Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). According to the American Cancer Society, CLL is the most common type of leukemia in North America and Europe. It usually occurs during or after middle age and rarely occurs in children.

Other Names

• Chronic lymphoid leukemia
• CLL

Signs and Symptoms

In the early stages of the disease, patients may have no symptoms and the disease may be diagnosed based on the results of a blood test. Later symptoms include:

• Pale skin
• Easy bruising
• Fatigue
• Enlarged lymph nodes
• Loss of appetite (anorexia)
• Weight loss
• Shortness of breath
• Abdominal distension or fullness (from an enlarged spleen)

Causes

Normally, the body makes blood stem cells (immature cells) that develop into mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell.

The myeloid stem cell develops into one of three types of mature blood cells:

• Red blood cells that carry oxygen and other materials to all tissues of the body.
• White blood cells that fight infection and disease.
• Platelets that help prevent bleeding by causing blood clots to form.

The lymphoid stem cell develops into a lymphoblast cell and then into one of three types of lymphocytes (white blood cells):

• B lymphocytes that make antibodies to help fight infection.
• T lymphocytes that help B lymphocytes make antibodies to fight infection.
• Natural killer cells that attack cancer cells and viruses.

In CLL, too many blood stem cells develop into abnormal lymphocytes and do not become healthy white blood cells. The abnormal lymphocytes may also be called leukemic cells. The lymphocytes are not able to fight infection very well. Also, as the number of lymphocytes increases in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets. This may result in infection, anemia, and easy bleeding.

Heredity may play a role in the development of this disease.

Diagnosis

The World Health Organization (WHO) classification of hematopoietic neoplasias describes CLL as leukemic, lymphocytic lymphoma. In the WHO classification, CLL is always a disease of neoplastic B cells, whereas the entity formerly described as T-CLL is now called T-cell prolymphocytic leukemia. ^[1]

Tests that examine the blood, bone marrow, and lymph nodes are used to diagnose chronic lymphocytic leukemia.

The following tests and procedures may be used:

• Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease and a history of symptoms and prior disease is performed.
• Complete blood count (CBC): A sample of blood is drawn and checked for the following:
  • The number of red blood cells, white blood cells, and platelets.
  • The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
  • The portion of the blood sample made up of red blood cells.
  • The diagnosis of CLL requires the presence of more than or equal to 5 x 109/L B lymphocytes (5000/µL) in the peripheral blood for the duration of at least 3 months.
• Bone marrow aspiration and biopsy: The removal of bone marrow, blood, and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow, blood, and bone under a microscope to look for abnormal cells.
• A Blood smear (peripheral smear) involves a sample of blood which is examined under a microscope. Valuable information about number and kinds of white blood cells, evaluation of abnormally shaped blood cells, and a rough estimate of white cell and platelet counts may be obtained.
• Cytogenetic analysis: A test in which cells in a sample of blood or bone marrow are viewed under a microscope to look for changes in the structure or number of chromosomes in the lymphocytes.
• Immunophenotyping: A test in which the cells in a sample of blood or bone marrow are looked at under a microscope to find out if malignant lymphocytes (cancer) began from the B lymphocytes or the T lymphocytes.

Staging

After chronic lymphocytic leukemia has been diagnosed, tests are done to find out how far the cancer has spread in the blood and bone marrow.

Staging is the process used to find out how far the cancer has spread. It is important to know the stage of the disease in order to plan the best treatment. The following tests may be used in the staging process:

• Bone marrow aspiration and biopsy: The removal of bone marrow, blood, and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow, blood, and bone under a microscope to look for abnormal cells.
• Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body, such as the lymph nodes.
• MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the brain and spinal cord. This procedure is also called nuclear magnetic resonance imaging (NMRI).
• CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
• Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it.
• Antiglobulin test: A test in which a sample of blood is looked at under a microscope to find out if there are any antibodies on the surface of red blood cells or platelets. These antibodies may react with and destroy the red blood cells and platelets. This test is also called a Coomb's test.

Stages of CLL

Treatment

Certain factors affect treatment options in CLL:

• The stage of the disease.
• Red blood cell, white blood cell, and platelet blood counts.
• Whether there are symptoms, such as fever, chills, or weight loss
• Whether the liver, spleen, or lymph nodes are larger than normal.
• The response to initial treatment.
• Whether the CLL has recurred (come back).

Refractory chronic lymphocytic leukemia is cancer that does not get better with treatment.

Five types of standard treatment are used:

• Watchful waiting is closely monitoring a patient's condition without giving any treatment until symptoms appear or change. This is also called observation. During this time, problems caused by the disease, such as infection, are treated.
• Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.
• Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the spinal column, an organ, or a body cavity such as the abdomen, or the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.
• Splenectomy is surgery to remove the spleen.
• Monoclonal antibody therapy is a cancer treatment that uses antibodies made in the laboratory from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances in the body that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells.

New types of treatment are being tested in clinical trials. These include the following:

• Chemotherapy with stem cell transplant is a method of giving chemotherapy and replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body's blood cells.

Treatment Options by Stage

Treatment of stage 0 chronic lymphocytic leukemia is usually watchful waiting.

