Acute Lymphocytic Leukemia (ALL)

About 3,970 new cases of acute lymphocytic leukemia (ALL) are diagnosed each year in the United States. It is the most common type of leukemia under the age of 19. Children are most likely to develop the disease, but it can occur at any age. Acute lymphocytic leukemia may be called by several names, including acute lymphoid leukemia and acute lymphoblastic leukemia.

ALL results from an acquired (not inherited) genetic injury to the DNA of a single cell in the bone marrow. The disease is often referred to as acute lymphoblastic leukemia because the leukemic cell that replaces the normal marrow is the (leukemic) lymphoblast. The effects are: 1) the uncontrolled and exaggerated growth and accumulation of cells called "lymphoblasts" or "leukemic blasts," which fail to function as normal blood cells and 2) the blockade of the production of normal marrow cells, leading to a deficiency of red cells (anemia), platelets (thrombocytopenia), and normal white cells (especially neutrophils, i.e., neutropenia) in the blood. In most cases, the cause of acute lymphocytic leukemia is not evident. Few factors have been associated with an increased risk of developing the disease. Exposure to high doses of irradiation, as carefully studied in the Japanese survivors of atomic bomb detonations, is one such factor. Unlike other forms of leukemia, acute lymphocytic leukemia occurs at different rates in different locations. There are higher leukemia rates in more developed countries and in higher socioeconomic groups.

The current causes of acute lymphoblastic leukemia in children or adults are not known. Scientists continue to explore possible relationships with life-style or environmental factors but no firm conclusions have yet been reached. Given the amount of study, this suggests that multifaceted complex factors may be involved. It is extremely disconcerting to patients and their families to wonder what they may have done differently to avoid the disease. Unfortunately, at the present time there is no known way to prevent the disease. Acute lymphocytic leukemia occurs most often in the first decade of life but increases in frequency again in older individuals. Acute lymphocytic leukemia can develop from primitive lymphocytes that are in various stages of development.

The principal subtypes are uncovered by special tests on the leukemic lymphoblasts called "immunophenotyping." Phenotype is the physical characteristics of the cells and these are measured using immune tools. The subclassification of cell types is important since it helps to determine the best treatment to apply in each type of leukemia. The principle subtypes are T lymphocyte and B lymphocyte types, so named because the cell has features that are similar to normal T or B lymphocytes. In addition, the B cell type can be divided into a precursor B cell type, as well. Once these features are determined the term used may be acute T lymphoblastic leukemia or acute precursor (or pre) B cell lymphoblastic leukemia. Other markers on the lymphoblasts that can be detected with immunophenotyping and may be useful to the physician include the common acute lymphoblastic leukemia antigen, cALLa, now called CD 10.

Most patients feel a loss of well-being. They tire more easily and may feel short of breath when physically active. They may have a pale complexion from anemia. Signs of bleeding because of a very low platelet count may be noticed. These include black-and-blue marks occurring for no reason or because of a minor injury, the appearance of pinhead-sized, red spots under the skin, called petechiae, or prolonged bleeding from minor cuts. Discomfort in the bones and joints may occur. Fever in the absence of an obvious cause is common. Leukemic lymphoblasts may accumulate in the lymphatic system, and the lymph nodes can become enlarged. The leukemia cells can also collect on the lining of the brain and spinal cord and lead to headache or vomiting.

• Medical history and physical examination
• Complete blood counts
• Bone marrow examination
• Cytogenetics
• Immunophenotyping

To diagnose the disease, the blood and marrow cells must be examined. In addition to low red cell and platelet counts, examination of the stained (dyed) blood cells with a light microscope will usually show the presence of leukemic blast cells. This is confirmed by examination of the marrow which almost always shows leukemia cells. The blood and/or marrow cells are also used for studies of the number and shape of chromosomes (cytogenetic examination), immunophenotyping, and other special studies, if required.

Blood and bone marrow samples are used to diagnose and classify the disease. The following tests are used in the further classification of the disease. Examination of leukemic cells by cytogenetic techniques permits identification of chromosomes or gene abnormalities in the cells. The immunophenotyping and chromosome abnormalities in the leukemic cells are very important guides in determining the approach to treatment and the intensity of the drug combinations to be used. This is a laboratory test that enables the physician to determine the type of disease that is present in the patient. It uses the antigens (proteins) on the cell surface and the antibodies produced by the body that match the antigen.

