Leukemias are cancers of white blood cells or of cells that develop into white blood cells.
White blood cells develop from stem cells in the bone marrow. Sometimes the development goes awry, and pieces of chromosomes get rearranged. The resulting abnormal chromosomes interfere with normal control of cell division, so that affected cells multiply uncontrollably and become cancerous (malignant), resulting in leukemia. Leukemia cells ultimately occupy the bone marrow, replacing or suppressing the function of cells that develop into normal blood cells. This interference with normal bone marrow cell function can lead to inadequate numbers of red blood cells (causing anemia), white blood cells (increasing the risk of infection), and platelets (increasing the risk of bleeding). Leukemia cells may also invade other organs, including the liver, spleen, lymph nodes, testes, and brain.
Leukemias are grouped into four main types
Acute lymphocytic leukemia
Acute myelocytic leukemia
Chronic lymphocytic leukemia
Chronic myelocytic leukemia
The types are defined according to how quickly they progress and the type and characteristics of the white blood cells that become cancerous. Acute leukemias progress rapidly and consist of immature cells. Chronic leukemias progress slowly and consist of more mature cells. Lymphocytic leukemias develop from cancerous changes in lymphocytes or in cells that normally produce lymphocytes. Myelocytic (myeloid) leukemias develop from cancerous changes in cells that normally produce neutrophils, basophils, eosinophils, and monocytes.
The cause of most types of leukemia is not known. Exposure to radiation, to some types of chemotherapy, or to certain chemicals (such as benzene) increases the risk of developing some types of leukemia, although leukemia develops only in a very small number of such people. Certain hereditary disorders, such as Down syndrome and Fanconi's syndrome, increase the risk as well. In some people, leukemia is caused by certain abnormalities of the chromosomes. A virus known as human T lymphotropic virus 1 (HTLV-1), which is similar to the virus that causes AIDS, is strongly suspected of causing a rare type of lymphocytic leukemia called adult T-cell leukemia. Infection with the Epstein-Barr virus has been associated with an aggressive form of lymphocytic leukemia called Burkitt's leukemia.
Many leukemias can be effectively treated, and some can be cured. When leukemia is under control, people are said to be in remission. If leukemia cells appear again, people are said to have a relapse. For some people in relapse, quality of life eventually deteriorates, and the potential benefit for further treatment may be extremely limited. Keeping people comfortable may become more important than trying to modestly prolong life. Affected people and their family members must be involved in these decisions. Much can be done to provide compassionate care, relieve symptoms (see Death and Dying: Quantity Versus Quality), and maintain dignity.
In myelodysplastic syndromes, a line of identical cells (clone) develops and occupies the bone marrow. These abnormal cells do not grow and mature normally. The cells also interfere with normal bone marrow function, resulting in deficits of red blood cells, white blood cells, and platelets. In some people, red blood cell production is predominantly affected. Myelodysplastic syndromes occur most often in people older than 50 years. Men are more than twice as likely as women to be affected.
The cause is usually not known. However, in some people, exposure of bone marrow to radiation therapy or certain types of chemotherapy drugs may play a role.
Symptoms develop very slowly. Fatigue, weakness, and other symptoms of anemia are common. Fever due to infections may develop if the number of white blood cells decreases. Easy bruising and abnormal bleeding can result if the number of platelets drops.
A myelodysplastic syndrome may be suspected when people have unexplained persistent anemia, but diagnosis requires a bone marrow biopsy.
People with myelodysplastic syndromes often need transfusions of red blood cells. Platelets are transfused only if people have uncontrolled bleeding, or if surgery is needed and the number of platelets is low. People who have very low numbers of neutrophils—the white blood cells that fight infection—may benefit from intermittent injections of a special type of protein called a colony-stimulating factor.
The drugs azacitidine Some Trade Names
and deoxyazacitidine can reduce the need for transfusions and prolonging survival, but they do not cure myelodysplastic syndromes. Allogeneic stem cell transplantation cures a few patients.
