- Also Known As:
- Myeloproliferative Disorders
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What are myeloproliferative neoplasms?
Myeloproliferative neoplasms (MPNs) are a subset of bone marrow disorders. They are a group of diseases characterized by the production of too many of one or more types of blood cells in the bone marrow.
Bone marrow is a soft fatty tissue that is located in the center of the body’s larger bones. It has a honeycomb or sponge-like structure, consisting of a highly organized meshwork that is filled with liquid. The liquid contains …
Myeloproliferative neoplasms (MPNs) are a subset of bone marrow disorders. They are a group of diseases characterized by the production of too many of one or more types of blood cells in the bone marrow.
Bone marrow is a soft fatty tissue that is located in the center of the body’s larger bones. It has a honeycomb or sponge-like structure, consisting of a highly organized meshwork that is filled with liquid. The liquid contains stem cells and a mixture of red blood cells (RBC), white blood cells (WBC), and platelets in various stages of development.
Normally, the body maintains a dynamic but relatively stable number of blood cells in circulation. As cells age, die, or are removed from circulation, new ones are made in the marrow to replace them. When a particular kind of blood cell is needed, some of the stem cells in the bone marrow begin to change. Those stem cells become immature “blast” forms of whatever cell type is in short supply. These blasts mature to become white blood cells, red blood cells, or platelets. Usually only fully mature cells are released into circulation.
With an MPN, too much production of a cell’s precursors (e.g., stem cells and blasts) leads to an increase in that type of mature cell. That causes a corresponding increase or decrease in the number of other normal blood cells, which may be inhibited and crowded out of the bone marrow. This results in symptoms related to blood cell overproduction, shortages, and dysfunction throughout the body.
About Myeloproliferative Neoplasms
The common types of MPNs include:
- Chronic myeloid (myelogenous, myelocytic) leukemia (CML)—CML usually occurs in adults, with people 65 and over at greater risk. It rarely occurs in children but is the most common pediatric MPN. People with CML often have no symptoms at first and frequently are diagnosed incidentally during a routine blood test or physical. When symptoms do appear, they are similar to common, less serious illness and include low energy, pale skin, stomach discomfort caused by an enlarged spleen, and unexplained weight loss. CML can be traced to abnormal chromosomes where, inside a stem cell in the bone marrow, pieces from two chromosomes break off and switch places (translocation). This results in an altered, fused gene (called BCR/ABL1) on an abnormal chromosome 22 (also known as the Philadelphia chromosome). This altered gene makes an abnormally functional protein that leads to the overproduction of white blood cells. Left untreated, CML leads to anemia, poor immunity, excessive bruising and bleeding, and a markedly enlarged spleen.
- Polycythemia vera (also known as PV, primary polycythemia (neoplastic))—a disease in which too many red blood cell precursors are produced in the bone marrow, independent of the mechanisms that normally regulate red blood cell production. This leads to too many red blood cells circulating in the blood. When RBCs build up in the bloodstream, the blood becomes thicker and does not flow smoothly in the blood vessels, causing symptoms such as headache, dizziness, problems with vision, and even excessive clotting or heart attack. A variety of other factors can cause increased red blood cell production; for instance, long-term exposure to low concentrations of oxygen (e.g., emphysema/COPD or living at high altitude). These increases in RBCs are referred to as secondary polycythemia (reactive).
- Primary myelofibrosis (PMF, previously known as chronic idiopathic myelofibrosis and agnogenic myeloid metaplasia)—a disease where fibrous cells gradually replace normal bone marrow tissue. The dense fiber network impairs bone marrow function and blood cell production and can lead to production of blood cells outside the bone marrow, typically in the liver or spleen (so-called extramedullary hematopoiesis or EMH). The red blood cells that do enter the bloodstream can be malformed, looking like teardrops instead of circles. There may be too few normal, mature red blood cells to carry oxygen, causing anemia.