A method that uses the reaction of antibodies with cell antigens to determine a specific type of cell in a sample of blood cells, marrow cells, or lymph node cells. The antibodies react with specific antigens on the cell. A tag is attached to an antibody so that it can be detected. The tag can be identified by the laboratory equipment used for the test. As cells carrying their array of antigens are tagged with specific antibodies they can be identified; for example, myelogenous leukemic cells can be distinguished from lymphocytic leukemic cells. Normal lymphocytes may be distinguished from leukemic lymphocytes. This method also helps to subclassify cell types, which may, in turn, help to decide on the best treatment to apply in that type of leukemia or lymphoma. The antigen on a cell is referred to as cluster of differentiation or "CD" with an associated number. For example, CD7 and 19 may be present on leukemic lymphoblasts and CD13 and 33 on leukemic myeloblasts.

Cytogenetic examination of tissue is the process of analyzing the number and shape of the chromosomes of cells. The individual, who prepares, examines and interprets the number and shape of chromosomes in cells is called a cytogeneticist. In addition to identifying chromosome alterations, the specific genes affected can be identified in some cases. These findings are very helpful in diagnosing specific types of leukemia and lymphoma, in determining treatment approaches, and in following the response to treatment.

The WBC's seen here are lymphocytes, but they are blasts--very immature cells with larger nuclei that contain nucleoli. Such lymphocytes are indicative of acute lymphocytic leukemia (ALL). ALL is more common in children than adults. Many cases of ALL in children respond well to treatment, and many are curable

Acute Myelogenous Leukemia (AML)

About 11,920 new cases of acute myelogenous leukemia are diagnosed each year in the United States. Acute myelogenous leukemia (AML) may be called by several names, including: acute myelocytic leukemia, acute myeloblastic leukemia, acute granulocytic leukemia or acute nonlymphocytic leukemia.

AML results from acquired (not inherited) genetic damage to the DNA of developing cells in the bone marrow. The effects are: 1) the uncontrolled, exaggerated growth and accumulation of cells called "leukemic blasts" which fail to function as normal blood cells and 2) the blockade of the production of normal marrow cells, leading to a deficiency of red cells (anemia), and platelets (thrombocytopenia) and normal white cells (especially neutrophils, i.e., neutropenia) in the blood. In most cases the cause of AML is not evident. Several factors have been associated with an increased risk of disease. These include:

• Exposure to high doses of irradiation, as carefully studied in the Japanese survivors of atomic bomb detonations
• Exposure to the chemical benzene, usually in the work place
• Exposure to chemotherapy used to treat cancers such as breast cancer, cancer of the ovary or the lymphomas. Alkylating agents and topoisosomerase inhibitors are most frequently associated with higher risk
• Therapeutic radiation, depending on the dose and setting

AML is not contagious and is not inherited. Uncommon genetic disorders such as Fanconi anemia, Schwachman-Diamond syndrome, Down syndrome and others are associated with an increased risk of AML. Older people are more likely to develop the disease. Very rarely, AML may occur in unexpectedly high frequencies in certain families. It is thought that these families transmit a susceptibility gene(s) to offspring through the germ-line. AML incidence increases dramatically among people who are over the age of 40. It is most prevalent in the sixth, seventh, eighth and ninth decades of life.

Leukemia is a malignant disease (cancer) of the bone marrow and blood. AML can occur in a variety of ways; different types of cells may be seen by the physician in blood or marrow. Since most patients have one of seven different patterns of blood cell involvement, these patterns have formed a sub classification which is shown in the table. If there are cells that are developing features of monocytes (monocytic type) or red cells (erythroleukemic), these designations are used and so forth. Even though the leukemia cells look somewhat like blood cells, the process of their formation is incomplete. Normal, healthy blood cells are insufficient in quantity.

The sub classification of the disease is important. Different types of therapy may be used and the likely course of the disease and prognosis may be different. Additional features may be important in guiding the choice of therapy, including: abnormalities of chromosomes, the cell immunophenotype, the age and the general health of the patient, and others. Most patients feel a loss of well-being. They tire more easily and may feel short of breath when physically active. They may have a pale complexion from anemia. Several signs of bleeding caused by a very low platelet count may be noticed. They include black-and-blue marks or bruises occurring for no reason or because of a minor injury, the appearance of pin-head sized spots under the skin, called petechiae, or prolonged bleeding from minor cuts. Mild fever, swollen gums, frequent minor infections like pustules or perianal sores, slow healing of cuts or discomfort in bones or joints may occur.