Although myelodysplastic syndromes are thought to be a type of leukemia, they progress gradually, over a period of several months to years. In 10 to 30% of people, a myelodysplastic syndrome transforms into acute myelocytic leukemia (AML). Treatment with chemotherapy during the early stages of a myelodysplastic syndrome does not help prevent transformation to AML. If transformation to AML occurs, chemotherapy may be helpful, but the AML is unlikely to be curable.
Acute Lymphocytic Leukemia (ALL)
Acute lymphocytic (lymphoblastic) leukemia is a life-threatening disease in which the cells that normally develop into lymphocytes become cancerous and rapidly replace normal cells in the bone marrow.
People may have symptoms, such as fever, weakness, and paleness, because they have too few normal blood cells.
Blood tests and a bone marrow biopsy are usually done.
Chemotherapy is given and is often effective.
Acute lymphocytic leukemia (ALL) occurs in people of all ages but is the most common cancer in children, accounting for 25% of all cancers in children younger than 15 years. ALL most often affects young children between the ages of 2 and 5 years. Among adults, it is somewhat more common in people older than 45.
In ALL, very immature leukemia cells accumulate in the bone marrow, destroying and replacing cells that produce normal blood cells. The leukemia cells are also carried in the bloodstream to the liver, spleen, lymph nodes, brain, and testes, where they may continue to grow and divide. They can irritate the layers of tissue covering the brain and spinal cord, causing inflammation (meningitis), and can cause anemia, liver and kidney failure, and other organ damage.
Acute Lymphocytic Leukemias (ALL)
Symptoms and Diagnosis
Early symptoms result from the inability of the bone marrow to produce enough normal blood cells. Fever and excessive sweating, which may indicate infection, result from too few normal white blood cells. Weakness, fatigue, and paleness, which indicate anemia, result from too few red blood cells. Easy bruising and bleeding, sometimes in the form of nosebleeds or bleeding gums, result from too few platelets. Leukemia cells in the brain may cause headaches, vomiting, and irritability, and leukemia cells in the bone marrow may cause bone and joint pain. A sense of fullness in the abdomen and sometimes pain can result when leukemia cells enlarge the liver and spleen.
Did You Know...
Nearly 80% of children with acute lymphocytic leukemia are cured.
Blood tests, such as a complete blood count (see Symptoms and Diagnosis of Blood Disorders: Complete Blood Count), can provide the first evidence of ALL. The total number of white blood cells may be decreased, normal, or increased, but the number of red blood cells and platelets is almost always decreased. In addition, very immature white blood cells (blasts) are present in blood samples examined under a microscope. A bone marrow biopsy (see Symptoms and Diagnosis of Blood Disorders: Bone Marrow Examination) is almost always done to confirm the diagnosis and to distinguish ALL from other types of leukemia.
Before treatment was available, most people who had ALL died within 4 months of the diagnosis. Now, nearly 80% of children and 30 to 40% of adults with ALL are cured. For most people, the first course of chemotherapy brings the disease under control (complete remission). Children between the ages of 3 and 7 have the best prognosis. Children younger than 2 and older adults fare least well. The white blood cell count and particular chromosome abnormalities in the leukemia cells also influence outcome.
Chemotherapy is highly effective and is administered in phases. The goal of initial treatment (induction chemotherapy) is to achieve remission by destroying leukemia cells so that normal cells can once again grow in the bone marrow. People may need to stay in the hospital for a few days or weeks, depending on how quickly the bone marrow recovers. Blood and platelet transfusions may be necessary to treat anemia and to prevent bleeding, and antibiotics may be needed to treat bacterial infections. Intravenous fluids and therapy with a drug called allopurinol Some Trade Names
may also be used to help rid the body of harmful substances, such as uric acid, that are released when leukemia cells are destroyed.
One of several combinations of drugs is used, and doses are repeated for several days or weeks. One combination consists of prednisone (a corticosteroid) taken by mouth and weekly doses of vincristine (a chemotherapy drug) given with an anthracycline drug (usually daunorubicin Some Trade Names
), asparaginase Some Trade Names
, and sometimes cyclophosphamide Some Trade Names
, given intravenously. Other drugs are being investigated.
