Leukemia is a disease of the blood-forming organs. Primary tumors are found in the bone marrow and lymphoid tissues, specifically the liver, spleen, and lymph nodes. The characteristic common to all types of leukemia is the uncontrolled proliferation of leukocytes (white blood cells) in the blood stream. This results in a lack of normal bone marrow growth, and bone marrow is replaced by immature and undifferentiated leukocytes or “blast cells.” These immature and undifferentiated cells then migrate to various organs in the body, resulting in the pathogenesis of normal organ development and processing.
Leukemias are categorized as acute leukemia and chronic leukemia.
Leukemia occurs with varying frequencies at different ages, but it is most frequent among the elderly. Acute lymphoblastic leukemia, most common in children, is responsible for two-thirds of all cases. Acute nonlymphoblastic leukemia and chronic lymphocytic leukemia are most common among adults. While there is clear evidence that some leukemias are linked to genetic traits, environmental exposure to radiation, toxic substances, and other risk factors plays an important role in manifesting some leukemias.
Medical science classifies acute leukemia by the type of white blood cell that undergoes mutation. The most common of these are:
Acute leukemias progress rapidly, while the chronic leukemias progress more slowly. The vast majority of the childhood leukemias are of the acute form.
Chronic leukemia is a type of cancer in which excessive quantities of abnormal white blood cells are produced, usually slowly, often over a period of years.
Chronic leukemia is classified by the type of white blood cell that undergoes mutation. The most common of these are:
Chronic leukemias are typically much less rapid-growing than acute leukemia, and affect adults far more often than children. In fact, nearly all the people who develop CLL are over 50 years of age. CML is also a disease primarily of middle-aged to elderly people, but 3% of all childhood leukemias are classified as CML, and the average age for developing CML in children is between ages 10 and 12 years.
The cells found in the blood include red blood cells (RBCs) that carry oxygen and other materials to all tissues of the body; white blood cells (WBCs) that fight infection; and platelets, which play an important role in the clotting of the blood. White blood cells can be further subdivided into three main types: granulocytes, monocytes, and lymphocytes.
The granulocytes, as their name suggests, have particles (granules) inside them. These granules contain special proteins (enzymes) and several other substances that can break down chemicals and destroy microorganisms, such as bacteria. Monocytes are the second type of white blood cell. They are also important in defending the body against pathogens.
Lymphocytes are the third type of white blood cell. There are two primary types of lymphocytes—T lymphocytes and B lymphocytes—with different functions in the immune system. B cells protect the body by making antibodies. Antibodies are proteins that can attach to the surfaces of bacteria and viruses. This “attachment” sends signals to many other cell types to come and destroy the antibody-coated organism. T cells protect the body against viruses. When a virus enters a cell, it produces certain proteins that are projected onto the surface of the infected cell. T cells recognize these proteins and make certain chemicals that are capable of destroying the virus-infected cells. In addition, T cells can destroy some types of cancer cells.
Bone marrow makes stem cells, which are the precursors of the different blood cells. These stem cells mature through stages into RBCs, WBCs, or platelets. In acute leukemias, the maturation process of the white blood cells is interrupted. The immature cells (or “blasts”) proliferate rapidly and begin to accumulate in various organs and tissues, thereby affecting their normal function. This uncontrolled proliferation of the immature cells in the bone marrow affects the production of the normal red blood cells and platelets as well.
As noted, there are two major types of acute leukemias—acute lymphocytic leukemia and acute myelogenous leukemia. Different types of white blood cells are involved in the two leukemias. In acute lymphocytic leukemia (ALL), it is the T or the B lymphocytes that are involved. The B cell leukemias are more common than T cell leukemias. Acute myelogenous leukemia, also known as acute nonlymphocytic leukemia (ANLL), is a cancer of the monocytes and/or granulocytes.
Different types of white blood cells are involved in chronic lymphocytic leukemia and chronic myeloid leukemia. Although some blasts, or immature cells (the hallmark of acute leukemia), are also present in chronic leukemia, it is the T or B lymphocytes that gradually mutate and become cancerous. The scenario is similar for chronic myelogenous leukemia, also known as chronic granulocytic leukemia (CGL), which occurs when unusually large numbers of granulocytes begin to appear in the bloodstream.
Leukemias account for 2% of all cancers. According to the estimates of the American Cancer Society (ACS), approximately 50,000 new cases of leukemia are diagnosed each year in the United States. Of these, new cases most will be diagnosed in adults.