- Essential thrombocythemia (ET)—a disease characterized by an increased number of megakaryocytes, precursors to platelets (also called thrombocytes), in the bone marrow as well as sustained and dramatic increases of platelets in the blood. Excess platelets in blood can make it hard for the blood to flow normally and therefore increases a person’s risk of developing inappropriate blood clots or of having a stroke. On the other hand, the platelets may not function normally, leading to bleeding. Essential thrombocythemia must be distinguished from secondary or reactive thrombocytosis, which is an increased number of platelets caused by non-neoplastic marrow disorders such as iron deficiency, infection, inflammation (e.g., rheumatoid arthritis), bleeding, or removal of the spleen.
MPNs are generally not curable, but their slow progression can usually be controlled and their symptoms managed. For each MPN, there is a slight chance that the disease will develop into an acute leukemia. If this occurs, the course of the disease will be accelerated, the symptoms will intensify, and more aggressive treatment will be required.
Signs and Symptoms
The severity of an MPN varies from person to person. The condition may be acute and life-threatening or it may be very subtle, existing for years before being diagnosed, frequently discovered during a routine physical. While each condition has its own set of symptoms, some signs and symptoms are common to more than one. Examples include:
- Unexplained weight loss
- Weakness and fatigue
- Enlarged spleen (splenomegaly) – cells accumulate in the spleen because it makes blood cells and because it filters old or abnormal cells out of the bloodstream; this causes the spleen to swell, which can cause abdominal discomfort.
- Excessive bleeding and easy bruising, due to insufficient and/or abnormal platelets
- Night sweats
- Bone and joint pain
- Pallor (pale complexion) due to anemia (when red blood cells are decreased)
- Frequent infections
- Headache, dizziness, numbness and/or problems with vision
In someone with polycythemia vera, the excess number of RBCs produced increases the thickness (viscosity) of the blood. This can cause symptoms such as headaches, dizziness, visual distortion, itching, and numbness or tingling (paresthesia). Sometimes the excessive RBCs may lead to complications, such as stomach ulcers, kidney stones, venous thrombosis, stroke, and rarely to congestive heart failure.
In people with polycythemia vera or primary thrombocythemia, especially if they are older than 60, their disease may progress to myelofibrosis. In myelofibrosis, fibrous scar tissue replaces bone marrow, similar to what is seen with primary myelofibrosis. Myelofibrosis often causes no symptoms early in the course of the disease; about one-third of those who are diagnosed are asymptomatic. People who do have symptoms may experience fatigue, shortness of breath, and enlargement of the spleen. Fibrous tissue eventually fills the bone marrow, reducing the production of all blood cells. Anemia may become severe.
Most people with essential thrombocythemia are asymptomatic, but some develop a blood clot (thrombosis) or experience excessive bleeding because of increased numbers of platelets that do not function properly. They also may have tingling in the hands and feet, headaches, chest pain or discomfort, bloating in the upper left abdominal area, weakness, dizziness, nosebleeds, and easy bruising.
Complete blood count (CBC) with differential and blood smear
CBCs and differentials are common tests and may be used to help diagnose and monitor MPNs. They are routine tests that count the number and relative proportion of each of the different types of cells in a blood sample. Along with blood smears, they also provide information about the size, shape, and relative maturity of the blood cells present in a person’s blood at that moment.
CBCs and differentials can be used to detect WBC, RBC, and platelet increases, decreases, and abnormalities. They can help determine the severity of these changes (i.e., increases, decreases), diagnose their cause, monitor the course of a disease, and monitor the response to treatment.
- With polycythemia vera, increased RBCs, platelets, and sometimes WBCs may be seen.
- With myelofibrosis, immature granulocytes, misshapen teardrop-shaped red blood cells, and immature nucleated red blood cells are often seen, and WBC and RBC numbers are often decreased.
- With thrombocythemia, greatly increased numbers of platelets are seen along with abnormally large or giant platelets and platelet clumps.
Irregularities in cell counts may be due to MPNs, but they may also be due to a variety of other temporary or chronic conditions. Other testing is usually done to confirm or rule out the diagnosis of an MPN.