For treatment of leukemia cells in the layers of tissue covering the brain and spinal cord (the meninges), methotrexate Some Trade Names
, cytosine arabinoside, or both is usually injected directly into the cerebrospinal fluid. This chemotherapy may be given in combination with radiation therapy to the brain. Even when there is little evidence that the leukemia has spread to the brain, a similar type of treatment is usually given as a preventive measure because of the high likelihood of spread to the meninges.
A few weeks after the initial, intensive treatment, additional treatment (consolidation chemotherapy) is given to destroy any remaining leukemia cells. Additional chemotherapy drugs, or the same drugs as were used during the induction phase, may be used a few times over a period of several weeks. Further treatment (maintenance chemotherapy), which usually consists of fewer drugs, sometimes at lower doses, may continue for 2 to 3 years. For some people who are at high risk of relapse because of particular chromosomal changes found in their cells, stem cell transplantation (see Transplantation: Stem Cell Transplantation) during the first remission is often recommended.
Leukemia cells may begin to appear again (a condition termed relapse), often in the blood, bone marrow, brain, or testes. Reappearance in the bone marrow is particularly serious. Chemotherapy is given again, and although most people respond to treatment, the disease has a strong tendency to come back, especially in children younger than 2 and in adults. When leukemia cells reappear in the brain, chemotherapy drugs are injected into the cerebrospinal fluid 1 or 2 times a week. When leukemia cells reappear in the testes, radiation therapy is given along with chemotherapy.
For people who have relapsed, high doses of chemotherapy drugs along with allogeneic stem cell transplantation offers the best chance of cure. But transplantation can be done only if stem cells can be obtained from a person who has a compatible tissue type (HLA-matched). The donor is usually a sibling, but cells from matched, unrelated donors (or occasionally partially matched cells from family members or unrelated donors, as well as umbilical stem cells) are sometimes used. Stem cell transplantation is rarely used for people older than 65, because it is much less likely to be successful and side effects are much more likely to be fatal.
After relapse, additional treatment for people who are unable to undergo stem cell transplantation is often poorly tolerated and ineffective, frequently causing people to feel much sicker. However, remissions can occur. End-of-life care should be considered for people who do not respond to treatment (see Death and Dying: Introduction).
Acute Myelocytic Leukemia (AML)
Acute myelocytic (myeloid, myelogenous, myeloblastic, myelomonocytic) leukemia is a life-threatening disease in which the cells that normally develop into neutrophils, basophils, eosinophils, and monocytes become cancerous and rapidly replace normal cells in the bone marrow.
People may be tired or pale, easily susceptible to infection and fever, and bruise or bleed easily.
Blood tests and bone marrow examination are needed for diagnosis.
Treatment includes chemotherapy to achieve remission plus additional chemotherapy to avoid relapse.
Acute myelocytic leukemia (AML) is the most common type of leukemia among adults, although it affects people of all ages.
In AML, immature leukemia cells rapidly accumulate in the bone marrow, destroying and replacing cells that produce normal blood cells. The leukemia cells are released into the bloodstream and are transported to other organs, where they continue to grow and divide. They can form small masses (chloromas) in or just under the skin or gums or in the eyes.
Acute promyelocytic leukemia is a subtype of AML. In this subtype, chromosomal changes in promyelocytes—cells that are at an early stage in the development into mature neutrophils—prevent binding and activity of vitamin A Some Trade Names
. Without vitamin A Some Trade Names
activity, normal cell maturation is disrupted, and abnormal promyelocytes accumulate.
Acute Myelogenous Leukemias (AML)
Symptoms and Diagnosis
The first symptoms of AML are very similar to those of acute lymphocytic leukemia (see Leukemias: Acute Lymphocytic Leukemia (ALL)). Although meningitis occurs less often than in acute lymphocytic leukemia, AML cells can cause inflammation of the layers of tissue covering the brain and spinal cord (meninges).
