Chronic Lymphocytic Leukemia

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Historically considered to be one of the four major types of leukemia, chronic lymphocytic leukemia now is grouped together with small lymphocytic lymphoma as a cancer of the lymphocytes, the infection-fighting white blood cells that circulate throughout the body. Like all cancers, CLL/SLL is characterized by the unrestrained accumulation of abnormal cells. In this cancer, the disease starts in the lymphocytes.

In people with CLL/SLL, the lymphocytes don't mature properly. These faulty cells do not die normally but instead accumulate in the bone marrow, bloodstream, and organs of the body. The buildup of abnormal lymphocytes not only interferes with the function of the immune system but also disrupts the production of other blood cells and the functions of vital organs, including the spleen. As a result, a person becomes more at risk of developing infections, anemia, and other cancers, including skin cancer and more serious cancers of the lymphocytes.

Over 15,000 new cases of CLL/SLL are expected to be diagnosed in the United States this year. The disease is typically diagnosed in adults in their mid-60s and is rarely found in people under the age of 40. Men are nearly twice as likely to develop this disease as women. CLL/SLL is more common in Caucasians and Afro-Americans and rarely diagnosed in people with ancestors from China, Japan, and other parts of Southeast Asia.

The outlook for a person diagnosed with CLL/SLL varies widely. For 2 out of 3 patients, the disease either remains stable for many years or progresses very slowly. These patients can delay treatment for several years or may never need treatment at all. In the remaining third of patients, the disease progresses quickly and brings about debilitating symptoms. For these patients, treatment is critical to slow down the disease and prolong their life. Approximately 4,500 people in the United States are expected to die this year from CLL/SLL. A thorough evaluation by a doctor who specializes in blood disorders and is experienced with CLL/SLL is vital to ensure that life-sustaining treatment is started when needed.

This section includes information on:

  • Need-to-know anatomy: blood
  • Need-to-know anatomy: lymphatic system
  • Causes
  • Stages
  • Biological markers
  • Risk factors
  • Need-to-know anatomy: blood

    Blood consists of three types of blood cells suspended in plasma. Plasma is a watery liquid that contains proteins, hormones, minerals, vitamins, and antibodies. The different types of blood cells—red blood cells, platelets, and white blood cells—are produced in the bone marrow.

    Red blood cells, or erythrocytes, account for 35 to 50 percent of the blood volume. Red blood cells are filled with hemoglobin, which enables them to deliver oxygen to the tissues of the body. When blood circulates through the lungs, the hemoglobin releases carbon dioxide and picks up oxygen. The oxygen-rich cells then circulate in the body, where they deliver oxygen to tissues in exchange for carbon dioxide before cycling back to the lungs. If the red blood cell volume falls below 35 percent, the cells can no longer meet the body's demand for oxygen, and anemia can develop. Anemia can cause shortness of breath, fatigue, and pale skin.

    Platelets, also known as thrombocytes, are small cells that help control blood loss. Platelets adhere to and repair damaged blood vessels as well as clump together, or clot, to control bleeding. A healthy body has about 150 billion to 450 billion platelets per liter of blood, depending upon the laboratory performing the analysis. When the platelet count drops considerably below this level, a person may bruise more easily, bleed longer, and have nosebleeds or bleeding gums. If the count falls as low as 10 billion platelets per liter, dangerous bleeding may develop.

    White blood cells, or leukocytes, are the warriors of the immune system. Unlike red blood cells or platelets, white blood cells are able to enter the tissues of the body in order to fight infections caused by fungi, bacteria, viruses, and cancer. Changes in the white blood cell count can indicate infection, development of leukemia, or other conditions. The five main types of white blood cells are lymphocytes, neutrophils, eosinophils, basophils, and monocytes. White blood cell counts can range from about 3.5 billion to 10.5 billion cells per liter.

    The rate at which cells are produced in the bone marrow is regulated similarly to the way heat is controlled in a house. As the temperature drops in a house, the thermostat calls for heat. When the temperature reaches the thermostat's set point, the thermostat turns off the furnace. In the body, there are many different triggers for the bone marrow to produce blood cells. For example, an infection is a common trigger for the production of white blood cells. Once the infection is under control, the rate of white blood cell production drops off until it returns to normal.

    Need-to-know anatomy: lymphatic system

    Lymphocytes, a type of white blood cells, are the building blocks of the immune system. A healthy body can have up to 3 billion lymphocytes per liter of blood. These white blood cells can be divided into three main types: B cells, T cells, and natural killer cells. Lymphocytic cancer develops most often in the B cells, less frequently in the T cells, and rarely in the natural killer cells.

    The largest concentrations of lymphocytes are found in the bone marrow—where they are made—followed by the lymph nodes, spleen, tonsils and adenoids, the digestive and respiratory systems, and the thymus. After maturing in the bone marrow, lymphocytes travel to the lymph nodes, where the B lymphocytes undergo further development to refine their ability to find and fight foreign substances. Then the lymphocytes return to the bone marrow, ready to be sent out on patrol. When a lymphocyte encounters an infection or abnormal cell, it will destroy the fungus, bacterium, virus, or cancer cell that is causing the disease.

    Lymphocytes travel in the bloodstream and in a network of small vessels called the lymphatic system. These vessels carry lymph, an opalescent fluid that seeps from the tissues of the body. Lymph contains white blood cells, germs and other foreign substances, and a few red blood cells. The lymphatic system filters lymph through the lymph nodes, where the germs and other foreign substances collect before the lymph is discharged into the bloodstream.