• Medical history and physical examination
• Complete blood counts
• Bone marrow examination
• Cytogenetic studies
• Immunophenotyping

To diagnose the disease the blood and marrow cells must be examined. In addition to low red cell and platelet counts, examination of the stained (dyed) blood cells with a light microscope will usually show the presence of leukemic blast cells. This is confirmed by examination of the marrow, which invariably shows leukemic blast cells. The blood and/or marrow cells are also used for studies of the number and shape of chromosomes (cytogenetic examination), immunophenotyping and other special studies, if required.

Blood and bone marrow aspirate are used for specific laboratory tests to diagnose and classify the disease. The following tests are used in the diagnosis of the disease. Examination of leukemic cells by cytogenetic techniques permits identification of chromosomes or gene abnormalities in the cells. The immunophenotype and chromosome abnormalities in the leukemic cells are very important guides in determining the approach to treatment and the intensity of the drug combinations to be used. This is a laboratory test that enables the physician to determine the type of disease that is present in the patient. It uses the antigens (proteins) on the cell surface and the antibodies produced by the body that match the antigen.

The method uses the reaction of antibodies with cell antigens to determine a specific type of cell in a sample of blood cells, marrow cells, or lymph node cells. The antibodies react with specific antigens on the cell. A tag is attached to an antibody so that it can be detected. The tag can be identified by the laboratory equipment used for the test. As cells carrying their array of antigens are tagged with specific antibodies they can be identified; for example, myelogenous leukemic cells can be distinguished from lymphocytic leukemic cells. Normal lymphocytes may be distinguished from leukemic lymphocytes. This method also helps to subclassify cell types, which may, in turn, help to decide on the best treatment to apply in that type of leukemia or lymphoma. The antigen on a cell is referred to as cluster of differentiation or "CD" with an associated number. For example, CD7 and 19 may be present on leukemic lymphoblasts and CD13 and 33 on leukemic myeloblasts.

Cytogenetic examination of tissue is the process of analyzing the number and shape of the chromosomes of cells. The individual, who prepares, examines and interprets the number and shape of chromosomes in cells is called a cytogeneticist. In addition to identifying chromosome alterations, the specific genes affected can be identified in some cases. These findings are very helpful in diagnosing specific types of leukemia, in determining treatment approaches and in following the response to treatment.

Chronic Myelogenous Leukemia (CML)

About 4,600 new cases of chronic myelogenous leukemia (CML) are diagnosed each year in the United States. Chronic myelogenous leukemia may be called by several names, including chronic granulocytic, chronic myelocytic or chronic myeloid leukemia.CML results from an acquired (not inherited) injury to the DNA of a stem cell in the marrow. This injury is not present at birth. Scientists do not yet understand what produces this change in the DNA in patients with CML. This change in the stem cell's DNA confers a growth and survival advantage on the malignant stem cell. The result of this injury is the uncontrolled growth of white cells leading, if unchecked, to a massive increase in their concentration in the blood. Unlike acute myelogenous leukemia (AML), chronic myelogenous leukemia permits the development of mature white blood cells that generally can function normally. This important distinction from acute leukemia accounts for the less severe early course of the disease. Most cases of chronic myelogenous leukemia occur in adults. Only 2.6 percent of leukemias in children ages 0-19 are CML. The frequency of the disease increases with age from about one in 1 million children in the first 10 years of life to nearly two in 100,000 people at age 50, to one in 10,000 people at age 80 and above . The disease in children is similar in behavior to that of adults; however, the outcome of stem cell transplantation is better in younger individuals.

Chronic myelogenous leukemia is distinguished from other leukemias by the presence of a genetic abnormality in blood cells, called the Philadelphia chromosome. The changes that result in this chromosome "causing" chronic myelogenous leukemia have been studied intensively. In 1960, two physicians studying chromosomes in cancer cells noticed that a chromosome in CML patients was shorter in length than that of the same chromosome in normal cells. They named this shortened chromosome the Philadelphia chromosome, because the observation was made at the University Of Pennsylvania School Of Medicine in that city. The total of 46 chromosomes in normal human cells is composed of 22 pairs of chromosomes numbered 1 to 22 and two sex chromosomes (either an X and Y in males or two X's in females). The Philadelphia chromosome (No. 22), which is an abnormally short chromosome, is usually referred to as the Ph-chromosome. Further studies established that two chromosomes, usually chromosome Nos. 9 and 22, were abnormal. Pieces of the chromosomes, which are broken off in the blood cells of patients with chronic myelogenous leukemia, switch with each other. The detached portion of chromosome 9 sticks to the broken end of chromosome 22, and the detached portion of chromosome 22 sticks to the broken end of chromosome 9. This abnormal exchange of parts of chromosomes is called a translocation. This translocation of chromosome pieces occurs only in the stem cell and in the various blood cells derived from that stem cell. The chromosomes of the cells in other tissues are normal.