The diagnosis of AML is also similar to that of acute lymphocytic leukemia. A bone marrow biopsy (see Symptoms and Diagnosis of Blood Disorders: Bone Marrow Examination) is almost always done to confirm the diagnosis and to distinguish AML from other types of leukemia.
Without treatment, most people with AML die within a few weeks to months of the diagnosis. With therapy, between 20% and 40% of people survive at least 5 years, without any relapse. Because relapses almost always occur within the first 5 years after initial treatment, most people who remain leukemia-free after 5 years are considered cured. People who have the poorest prognosis are those older than 60, those who develop AML after undergoing chemotherapy and radiation therapy for other cancers, and those whose leukemia evolved slowly after a period of months to years of abnormal blood counts.
Treatment is aimed at bringing about prompt remission—the destruction of all leukemia cells. However, AML responds to fewer drugs than does acute lymphocytic leukemia. In addition, treatment often makes people sicker before they get better, because the treatment suppresses bone marrow activity, resulting in fewer white blood cells, particularly neutrophils. Having too few neutrophils makes infection likely. Meticulous care is taken to prevent infections, and any that occur are promptly treated. Red blood cell and platelet transfusions are invariably also needed.
The first course of drug treatment (induction chemotherapy) generally includes cytarabine for 7 days by a continuous infusion and daunorubicin Some Trade Names
(or idarubicin or mitoxantrone Some Trade Names
) for 3 days.
Once AML is in remission, people usually receive a few courses of additional chemotherapy (consolidation chemotherapy) a few weeks or months after the initial treatment to help ensure that as many leukemia cells as possible are destroyed. A preventive treatment to the brain usually is not needed, and long-term lower-dose chemotherapy (as is used in acute lymphocytic leukemia) has not been shown to improve survival.
People who have not responded to treatment and younger people who are in remission but who are likely to have a high rate of relapse (generally identified by certain chromosomal abnormalities) may be given high doses of chemotherapy drugs followed by stem cell transplantation (see Transplantation: Stem Cell Transplantation).
When relapse occurs, additional chemotherapy for people unable to undergo stem cell transplantation is less effective and often poorly tolerated. Another course of chemotherapy is most effective in younger people and in people whose initial remission lasted more than 1 year. Doctors take many factors into consideration when determining the advisability of additional intensive chemotherapy for people with AML in relapse. A newer drug, gemtuzumab ozogamicin Some Trade Names
, which combines an antibody with a chemotherapy drug as an attempt to specifically "target" the leukemia cells, is effective in some people after relapse has occurred. The long-term benefits of the drug have not been determined.
People with acute promyelocytic leukemia can be treated with a type of vitamin A Some Trade Names
called all-trans- retinoic acid Some Trade Names
. Results are best when chemotherapy is used also; currently more than 70% of people with acute promyelocytic leukemia can be cured. Arsenic chemical compounds are also uniquely effective in this subtype of AML.
Chronic Lymphocytic Leukemia (CLL)
Chronic lymphocytic leukemia is a disease in which mature lymphocytes become cancerous and gradually replace normal cells in lymph nodes.
People may have no symptoms or they may have general symptoms such as tiredness.
People may also have enlarged lymph nodes and a sense of abdominal fullness.
Blood tests and examination of a bone marrow sample are needed for diagnosis.
Treatment includes chemotherapy drugs, monoclonal antibodies, and sometimes radiation therapy.
More than three fourths of the people who have chronic lymphocytic leukemia (CLL) are older than 60, and the disease does not occur in children. This type of leukemia affects men 2 to 3 times more often than women. CLL is the most common type of leukemia in North America and Europe. It is rare in Japan and Southeast Asia, which indicates that heredity plays some role in its development.
The number of cancerous mature lymphocytes increases first in the blood and lymph nodes. They then spread to the liver and spleen, both of which begin to enlarge. Cancerous lymphocytes also invade the bone marrow, where they crowd out normal cells, resulting in a decreased number of red blood cells and a decreased number of normal white blood cells and platelets in the blood. The level of antibodies, proteins that help fight infections, also decreases. The immune system, which ordinarily defends the body against foreign organisms and substances, sometimes becomes misguided, reacting to and destroying normal body tissues. This misguided activity can sometimes result in the destruction of red blood cells and platelets.