    Causes

    Chronic lymphocytic leukemia/small lymphocytic lymphoma starts with an abnormal mutation in the DNA of a lymphocyte. This change in the DNA—the chemical that gives instructions for cell development, reproduction, and breakdown—jumbles the directions for what is known as programmed cell death. Instead of maturing and eventually disintegrating into fragments that are digested by other cells, the abnormal lymphocytes persist for a period of weeks to months and accumulate in the body.

    Scientists don't know exactly what causes a person to acquire the genetic mutations associated with CLL/SLL. In people, DNA is normally organized into 23 pairs of chromosomes that replicate themselves during cell reproduction. Some people with this disease are missing parts of their chromosomes; some may have an extra chromosome. The most common abnormality is a loss of part of chromosome 13; an extra copy of chromosome 12 is also common.

    Stages

    Chronic lymphocytic leukemia/small lymphocytic lymphoma can be classified into stages based upon the signs and symptoms of the disease. The CLL/SLL stages are used to help guide treatment and predict the patient's outlook for survival. However, most doctors now recognize that the genetic characteristics of the cells—the presence of certain genetic mutations and proteins, also known as biological markers—can be more important indicators of the progression of the disease and survival outlook than the stage.

    Two different staging systems are used worldwide.

    Rai, which is widely used in the United States, uses the numbers of red blood cells and platelets and the presence of swelling in the liver, spleen, or lymph nodes to distinguish five stages that can be grouped into three categories of risk.

    • Stage 0 is considered low risk. These patients have a lymphocyte count more than 5 billion cells per liter of blood above normal, normal or near normal red blood cell and platelet counts, and no swelling of the lymph nodes, spleen, or liver.

    • Stages I and II are considered intermediate risk. Stage I patients have a lymphocyte count more than 5 billion cells per liter of blood above normal, normal or near normal red blood cell and platelet counts, and enlarged lymph nodes. Stage II is characterized by an elevated lymphocyte count, normal or near normal red blood cell and platelet counts, and an enlarged spleen or liver.

    • Stage III and IV are high-risk classifications. Stage III patients have an elevated lymphocyte count and anemia. Stage IV patients have an elevated lymphocyte count and a low platelet count (less than 100 billion platelets per liter).

    The Binet system, which is more commonly used in Europe, includes three stages denoted by the letters A, B, and C. Similar to the Rai classification, the Binet system relies on the platelet and red blood cell counts, but it also incorporates the number of affected lymphoid regions, such as the neck lymph nodes, groin lymph nodes, spleen, and liver.

    Biological markers

    After a diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma, the patient's lymphocytes should be evaluated for biological markers. Biological markers are the genetic characteristics of the leukemic cells that are used to predict how the cancer will progress. This information helps your doctor decide when to start treatment and which therapy to use. Patients with adverse biological factors are more likely to get worse and need treatment within a few years of diagnosis.

    Biological markers fall into three main categories:

    Chromosomal abnormalities are the presence of additional segments or lack of segments in a cell's chromosome. There are many possible chromosomal abnormalities, the most common of which occur in chromosomes 13 and/or 17. Patients missing only a segment in chromosome 13 are considered at low risk for rapid progression of CLL/SLL, with a life expectancy usually exceeding 15 to 20 years when no other abnormalities are detected and they are in an early stage of the disease. A loss of a segment in chromosome 17 indicates a high risk of developing the most aggressive form of the disease, with an average life expectancy of less than five years.

    Immunoglobulin gene mutation status, known as IgVH, can be used to predict the outcome of patients with CLL/SLL. A mutated status is associated with the longest survival rates. This test is technically difficult to perform in the laboratory and generally only available at academic institutions with active research laboratories.

    Protein concentrations of substances known as ZAP-70 and CD38 can be used to predict the progression of CLL/SLL. A high concentration of either of these two markers has been linked to aggressive CLL/SLL. However, these markers may not be accurate in up to 30 to 40 percent of patients. In addition, some research shows that levels of CD38 may change over time. Although this test is available in most medical centers, the testing procedures used to analyze ZAP-70 and CD38 have not been standardized.

    Risk factors

    Medical research is just beginning to identify the complex interplay of factors that may cause the mutations in the DNA of blood cells that can lead to chronic lymphocytic leukemia/small lymphocytic lymphoma. Not everyone with the mutations develops this disease. The exact trigger for the development of CLL/SLL is unknown.

    However, the following risk factors are associated with the disease:

    • Age. The disease is typically diagnosed in adults in their mid-60s and is rarely found in people under the age of 40.
    • Sex. Men are nearly twice as likely to develop this disease as women.
    • Race. CLL/SLL is more common in Caucasians and Afro-Americans and rarely diagnosed in people with ancestors from China, Japan, and other parts of Southeast Asia.
    • Family history. Although leukemia is not considered a congenital disease, you can inherit the predisposition to develop CLL/SLL. If you have a parent or sibling with CLL/SLL, your risk of developing this cancer increases two- to fourfold.
    • Some studies suggest that agricultural chemicals, such as herbicides and insecticides, may increase a person's risk of developing CLL/SLL. Exposure to Agent Orange, a herbicide used during the Vietnam War, has been linked to an increased risk of developing CLL.

      Last reviewed on 07/01/2008

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