The breakage on chromosome 9 disrupts a gene referred to as "ABL" (for Abelson). The breakage on chromosome 22 involves a gene referred to as "BCR" (for breakpoint cluster region). The human ABL gene is mutated by the breakage of chromosome 9. The mutated gene is translocated to chromosome 22 and fuses with the remaining part of the BCR gene. This fusion between BCR and ABL leads to an abnormal fused gene, called BCR-ABL. Despite these changes, the BCR-ABL gene can function. The function of a gene is to direct the production of a protein in the cell. In chronic myelogenous leukemia, the protein produced by the BCR-ABL gene is abnormal. The protein produced is an enzyme called tyrosine kinase. The ABL when fused to BCR results in an elongated protein when compared to the protein made by the normal ABL gene. This elongated protein (enzyme) functions abnormally and leads to dysfunctional regulation of cell growth and survival. Evidence points to the abnormal protein as the cause of the leukemic conversion of the hematopoietic stem cell. The mutated gene results in an abnormal or mutated protein, which is responsible for the development of the disease.

The cause of the chromosomal breakage in virtually all CML patients is not known. In a small proportion of patients, the cause of the breakage is exposure to very high doses of radiation. This effect has been most carefully studied in the Japanese survivors of the atomic bomb, whose leukemia risk was significantly increased. A slight increase in risk also occurs in some individuals treated with high dose radiotherapy for other cancers, such as lymphoma. Exposures to diagnostic dental or medical x-rays have not been associated with a heightened risk of chronic myelogenous leukemia.

The onset of chronic myelogenous leukemia is associated with symptoms that usually develop gradually. Most patients feel a loss of well-being. They tire more easily and may feel short of breath when physically active. They may have a pale complexion from anemia. Discomfort on the left side of the abdomen from an enlarged spleen is a frequent complaint. Patients may experience excessive sweating, weight loss and inability to tolerate warm temperatures. Increasingly, the disease is discovered during the course of a "routine" medical examination. Since the disease worsens over weeks or months, most patients would have symptoms develop soon after such a medical examination in any case.

• Medical history and physical examination
• Complete blood counts
• Bone marrow examination
• Cytogenetic Analysis
• Polymerase Chain Reaction (PCR)

To diagnose the disease, the blood and, in most cases, the marrow cells must be examined. The white cell count invariably increases, often to very high levels. Examination of the stained (dyed) blood cells with a light microscope shows a characteristic pattern of white cells: a small proportion of very immature cells (leukemic blast cells), and a larger proportion of maturing and fully-matured white cells (myelocytes and neutrophils). In addition, a sample of marrow is examined to confirm the blood findings and to determine if there is an abnormality of chromosomes. This test, which measures the number and normalcy of chromosomes, is referred to as a cytogenetic analysis. The presence of the Philadelphia chromosome in the marrow cells, a shortened chromosome number 22, high white blood cell counts, and other characteristic blood and marrow findings, confirm that the disorder is chronic myelogenous leukemia. Cytogenetic examination of tissue is the process of analyzing the number and shape of the chromosomes of cells. The individual, who prepares, examines and interprets the number and shape of chromosomes in cells is called a cytogeneticist. In addition to identifying chromosome alterations, the specific genes affected can be identified in some cases. These findings are essential in verifying that the disease is BCR-ABL positive CML.

The chromosome abnormalities that characterize chronic myelogenous leukemia can be detected by other techniques as well. Fluorescence in situ hybridization (FISH) is another method to identify cells in which the nucleus that contains chromosomes with the 9:22 translocation characteristic of CML. FISH is also useful to follow the effects of treatment since it can reveal whether there has been a significant decrease of CML cells in the blood.A very sensitive test of blood cells, the polymerase chain reaction or PCR, can increase very small amounts of either RNA or DNA and make them easier to detect. The alteration in DNA caused by the chromosome breakage in CML can be detected by this very sensitive method. PCR is more sensitive than FISH and can detect one BCR-ABL-positive cell in a background of about 500,000 normal cells.

