primary tumors. These tumors most often originate in the breast, prostate, kidney, lung, or adrenal or thyroid gland. Myelofibrosis may occur as a secondary characteristic of another bone marrow disorder such as polycythemia vera, multiple myeloma, certain metabolic disorders, and/or chronic myeloid leukemia. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
Primary myelofibrosis is a chronic blood disorder that affects males and females in equal numbers. It can occur at any age although it usually affects individuals more than 50 years of age. The median age at diagnosis is approximately 65. The incidence is estimated to be 1.5 cases per 100,000 people in the United States. In studies of Northern European countries, the incidence was estimated to be .5 cases per 100,000 people. The worldwide incidence is unknown. When primary myelofibrosis affects children, it is usually before three years of age. In younger children, girls are affected twice as often as boys.
Diagnosis of primary myelofibrosis may be made based upon a thorough clinical evaluation, detailed patient history, and various specialized tests. In many cases, the presenting sign of the disorder is an abnormally enlarged spleen (splenomegaly) that may be detected upon routine examination or low levels of circulating red blood cells. A complete blood count (CBC) may demonstrate low levels of red blood cells or elevated levels of platelets or white blood cells. Since blood cell counts vary at different times in affected individuals, blood counts are not definitive in diagnosing primary myelofibrosis. Surgical removal and microscopic examination of bone marrow tissue (biopsy) is often used to confirm a suspected diagnosis of primary myelofibrosis.
Since the cause of primary myelofibrosis is unknown, treatment is directed toward the specific symptoms present in each case. In asymptomatic individuals, physicians may recommend that no therapy be given until symptoms appear (watch and wait). Affected individuals receive regular checkups to detect progression of the disease. Individuals may remain symptom-free for many years.
Blood transfusions may be prescribed if for individuals with severe anemia. However, several medications may be able to improve red blood cells so that blood transfusions are not necessary. In some cases, moderate success has been obtained using male hormones (androgens) and/or corticosteroids in an attempt to increase red blood cell production or decrease their destruction.
Drugs that hinder the ability of the bone marrow to develop blood cells (myelosuppressive agents) such as hydroxyurea have been used to treat primary myelofibrosis. Busulfan may be used in individuals who do not respond to therapy with hydroxyurea. These drugs may improve some symptoms associated with primary myelofibrosis, such as abnormally high levels of white blood cells in the blood (leukocytosis), abnormally high levels of platelets in the blood (thrombocyosis), and abnormally enlarged organs (organomegaly).
In some cases, an abnormally enlarged spleen (splenomegaly) may cause severe pain, anemia, a low platelet count or portal hypertension. If such cases fail to respond to other forms of therapy, surgery to remove the spleen (splenomegaly) or treatment with radiation (splenic irradiation) may be recommended. In some cases, these treatments have led to temporary improvement in some of the associated symptoms of primary myelofibrosis. Both of these procedures carry risks, which are weighed against benefits in each individual case.
Bisphosphates such as zoledronic acid have been used to relieve bone pain and may improve blood cell production.
Jakafi (ruxolitinib) was approved by the FDA in 2011 for treatment of patients with intermediate or high risk myelofibrosis, including primary myelofibrosis. This medication inhibits the JAK 1 and 2 enzymes that are involved in regulating blood and immunological functioning. Jakafi is manufactured by Incyte Corp. For more information contac. http://www.jakafi.com/ or 1-855-4-Jakafi (855-452-5234).
Some individuals with primary myelofibrosis have been treated with allogeneic or autologous stem cell transplantation. Stem cells are special cells found in bone marrow that manufacture different types of blood cells (e.g., red blood cells, platelets). In autologous stem cell transplantation, an affected individual’s stem cells are removed after prior treatment, usually with drugs. These healthy stem cells are later re-infused into the bone marrow after the disorder has progressed. In allogeneic stem cell transplantation, stem cells are donated from another person, usually from a closely matched family member.
Stem cell transplants have the potential to restore proper bone marrow function to individuals with primary myelofibrosis. However, because stem cell transplants can cause severe, even life-threatening complications, they are usually reserved for younger individuals or individuals who have no other viable treatment options.
Interferon-alfa is a drug that has been used to treat individuals with primary myelofibrosis. Interferon-alfa has been effective in reducing the production of blood cells by the bone marrow. In addition, interferon-alfa has delayed the formation of fibrous tissue (fibrosis) within the bone marrow of some individuals with primary myelofibrosis who received treatments early in the development of the disorder. More research is necessary to determine the long-term safety and effectiveness of interferon-alfa for the treatment of primary myelofibrosis.
Researchers are investing the use of thalidomide for the treatment of individuals with primary myelofibrosis. Thalidomide is used to treat a blood cancer known as multiple myeloma. The drug has shown promise in improving certain symptoms associated with primary myelofibrosis. However, thalidomide may cause certain side effects or undesirable effects such as increasing the numbers of white blood cells and platelets.
Lenalidomide is in the same class of drugs as thalidomide, but is more potent and is generally associated with fewer side effects. Studies have shown that lenalidomide is highly effective in treating peripheral blood and bone marrow abnormalities in certain individuals with primary myelofibrosis. Researchers are studying lenalidomide as a single or agent or in combination with corticosteroids. More research is necessary to determine the long-term safety and effectiveness of lenalidomide or thalidomide as potential treatments for individuals with primary myelofibrosis.
Additional drugs including imatinib, etanercept and bortezomib are being studying for use in treating individuals with primary myelofibrosis. Researchers are also studying methods of hinders or blocking the activity of an enzyme produced by the JAK2 gene, which is mutated in approximately 50 percent of cases of primary myelofibrosis. Researchers believe that this enzyme may play a role in the overproduction of blood cells.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Contact for additional information about primary myelofibrosis:
Ayalew Tefferi, MD
Professor of Medicine and Hematology
Department of Hematology
Mayo Clinic Transplant Center
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