Treatment of stage I, stage II, stage III, and stage IV chronic lymphocytic leukemia may include the following:

• Watchful waiting when there are few or no symptoms.
• Monoclonal antibody therapy.
• Chemotherapy with 1 or more drugs, with or without steroids or monoclonal antibody therapy.
• Low- dose external radiation therapy to areas of the body where cancer is found, such as the spleen or lymph nodes.
• A clinical trial of monoclonal antibodies with or without chemotherapy.
• A clinical trial of chemotherapy and monoclonal antibody therapy with stem cell transplant.

Treatment of refractory chronic lymphocytic leukemia may include the following:

• A clinical trial of chemotherapy with stem cell transplant.
• A clinical trial of a new treatment.

Chances of Developing Chronic lymphocytic leukemia

The estimated new cases of CLL in the United States for the year 2007 estimated by the American Cancer Society is 15,340 (8,960 men and 6,380 women). Deaths expected from CLL in 2007 were 4500 (2560 men and 1940 women). ^[2]

Risk Factors

Risk factors for CLL include the following:

• Being middle-aged or older, male, or white.
• A family history of CLL or cancer of the lymph system.
• Having relatives who are Russian Jews or Eastern European Jews.
• Males (chronic lymphocytic leukemia affects men two to three times more often as women).

Clinical Trials

There are a number of ongoing clinical trials available at ClinicalTrials.gov: chronic lymphocytic leukemia trials

Research

Current Research

• The use of fludarabine alone or with alemtuzumab or rituximab and fludarabine with cyclophosphamide in treating CLL is being studied. ^[3]
• Combined chemotherapy versus combined chemotherapy given with colony stimulating factors, such as G-CSF are being compared in the treatment of refractory CLL. ^[4]
• A trial to evaluate chlorambucil to see how well it works compared to fludarabine and cyclophosphamide or fludarabine alone in treating patients with newly diagnosed chronic lymphocytic leukemia is ongoing. ^[5]

Recent discoveries

• New insights into the possible causes of CLL (genetic factors) are discussed. Understanding the factors contributing to the development of CLL will help in the development of more effective treatment. ^[6]
• The physician-patient relationship and its effect on the quality of life of patients with CLL was evaluated. ^[7]
• The use of cottonseed oil (gossypol), an alternative treatment for CLL, is discussed. Gossypol appears to be a poweful anti-cancer agent in this study.^[8]

Expected Outcome

Doctors have learned that there are probably 2 different kinds of CLL:

• One kind of CLL grows very slowly and rarely needs to be treated. People with this kind of CLL survive an average of 15 years or more.

• The other kind of CLL grows faster and is a more serious disease. People with this form of CLL survive an average of about 8 years.

The leukemia cells from these 2 types look alike, but new lab tests can tell the difference between them. The tests look for a protein called ZAP-70 and for a substance called CD38. Patients whose CLL cells contain low amounts of ZAP-70 and CD38 have a better prognosis. ^[9]

The prognosis (chance of recovery) depends on:

• Whether there is a change in the DNA and the type of change, if there is one.
• Whether lymphocytes are spread throughout the bone marrow.
• The stage of the disease.
• Whether the CLL gets better with treatment or has recurred (come back).
• Whether the CLL progresses to lymphoma or prolymphocytic leukemia.
• The patient's general health.

Biomarkers (blood markers, cell abnormalities and gene mutations)have become the focus of many recent studies. Before being incorporated into daily practice, however, these markers require standardization and validation in large, prospective trials.^[10]

References

1. ↑ Hallek M, Cheson BD, Catovsky D, Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008 Jun 15;111(12):5446-56. Epub 2008 Jan 23. Abstract
2. ↑ American Cancer Society web site. Estimated New Cancer Cases and Deaths by Sex for All Sites, US, 2007
3. ↑ ClinicalTrials.gov. Fludarabine in Treating Patients With Chronic Lymphocytic Leukemia, in Treating Patients With Chronic Lymphocytic Leukemia, Fludarabine With or Without Cyclophosphamide in Treating Patients With Advanced Chronic Lymphocytic Leukemia
4. ↑ ClinicalTrials.gov. Combination Chemotherapy With or Without G-CSF in Treating Patients With Relapsed Stage I, Stage II, Stage III, or Stage IV Chronic Lymphocytic Leukemia
5. ↑ ClinicalTrials.gov. Chemotherapy in Treating Patients With Newly Diagnosed Chronic Lymphocytic Leukemia
6. ↑ Caligaris-Cappio F, Ghia P. Novel Insights in Chronic Lymphocytic Leukemia: Are We Getting Closer to Understanding the Pathogenesis of the Disease? J Clin Oncol. 2008 Jul 28. (Epub ahead of print) Abstract
7. ↑ Shanafelt TD, Bowen DA, Venkat C, et al. The physician-patient relationship and quality of life: Lessons from chronic lymphocytic leukemia. Leuk Res. 2008 Jul 23. (Epub ahead of print) Abstract
8. ↑ Politzer WM. Long-term clinical remission of a patient with chronic lymphocytic leukemia using alternative treatment option: cottonseed oil (gossypol). Phytomedicine. 2008 Aug;15(8):563-5. Epub 2008 Jun 24. Abstract
9. ↑ American Cancer Society web site. What is Chronic Lymphocytic Leukemia?
10. ↑ Montserrat E. New prognostic markers in CLL. Hematology Am Soc Hematol Educ Program. 2006:279-84. Abstract Full Text PDF

External Links

• Leukemia and Lymphoma Society

• National Cancer Institute

• Chronic Lymphocytic Leukemia Foundation

• Chronic Lymphocytic Leukemia Research Consortium (CRC)