Here is another view of a peripheral blood smear in a patient with CML. Often, the numbers of basophils and eosinophils, as well as bands and more immature myeloid cells (metamyelocytes and myelocytes) are increased. Unlike AML, there are not many blasts with CML

Chronic Lymphocytic Leukemia (CLL)

Each year, nearly 9,730 people in the United States learn that they have chronic lymphocytic leukemia. The disease may be referred to as chronic lymphoid leukemia or as CLL. CLL results from an acquired injury to the DNA of a single cell, a lymphocyte, in the bone marrow. This injury is not present at birth. Scientists do not yet understand what produces this change in the DNA of CLL patients. The change in the cell's DNA gives the CLL cell a growth and survival advantage. The result is the uncontrolled growth of CLL cells in the marrow, leading to an increased concentration in the blood. The CLL cells that accumulate in the marrow do not impede normal blood cell production to the extent that is the case with acute lymphocytic leukemia. This important distinction from acute leukemia accounts for the less severe early course of the disease.

Chronic lymphocytic leukemia is not associated with high-dose radiation or benzene exposures, as is the case with the other three major types of leukemia. CLL is very uncommon in individuals under 45 years of age. At the time of diagnosis, about 95 percent of patients are over age 50 and the incidence of the disease increases dramatically. The risk of chronic lymphocytic leukemia becomes measurable after age 35 and increases dramatically over succeeding decades. Early in the disease, chronic lymphocytic leukemia may have little effect on a person's well-being. The symptoms of CLL usually develop gradually:

• Patients tire more easily.
• They may feel short of breath when physically active.
• They may lose weight.
• They may experience frequent infections of the skin, lungs, kidneys or other sites.

Many CLL patients say they learned they had CLL after a routine check-up. When an enlarged lymph node or an enlarged spleen is found during a physical examination, or when a routine blood test shows a higher than normal number of lymphocytes, a physican will order lab tests to get more information. Diagnosis begins with a medical history and physical examination by the physician. To complete the diagnosis, the blood and, in most cases, the marrow cells must be examined. Physicians use a number of lab tests to look at cells in blood and marrow. A test called flow cytometry is used to find out if a patient has CLL. This test is also called immunophenotyping. Flow cytometry shows if CLL is causing the high number of lymphocytes in the blood. Flow cytometry can also show if the CLL began with a B lymphocyte or a T lymphocyte. B lypmphocyte (or B-cell CLL) is most common.

Depending on the place in lymphocytic cell development in which the malignant transformation occurs, the leukemic cells may be principally B cells, T cells, or NK cells. Most patients have a B cell type of leukemia. A minority have T or NK cell types. These distinctions may be accounted for by the malignant transformation occurring after the common lymphocyte has differentiated into one of the three types of lymphocytes. The malignant event (mutation of DNA) would, therefore, occur at the point, or after, the early specialized lymphocytes were formed.

Other lab tests are done if flow cytometry shows the patient has CLL. A cytogenetic analysis looks to see if there are changes in the chromosomes of the CLL cells. (Every cell in the body has chromosomes that carry genes. Genes contain the instructions that tell each cell what to do.)FISH (fluorescence in situ hybridization) is another test that is used to check for chromosome changes. After CLL treatment begins it can be used to see if treatment is working. This is done by measuring the number of cells with abnormal chromosomes that remain after treatment.

A bone marrow biopsy is used to look at the amount and pattern of CLL cells in the marrow. In patients with more advanced CLL a bone marrow biopsy is usually done as a baseline. The results from the baseline are compared to a repeat bone marrow biopsy after treatment. This is one way to tell how the patient is doing after treatment. This test is not always done for low-risk CLL patients. Doctors also may check the blood for immunoglobulins (gamma globulins.) Immunoglobulins are proteins that help the body fight infection. CLL patients may not have enough of these proteins. With more advanced CLL, low levels of immunoglobulins may be a cause of repeated infections.

These mature lymphocytes are increased markedly in number. They are indicative of chronic lymphocytic leukemia, a disease most often seen in older adults. This disease responds poorly to treatment, but it is indolent.