What are myeloproliferative neoplasms?
Myeloproliferative neoplasms (MPNs) are a subset of bone marrow disorders. They are a group of diseases characterised by an overproduction of one or more types of blood cells in the bone marrow.
Bone marrow is a soft fatty tissue that is located in the centre of the body's larger bones. It has a honeycomb or sponge-like structure, consisting of a highly organised 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 maturity.
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, becoming the 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, excessive production of a cell's precursor leads to an increased number of that type of mature cell and to a corresponding increase or decrease in the number of other blood cells, which may be inhibited and crowded out. This results in symptoms related to blood cell overproduction, underproduction and dysfunction throughout the body.
The common types of MPNs include:
- Chronic myeloid leukaemia (CML), a disease that leads to an overproduction of of granulocytes. Granulocytes are white blood cells that digest and kill invading microorganisms. In its early stages, CML results in an increase in the numbers of granulocytes (both mature and immature) and platelets in the blood, but these cells may still be functional and a person may have no obvious symptoms. Without treatment, however, CML starts to behave like other leukaemias.
- Polycythaemia vera (PV), a disease in which too many red blood cell precursors and erythrocytes (red blood cells) are made in the bone marrow, independent of the mechanisms that normally regulate red blood cell production. When RBCs build up in the blood stream, the blood becomes thicker and does not flow smoothly in the blood vessels, causing clinical symptoms such as headache, dizziness, visual disturbance, and even excessive clotting which may lead to symptoms such as heart attack. Polycythaemia vera is also called primary polycythaemia (neoplastic). There are a variety of other factors that can cause increased red blood cell production; for instance, long-term exposure to low concentrations of oxygen (e.g. living at high altitude). These increases in RBCs are referred to as secondary polycythaemia (reactive).
- Primary myelofibrosis (PMF, also known as chronic idiopathic myelofibrosis and agnogenic myeloid metaplasia) is a disease characterised by proliferation of predominantly megakaryocytes and granulocytes . The fully developed disease is associated with a reactive production of fiber-producing cells, leading to fibrous tissue being laid down in the marrow. The dense network of fibre impairs bone marrow function and blood cell production and can lead to production of blood cells outside of the bone marrow, such as in the spleen (so-called extramedullary haematopoiesis 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 anaemia.
- Essential Thrombocythaemia (ET), characterised by an increased number of megakaryocytes, precursor to platelets (also called thrombocytes), in the bone marrow as well as sustained and dramatic increase 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. This can lead to strokes or heart attacks. However, the platelets may not function normally and this can lead to bleeding. Essential thrombocythaemia must be distinguished from secondary or reactive thrombocytosis, increased numbers of platelets caused by non-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 alleviated. For each MPN, there is a slight chance that the disease will develop into an acute leukaemia. If this occurs, the course of the disease will be accelerated, the symptoms will intensify, and more aggressive treatment will be required.
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 during a routine physical. While each condition has its own set of symptoms, some symptoms are common to more than one. They include:
- Weight loss
- Weakness and fatigue
- Enlargement of the 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.
- Bleeding and bruising, due to insufficient and/or abnormal platelets
- Night sweats
- Bone and joint pain
- Pallor due to anaemia (eg in myelofibrosis when red blood cells are decreased, not increased)
- Frequent infections
- Headache, dizziness, numbness and/or visual disturbance due to thicker blood or inappropriate clotting
In someone with polycythemia vera, the excess number of RBCs increases the volume and thickness (viscosity) of the blood. This can cause symptoms such as headaches, dizziness, visual distortion, itching, and paraesthesia. Sometimes the excessive RBCs may lead to complications, such as stomach ulcers, kidney stones, venous thrombosis, stroke, and rarely to congestive heart failure.
People with polycythaemia vera or primary thrombocythemia, especially if they are older than 60, may have disease progression and develop myelofibrosis, in which fibrous tissue replaces bone marrow that is similar to that seen in primary myelofibrosis. It 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 splenomegaly. Fibrous tissue eventually fills the bone marrow, reducing the production of all blood cells. Anaemia may become severe.
Most people with essential thrombocythaemia are asymptomatic, but some develop thrombosis or haemorrhage because of increased numbers of dysfunctional platelets. This may cause tingling in the hands and feet, headaches, weakness, dizziness, nosebleeds, and easy bruising.