Bone marrow aspiration/biopsy
If a bone marrow disorder is suspected, a healthcare practitioner may order a bone marrow aspiration or biopsy to collect a small sample of marrow. When a specialist (a pathologist, oncologist, or hematologist) examines the bone and fluid portion of the bone marrow sample under the microscope, the type, number and appearance of various cells can be assessed and, if present, overgrowth of certain types of cells, fibrosis, and tumors can be determined. Most bone marrow disorders can be revealed during this examination, but further testing may be necessary to confirm a diagnosis.
- Cytogenetic analysis involves microscopic examination of chromosomes in a blood or bone marrow sample. It may be used to look for chromosomal abnormalities associated with chronic myeloid (myelogenous) leukemia.
- Molecular testing for certain genetic mutations associated with MPNs is an important tool for diagnosis and guiding treatment.
- BCR-ABL mutation test—a translocation in the BCR/ABL1 gene, present on the Philadelphia (Ph’) chromosome, is associated with chronic myeloid (myelogenous) leukemia.
- JAK2 test—mutations are associated with polycythemia vera, essential thrombocythemia, and primary myelofibrosis.
- MPL test— mutations are associated with essential thrombocythemia and primary myelofibrosis.
- CALR test–mutations are associated with essential thrombocythemia and primary myelofibrosis.
Other tests that sometimes are ordered include:
- Arterial blood gases (ABGs). This test measures the amount of gases in the blood from an artery and may be done when polycythemia vera is suspected. Low levels of oxygen are associated with secondary polycythemia.
- Erythropoietin is a hormone that stimulates the bone marrow to produce RBCs. Very low or absent erythropoietin levels are associated with primary polycythemia. Normal or high levels are associated with secondary polycythemia.
X-rays and other imaging scans are sometimes used to look for signs of disease, such as masses of cells in the chest, spleen, or liver.
MPNs are usually not preventable or curable. The goals of MPN treatment are to slow the progression of the disease and to alleviate the symptoms and complications brought on by excessive, insufficient, and dysfunctional blood cell production. Specific treatment depends on the type of MPN, severity, and symptoms. The following are a few examples.
- For some, watchful waiting may be sufficient for several years. These patients will visit their healthcare practitioners regularly for monitoring and take aspirin to prevent blood clots.
- Phlebotomy is the procedure for taking blood from a vein. Therapeutic phlebotomy is a procedure similar to making a blood donation and may be use in MPN treatment for removing excess blood cells. For example, with polycythemia vera, frequent therapeutic phlebotomies may be used to decrease the number and volume of red blood cells in the blood. Once the number of RBCs have been lowered as close to normal limits as possible, the person is monitored and occasional therapeutic phlebotomies are used to keep the levels under control.
- Some medications can also reduce the volume of blood cells. An example is the mild chemotherapy drug hydroxyurea, which can be used to lower RBCs, white blood cells, and platelets.
- Transfusions are used to add healthy red blood cells or platelets to the bloodstream to replace those destroyed by disease or medicines.
- If the spleen is enlarged, it may be surgically removed. If surgery is not an option, radiation therapy may be directed at the spleen to kill abnormal blood cells.
- Chemotherapy, like that used for acute myeloid leukemia (AML), may be used to control production of abnormal blood cells, especially if the MPN reaches a phase called a “blast crisis” when there is an increase in the number of the abnormal blasts (cell precursors) in the bone marrow or blood.
- People with severe or advanced MPN may be treated with bone marrow transplantation known as hematopoietic cell transplantation. This is currently the only type of treatment that has the potential to cure MPN.
- Several targeted therapies are aimed at inhibiting the abnormal proteins related to genetic mutations in MPNs. For example, drugs called tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib) can target the abnormal BCR-ABL protein in chronic myeloid leukemia cells. Ruxolitinib inhibits the JAK2 protein and is used to treat intermediate to high risk primary myelofibrosis and myelofibrosis derived from preexisting polycythemia vera or essential thrombocythemia. Other types of targeted therapies are being explored in clinical trials.
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