About 6,000 new cases of ALL in children and adults were anticipated to be diagnosed in the United States in 2018. Two of every three cases of ALL in the U.S. are diagnosed in children, in particular children under the age of five years. Most of the 1,500 deaths from ALL that occur each year in the United States occur in adults.
AML is diagnosed more frequently than ALL with approximately 20,000 new cases of AML reported annually in the U.S. AML is observed much more commonly in adults than in children. Most of the 11,000 annual deaths that occur from AML occur in adults. AML is not commonly diagnosed in individuals under age 40 years; the average age at time of diagnosis is 67 years.
However, leukemias, especially chronic leukemia, affect far more adults than children. Half of all leukemia cases occur in people who are 60 years of age or older, and the overwhelming majority of chronic leukemias occur in adults. The incidence of chronic leukemias varies among the major types. CLL, which account for about one-third of all leukemias, is diagnosed most often with about 16,000 new cases of CLL occurring each year. The average age at time of diagnosis of CLL is 72 years. About 5,500 new cases of CML are diagnosed annually. CMML is a rarer form of chronic leukemia; only about 1,000 new cases are diagnosed each year in the United States.
Leukemia is the most common form of childhood cancer, and it is often regarded as a disease of childhood However, leukemias, especially chronic leukemia, affect far more adults than children.
Leukemia affects both sexes and all ages. The human T-cell leukemia virus (HTLV-I), a virus with similarities to the human immunodeficiency virus (HIV), is believed to be the causative agent for some kinds of leukemias in some areas of the world including Japan and the Caribbean.
ACUTE LEUKEMIA. The cause of most leukemias is not known. However, a history of smoking is a proven life-style related risk factor for the development of AML.
Acute lymphoid leukemia (ALL) is more common among Caucasians than among African-Americans, while acute myeloid leukemia (AML) affects both races equally. The incidence of acute leukemia is slightly higher among men than women. A higher incidence of leukemia has also been observed among persons with Down syndrome and some other genetic abnormalities. Having a sibling with leukemia may increase risk for the development of childhood ALL especially in identical twins. The risk for developing ALL is an identical twin develops the disease is as high as 1 in 5.
Exposure to ionizing radiation, such as occurred in Japan after the atomic bomb explosions, has been shown to increase the risk of getting leukemia. Exposure to certain organic chemicals, such as benzene, is linked to the development of leukemia. Having a history of diseases that damage the bone marrow, such as aplastic anemia, or a history of treatment with some types of chemotherapy and radiation therapy for cancers of the lymphatic system puts people at a high risk for developing acute leukemias. Similarly, the use of immunosuppressants especially in organ transplant patients, is considered a risk factor for developing acute leukemias.
CHRONIC LEUKEMIA. As stated earlier, the cause of most leukemias is not known. Patients with chronic myeloid leukemia often show a chromosome abnormality called the Philadelphia chromosome that occurs when one chromosome attaches to another.
In 2003, the Institute of Medicine (IOM) released a report based upon scientific studies that found “sufficient evidence of an association” between CLL and exposure to herbicides during the Vietnam War. This report came from a Veterans Administration (VA) request to IOM to explore some similarities between CLL and non-Hodgkin's lymphoma. Non-Hodgkin's lymphoma has already been linked to Agent Orange exposure and is recognized by VA as a presumptive condition.
The symptoms of leukemia are generally vague and non-specific. A patient may experience all or some of the following symptoms:
Chronic leukemias may go for years without manifesting any symptoms at all, but also can develop symptoms similar to acute leukemias. Chronic myeloid leukemia, in particular, has two phases, a chronic one that can last for several years, and a malignant phase in which immature granulocytes are suddenly generated in huge numbers, producing similar symptoms to acute leukemia.
The doctor may perform a bone marrow biopsy to confirm the diagnosis of leukemia. During the biopsy, a cylindrical piece of bone and marrow is removed. The tissue is generally taken out of the hipbone. These samples are sent to the laboratory where they are examined under a microscope by a hematologist, oncologist, or pathologist. In addition to the diagnostic biopsy, another biopsy will also be performed during the treatment phase of the disease to see if the leukemia is responding to therapy.
A spinal tap (lumbar puncture) is another procedure that the doctor may order to diagnose leukemia. In this procedure, a small needle is inserted into the spinal cavity in the lower back to withdraw some cerebrospinal fluid and to look for leukemic cells.
Standard imaging tests, such as x rays, computed tomography scans (CT scans), and magnetic resonance imaging (MRI) may be used to check whether the leukemic cells have invaded other areas of the body, such as the bones, chest, kidneys, abdomen, or brain.