Laboratory Tests
Full blood count (FBC) and differential
FBCs and differentials are the most frequently ordered tests 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. They also provide information about the size, shape, and relative maturity of the blood cells present in a person's blood at that moment.
FBCs and differentials can be used to detect WBC, RBC, and platelet increases, decreases, and abnormalities. They can help determine their severity, diagnose their cause, monitor the course of a disease, and monitor the response to treatment.
With polycythaemia 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 thrombocythaemia, 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 and to determine if fibrosis is present.
Bone marrow aspiration/biopsy
If a bone marrow disorder is suspected, a doctor may order a bone marrow aspiration and biopsy to collect a small sample of marrow. When a specialist (a haematopathologist) 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 tumours can be determined. Most bone marrow disorders can be revealed during this examination, but further testing may be necessary to confirm a diagnosis.
Other tests that sometimes are requested include:
- Blood oxygen saturation or Arterial blood gases (ABGs). This test measures the amount of gases in the blood and may be done when polycythaemia vera is suspected. Low levels of oxygen are associated with secondary polycythemia.
- Erythropoietin is a hormone that stimulates the bone marrow to produce RBCs. With primary polycythaemia, erythropoietin levels will be very low or absent, but with secondary polycythaemia, they will be normal or high.
- Cytogenetic analysis and molecular testing may be used to help diagnose suspected MPNs. For example, genetic testing is used in suspected chronic myeloid leukaemia to check for the presence or absence of a Philadelphia (Ph') chromosome or a bcr-abl translocation (see BCR-ABL). If polycythaemia vera, primary myelofibrosis, or essential thrombocythaemia is suspected, a doctor may order a test to check for JAK2 mutation (see JAK2), CAL-R or MPL mutation.
Non-laboratory Tests
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.
For some, watchful waiting may be sufficient for several years. These patients will visit their doctors regularly for monitoring and in some cases take aspirin to prevent blood clots.
Treatment may include removal of the volume of problematic blood cells. For example, with polycythaemia vera, frequent phlebotomies, the removal of pints of blood, are used to decrease the number and volume of red blood cells in the blood. Once RBCs have been lowered as close to normal limits as possible, the person is monitored and occasional phlebotomies are used to keep the levels under control.
Some medications can also reduce the volume of problematic blood cells. These include the mild chemotherapy drug hydroxycarbamide, which can be used to lower RBCs, white blood cells, and platelets. Interferon-alpha, a human protein, can be used to lower all three types of blood cells, while anagrelide, lowers the platelet count.
In advanced disease and when the bone marrow doesn't produce enough healthy blood cells, steps may be recommended to reduce symptoms caused by low levels of blood cells, known as supportive care. These steps may include transfusions and medicines, including the growth factor erythropoietin (EPO) to increase red blood cells, the growth factor granulocyte colony-stimulating factor (G-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) to increase white blood cells, and antibiotics and antiviral drugs that fight infections when white blood cells cannot fight on their own.
Transfusions are used to add red blood cells or platelets to the bloodstream if medicines do not increase a person's levels enough and if the patient develops anaemia.
Chemotherapy, like that used for acute myelogenous leukaemia (AML), may be used to control production of abnormal blood cells, especially if MPN reaches a phase called a "blast crisis" when there is an increase in the number of the abnormal stem cells in the bone marrow or blood.
People with severe or advanced MPN may be treated with bone marrow transplantation known as haematopoietic cell transplantation. This is currently the only type of treatment that has the potential to cure MPN. MPN patients receive allogeneic transplants, or stem cells from a donor, preceded by chemotherapy to kill diseased stem cells in their marrow. A transplant is not appropriate for everyone. For instance, a transplant may be too difficult for older people to tolerate, especially if they have other health problems besides MPN.
Several novel treatments aimed at inhibiting the abnormal proteins related to genetic mutations in MPNs have been developed. For example, a few drugs called tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib) can target the abnormal BCR-ABL protein in chronic myeloid leukaemia cells and have produced a high rate of remission in most patients, meaning no detectable disease on continuous drug treatment. These drugs are now the standard treatment for patients with chronic myeloid leukemia. Ruxolitinib inhibits the JAK2 protein and is used to treat intermediate to high risk primary myelofibrosis and myelofibrosis derived from pre-existing polycythaemia vera or essential thrombocythaemia.