In the great majority of cases, CLL is a disorder of B lymphocytes (B cells—see Biology of the Immune System: B Cells). There are other types of CLL other than B-cell CLL. Hairy cell leukemia, a slow-growing uncommon type of B-cell leukemia, produces a large number of abnormal white blood cells with distinctive hairlike projections that are visible under a microscope. T-cell leukemia (leukemia of T lymphocytes) is much less common than B-cell leukemia. Sézary syndrome is a rare type of T-cell leukemia in which cancerous T lymphocytes that start as a skin cancer called mycosis fungoides (see Lymphomas: Unusual Non-Hodgkin Lymphomas) grow and divide more rapidly and enter the bloodstream, becoming leukemia cells.
Did You Know...
Chronic lymphocytic leukemia does not occur in children.
Symptoms and Diagnosis
In early stages of CLL, most people have no symptoms, and the disease is diagnosed only because of an increased white blood cell count. Later symptoms may include enlarged lymph nodes, fatigue, loss of appetite, weight loss, shortness of breath when exercising, and a sense of abdominal fullness resulting from an enlarged spleen.
As CLL progresses, people may appear pale and bruise easily. Bacterial, viral, and fungal infections generally do not occur until late in the course of the disease.
Sometimes the disease is discovered accidentally when blood counts ordered for some other reason show an increased number of lymphocytes. A bone marrow biopsy is usually not needed to confirm the diagnosis because specialized tests to characterize the lymphocytes can be done on the cells in the blood. Blood tests also may show that the numbers of red blood cells, platelets, and antibodies are low.
Most types of CLL progress slowly. Doctors determine how far the disease has progressed (staging) to predict the survival time. Staging is based on factors such as the number of lymphocytes in the blood and bone marrow, size of the spleen and liver, presence or absence of anemia, and platelet count.
People who have B-cell leukemia often survive 10 to 20 years or longer after the diagnosis is made and usually do not need treatment in the early stages. People who are anemic or who have a low number of platelets need more immediate treatment and have a less favorable prognosis. Usually, death occurs because the bone marrow can no longer produce a sufficient number of normal cells to carry oxygen, fight infections, and prevent bleeding. The prognosis for people who have T-cell leukemia is usually worse.
For reasons probably related to changes in the immune system, people who have CLL are more likely to develop other cancers, such as skin or lung cancers. CLL can also transform into a more aggressive type of cancer of the lymphatic system (lymphoma).
Because CLL progresses slowly, many people do not need treatment for years—until the number of lymphocytes begins to increase, the lymph nodes begin to enlarge, or the number of red blood cells or platelets decreases.
Drugs, which include corticosteroids, chemotherapy drugs, and monoclonal antibodies, used to treat the leukemia itself help relieve symptoms and shrink enlarged lymph nodes and spleen but do not cure the disease. For B-cell CLL, initial drug treatment includes alkylating drugs such as chlorambucil Some Trade Names
, which kill cancer cells by interacting with their DNA, or a drug called fludarabine Some Trade Names
, which interferes with the cell's ability to make DNA. Either treatment can control CLL for months to many years and can be used again with success when the leukemia regrows. Sometimes fludarabine Some Trade Names
is given together with a chemotherapy drug and a monoclonal antibody. This combination therapy often is successful in inducing remission. Eventually CLL becomes resistant to these drugs, and sometimes treatments with other drugs or monoclonal antibodies (such as rituximab Some Trade Names
or alemtuzumab Some Trade Names
) are considered. For hairy cell leukemia, 2-chlorodeoxyadenosine Some Trade Names
and deoxycoformycin Some Trade Names
are highly effective and can control the disease for more than 15 years.