Testing such as flow cytometry, cytogenetic testing and immunocytochemistry may be ordered to help determine treatment options and may provide insight into the patient's prognosis.
Cytogenetic analysis includes fluorescent in situ hybridization (FISH) and/or polymerase chain reaction (PCR) testing. These tests use blood and/or bone marrow samples to detect an abnormal chromosome, known as the Philadelphia chromosome, which is present in some patients with acute leukemia.
There are often no symptoms present for chronic leukemia, and there are no screening tests available. If the physician has reason to suspect leukemia, a very thorough physical examination will be conducted to look for enlarged lymph nodes in the neck, underarm, and pelvic region. Swollen gums, enlarged liver or spleen, bruises, or pinpoint red rashes all over the body are some of the signs of leukemia. Urine and blood tests may be ordered to check for microscopic amounts of blood in the urine and to obtain a complete differential blood count, which gives the numbers and percentages of the different cells found in the blood. An abnormal blood test might suggest leukemia. However, the diagnosis has to be confirmed by more specific tests.
Lab tests which may be ordered for patients with a suspected diagnosis of CLL include a complete blood count (CBC) with differential, and tests to determine renal and liver function. Testing may be done to determine if the abnormal proteins ΖAP-70 and CD38 are present in the patient's blood. Patients with CLL with lower concentrations of these proteins in the blood typically exhibit a better overall prognosis. A blood test for hepatitis B may be ordered if the patient is to be treated with the monoclonal antibody Rituxan. Immunoglobulin testing may be ordered to determine if the patient has enough antibodies to fight infection. Elevated Beta-2-macroglobulin blood test results may indicate a more advanced form of CLL. Testing such as flow cytometry, cytogenetic testing and immunocytochemistry may be ordered to help determine treatment options and may provide insight into the patient's prognosis.
Cytogenetic testing done to diagnose CML includes fluorescent in situ hybridization (FISH) and/or polymerase chain reaction (PCR) testing. These tests use blood and/or bone marrow samples to detect the abnormal chromosome, known as the Philadelphia chromosome, which is present in many patients with CML. If the presence of the Philadelphia chromosome cannot be confirmed, the tests may be used to detect the BCR-ABL oncogene in leukemic cells which is a confirmation of a diagnosis of CML. PCR testing may be conducted during and after treatment for CML to monitor response to treatment.
The physician may perform a bone marrow biopsy, during which a small piece of bone and marrow is removed, generally taken from hipbone. A spinal tap (lumbar puncture) is another procedure that may be ordered. In this procedure, a small needle is inserted into the spinal cavity in the lower back to withdraw some cerebrospinal fluid and to look for leukemic cells. Lumbar puncture is not typically ordered in patients with a diagnosis of CLL unless metastasis to the brain or spinal fluid is suspected in rare cases.
Standard imaging tests such as x rays, computed tomography (CT) scans, and magnetic resonance imaging (MRI) may be used to check whether the leukemic cells have invaded other areas of the body, such as the bones, chest, kidneys, abdomen, or brain. A gallium scan, or bone scan, is a test in which a radioactive chemical is injected into the body. The chemical accumulates in the areas of cancer or infection, allowing them to be viewed with a special camera.
As noted, treatment must be started as soon as possible. The goal of treatment is remission, or an arresting of the disease process of the leukemia. Some newly diagnosed acute leukemia patients may need supportive care prior to the initiation of treatment for the leukemia. This may include the administration of antibiotics and growth factors as well as transfusions of platelets and blood.
TREATMENT OF ALL IN ADULTS. The treatment of ALL in adults with chemotherapy is conducted over three distinct phases: remission induction, consolidation (which may also be referred to as intensification), and maintenance therapy. Combination chemotherapy is administered in cycles of active treatment followed by rest periods which may last 2 years. Chemotherapy is given primarily intravenously. If leukemia is suspected in the brain or in spinal fluid, chemotherapy may be given via the intrathecal route. The specific chemotherapy agents used to treat adult AML are comparable to the agents used to treat pediatric ALL.
About 25% of adults with AML have leukemic cells with the Philadelphia chromosome. These patients are able to be treated with tyrosine kinase inhibitors which target the abnormal chromosome specifically. The TKIs used in the treatment of adult ALL include imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna). The TKIs are oral preparations with a less severe side effect profile as compared to chemotherapy.
As in the treatment of childhood ALL, external beam radiation therapy may be used to treat areas of the body such as the brain, spinal column, and testicles suspected of harboring leukemic cells. Total body irradiation may also be used in preparation for a stem cell transplant procedure in some patients with ALL.