Anemia due to a decreased number of red blood cells is treated with blood transfusions and occasionally with injections of erythropoietin Some Trade Names
or darbepoietin (drugs that stimulate red blood cell formation). Low platelet counts are treated with platelet transfusions, and infections are treated with antibiotics. Radiation therapy is used to shrink enlarged lymph nodes or an enlarged liver or spleen if the enlargement is causing discomfort and chemotherapy is ineffective.
Chronic lymphocytic leukemias (CLL)
Chronic Myelocytic Leukemia (CML)
Chronic myelocytic (myeloid, myelogenous, granulocytic) leukemia is a disease in which cells that normally would develop into neutrophils, basophils, eosinophils, and monocytes become cancerous.
People pass through a phase in which they have nonspecific symptoms such as tiredness, anorexia, and weight loss.
As the disease progresses, the lymph nodes and spleen enlarge, and people may also be pale and bruise or bleed easily.
Blood tests, bone marrow examination, and chromosome analysis are needed for diagnosis.
Treatment is with imatinib Some Trade Names
or with high doses of chemotherapy drugs followed by stem cell transplantation.
Chronic myelocytic leukemia (CML) may affect people of any age and of either sex but is uncommon in children younger than 10 years. The disease most commonly develops in adults between the ages of 40 and 60. The cause usually is a rearrangement of two particular chromosomes into what is called the Philadelphia chromosome. The Philadelphia chromosome produces an abnormal enzyme (tyrosine kinase), which is responsible for the abnormal growth pattern of the white blood cells in CML.
In CML, most of the leukemia cells are produced in the bone marrow, but some are produced in the spleen and liver. In contrast to the acute leukemias, in which large numbers of immature white blood cells (blasts) are present, the chronic stage of CML is characterized by marked increases in the numbers of normal-appearing white blood cells and sometimes platelets. During the course of the disease, more and more leukemia cells fill the bone marrow and others enter the bloodstream.
Eventually the leukemia cells undergo more changes, and the disease progresses to an accelerated phase and then inevitably to blast crisis. In blast crisis, only immature leukemia cells are produced, a sign that the disease has become much worse. Massive enlargement of the spleen is common in blast crisis, as well as fever and weight loss.
Symptoms and Diagnosis
Early on, in its chronic stage, CML may produce no symptoms. However, some people become fatigued and weak, lose their appetite, lose weight, develop a fever or night sweats, and notice a sensation of being full—which is usually caused by an enlarged spleen. As the disease progresses to blast crisis, people become sicker because the number of red blood cells and platelets decreases, leading to paleness, bruising, and bleeding.
Chronic Myelogenous Leukemias (CML)
The diagnosis of CML is suspected based on the results of a simple blood test. The test may show an abnormally high white blood cell count. In blood samples examined under a microscope, less mature white blood cells, normally found only in bone marrow, are seen.
Tests that analyze chromosomes (cytogenetics or molecular genetics) are needed to confirm the diagnosis by detecting the Philadelphia chromosome.
Prognosis and Treatment
Although most treatments do not cure the disease, they do slow its progress. The drug imatinib Some Trade Names
and similar newer drugs block the abnormal enzyme produced by the Philadelphia chromosome. These drugs are more effective than other treatments and cause only minor side effects. With imatinib Some Trade Names
therapy, taken by mouth, survival is over 90% at 5 years past diagnosis.
Stem cell transplantation (see Transplantation: Stem Cell Transplantation) combined with high doses of chemotherapy drugs may cure CML. However, only certain people can have transplantation. Stem cells must come from a donor who has a compatible tissue type, usually a sibling. Transplantation is most effective during the early stage of the disease and is considerably less effective if the CML is rapidly progressing or there is a blast crisis.
People in a blast crisis live only a few months without treatment. Treatment with imatinib Some Trade Names
plus chemotherapy drugs sometimes extends survival to 12 months or more. There are also older chemotherapy regimens that can be given to people who relapse after receiving imatinib Some Trade Names
or who have CML without a Philadelphia chromosome. The main drugs used are busulfan Some Trade Names
, hydroxyurea Some Trade Names
, and interferon. None of these drugs prolongs survival but, they may help relieve symptoms.