Some adult patients with ALL may be candidates for allogeneic or autologous stem cell transplant which is preceded by high dose chemotherapy and/or radiation therapy. There are many immediate and short-term side effects associated with this form of treatment which may not be covered by insurance.
Most patients with ALL, about 80–90%, are able to achieve a complete remission with treatment. However, the relapse rate after treatment remains high and is about 50%.
TREATMENT OF AML IN ADULTS. Treatment of AML is determined by the subtype of the leukemia.
AML tends to be a very aggressive, rapidly progressive disease without therapy. Therefore, the goal is to initiate treatment as soon as possible after the diagnosis of a subtype. As with other forms of acute leukemia, combination chemotherapy is the cornerstone of treatment. There are two phases of treatment with chemotherapy for most patients: induction and consolidation. Patients diagnosed with some subtypes may require a third phase as well which is the maintenance phase. The chemotherapy agents most commonly used to treat adult AML are cytarabine and anthracyline drugs such as daunorubicin, daunomycin, idarubicin, and/or mitoxantrone.
External beam radiation therapy may be used to treat areas of the body such as the brain, spinal column, and testicles suspected of harboring leukemic cells. Total body irradiation may also be used in preparation for a stem cell transplant procedure in some patients with AML.
High dose chemotherapy followed by bone marrow transplant or peripheral blood stem cell transplant may be a treatment option for those patients diagnosed with AML who require higher doses of chemotherapy to effectively treat their leukemia.
The need for treatment is assessed according to the degree of enlargement of the liver and spleen, a serious decline in the number of platelets in the blood, and whether or not anemia is present, and if present, how severe. Once no leukemic cells are detected in blood tests and bone marrow biopsies, the patient is said to be in remission.
TREATMENT OF CLL. Patients with CLL who are considered to be in low risk groups may not require active treatment. However, these patients do require close surveillance and follow-up. Treatment will be initiated should symptoms progress to indicate a more active form of the disease. Even with treatment, there is no current cure for CLL, and many patients will experience relapse of the disease after treatment.
Patients with CLL may be treated with chemotherapy drugs classified as purine analogs, including the drugs:
Treatment with monoclonal antibodies has become standard treatment for many patients with CLL. The antibody rituximab (Rituxan), which is administered intravenously, can be used alone or in combination with chemotherapy agents. The drug alemtuzumab (Campath) may also be used to treat CLL. The newer monoclonal antibody ofatumumab (Arzerra) may be used in patients who have not responded to treatment with chemotherapy or to treatment with Campath.
Radiation therapy is not usually used in the treatment of CLL. Radiation therapy may be administered to patients who are experiencing symptoms from enlarged internal organs such as the spleen or to treat pain from bone damaged by leukemic cells. Total body irradiation may be ordered for patients who are scheduled to undergo stem cell transplantation.
Effectiveness of bone marrow transplant or PBSCT to treat CLL has not yet been determined. This option may be used in patients enrolled as part of a clinical trial.
TREATMENT FOR CML. There are three major phases of CML
Release of the drug imatinib (Gleevec) in 2001 revolutionized the treatment of CML. Imatinib specifically targets the abnormal BCR-ABL protein produced in CML. BCR-ABL is a tyrosine kinase. Imatinib and other similar drugs in its classification are known as tyrosine kinase inhibitors (TKIs). These drugs work best in the chronic phase of the disease. They do not cure CML but can control the disease for many years for most patients. Imatinib is an oral preparation and must be taken indefinitely or until it is no longer effective. The drug is associated with some mild side effects and there are many drug interactions associated with Imatinib. Some patients do develop a resistance to the effects of the drug and may be switched to a different TKI an attempt to overcome the resistance to the effects of the drug.
Second generation TKIs include dasatinib (Sprycel) and nilotinib (Tasigna). Both were in 2012 considered as first-line therapies for the treatment of CML.
Immunotherapy using interferon-alpha therapy may be ordered for some patients with CML. Interferon was much more widely used before the advent of the TKIs. This therapy has a significant side-effect profile.
Like interferon therapy, chemotherapy is used infrequently to treat CML since the release of the TKIs. Chemotherapy agents which may be ordered include hydroxyurea (Hydrea), an oral preparation, and cytarabine (Ara-C), busulfan, cyclophosphamide (Cytoxan), and vincristine (Oncovin).
Radiation therapy is not used in the treatment of CML. Radiation therapy may be used to treat pain from bone damaged by leukemic cells. Total body irradiation may be ordered for patients who are scheduled to undergo stem cell transplantation.
Now that many patients can be effectively treated long-term using TKIs, transplants are not used as frequently. However, allogeneic stem cell transplant remains the only proven option to cure CML. Transplants are usually offered as an option to younger individuals with a HLA matched donor, known as an allogeneic transplant, or to individuals whose CML is not responding to TKI. There are disadvantages to the transplant procedure including lengthy hospital stay, potential for long-term after effects associated with the transplant, and the expense of the procedure which may not be covered by insurance companies.
CHEMOTHERAPY. Treatment of childhood ALL includes administration of combination chemotherapy usually given in treatment cycles over 2 to 3 years. The goal is to induce and sustain a remission. A variety of chemotherapy drugs are availabe to effectively treat ALL in children:
RADIATION THERAPY. External beam radiation therapy may be used to treat areas of the body such as the brain, spinal column, and testicles suspected of harboring leukemic cells. Total body irradiation may also be used in preparation for a stem cell transplant procedure in some patients with ALL.
TARGETED THERAPY. A small percentage of children diagnosed with ALL have leukemic cells with the Philadelphia chromosome present. In clinical trials, these children have been treated with tyrosine kinase inhibitors (TKIs), such as imatinib (Gleevec) and dasatinib (Sprycel), with promising results observed to date.
HIGH DOSE CHEMOTHERAPY AND PERIPHERAL BLOOD STEM CELL TRANSPLANT. High dose chemotherapy and stem cell transplant may be a treatment option for some children who do not respond to chemotherapy or who experienced early relapse after treatment with standard chemotherapy for ALL. Transplant may also be indicated for the treatment of children diagnosed with rarer subtypes of ALL.
Local, state, and federal governmental and public health agencies often work in collaboration to pool resources to investigate instances of reported cancer case clusters. One recent example of a multi-agency public health response was reported by the Centers for Disease Control (CDC) in 2012. The CDC worked with the Nevada State Health Division and with researchers from St. Jude's Children's Hospital to investigate a cluster of childhood leukemia cases in Churchill County, Nevada. An epidemiological study was conducted to identify possible environmental exposures in Churchill County where 15 cases of childhood leukemia were diagnosed in the five-year period between 1997 and 2002.
As a result of the CDC investigation, it was found that residents in this county had higher urinary levels of the metals tungsten and arsenic as compared to urinary levels of these substances in the general U.S. population. However, the levels were comparable for families in Churchill County in which a case of childhood leukemia had been diagnosed and for families in which no case of leukemia was diagnosed.
Like all cancers, the prognosis for leukemia depends on the patient's age and general health as well as the specific type and subtype of leukemia with which they are diagnosed.
The cure rate for adults diagnosed with ALL is about 40% with higher cure rates noted in younger patients. Survival rates among younger adults, less than age 60 years at time of diagnosis, are also higher in AML. Approximately 30-35% of patients treated with current standard chemotherapy regimens survive longer than 5 years and are considered cured. Unfortunately only about 10% of adults over age 60 survive at least 5 years after diagnosis and treatment of AML.
The median survival for CML patients is 5 years and greater from time of diagnosis with a five-year survival rate of 50-60%. Some patients diagnosed with CLL will die rapidly within 2-3 years after diagnosis from the complications of the leukemia. Most patients with CLL, however, live 5 to 10 years after diagnosis and treatment.
Due to the new combinations of anticancer drugs being used, the survival rates among children with ALL have improved dramatically. Ninety-five percent of all childhood ALL patients will enter remission, and over 85% of pediatric ALL patients will remain in remission after five years, depending upon the type. The 5 year survival rate for childhood AML patients has increased in the last decade with the current 5 year survival rate at 60-70% depending on subtype.
Most cancers can be prevented by changes in lifestyle or diet, which will reduce the risk factors. As of 2012 there was no known way to prevent most leukemias from developing. However, there is a direct link between smoking and the development of AML. Individuals who smoke should be aware they are at higher risk for the development of AML. People who are at an increased risk for developing leukemia because of proven exposure to ionizing radiation or exposure to the toxic chemical benzene, and people with Down syndrome and other congenital and inherited disorders, should undergo periodic medical checkups.
See also Benzene ; Benzene and benzene derivatives exposure ; Radiation ; Viruses .
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American Society of Clinical Oncology, 2318 Mill Road, Suite 800, Alexandria, Virginia, United States, 22314, (571) 483-1300, http://www.asco.org .
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Melinda Granger Oberleitner, RN, DNS