| Carolyn Vachani, RN, MSN, AOCN
Modified by: Lara Bonner Millar, MD
|Abramson Cancer Center of the University of Pennsylvania|
| Last Modified: February 20, 2013
This article is a more specific discussion of CLL. Please be sure to read Leukemia: The Basics first, so you have a basic understanding of leukemia.
What is CLL?
CLL is a chronic blood cancer that affects the lymphocytes, of which there are two types, B and T lymphocytes. These white blood cells are an important component of the immune system, helping to fight infection. More than 90% of CLL cases affect the B cells. In acute leukemia, one cell begins rapidly reproducing, leaving little room for healthy cells, eventually causing symptoms. In CLL, the abnormal B cells accumulate over time, but the rate they are reproducing is not abnormal. Rather than overgrowth, CLL is caused by a loss of apoptosis, or programmed cell death. The B cells should die once they reach a certain number, but cancerous B cells have lost the ability to self destruct in this situation.
CLL accounts for a little over 30% of all adult leukemia cases in the United States, making it the most common form of leukemia in adults with an estimated 14,990 new cases diagnosed in 2010. The Leukemia & Lymphoma Society estimates that over 95,000 people are living with CLL. The average age at diagnosis is 55-60 and it is more common as age increases, but can develop as early as age 18. It is more common in men and much less common in Asian populations, compared with U.S. or European populations.
What causes CLL?
No one really knows what causes CLL. Exposure to radiation and a chemical called benzene can lead to other types of leukemia, but this is not a cause of CLL. The Veteran's Administration has concluded that exposure to Agent Orange is associated with CLL. In rare cases, more than one person in a family may have CLL, but in the large majority of cases it is not familial in nature.
How do people with CLL present?
The majority of people will not have any symptoms of the disease, and are diagnosed after a routine blood test shows an abnormally high white blood cell count. If present, symptoms can include: repeated infections, fatigue (due to anemia or low red blood count), bleeding or bruising (due to low platelet count), and enlarged lymph nodes. As the disease progresses, healthcare practitioners may find enlargement of the spleen (splenomegaly) or liver (hepatomegaly) and/or enlarged lymph nodes.
Once suspected, a blood sample will be sent for a test called "flow cytometry," which detects "markers" on the surface of the cancer cells, confirming the diagnosis. Markers seen on CLL cells include: CD5, CD19, CD23 and CD20. The presence or absence of a marker called ZAP-70 (zeta chain associated protein kinase) can provide information on prognosis. ZAP-70 positive CLL has an average survival of 5 years which ZAP-70 negative CLL has an average survival of more than 25 years.
How is CLL staged?
Some patients with CLL will have aggressive disease, which requires treatment and has a poor prognosis of 2-3 years, while others have a very slow growing disease and can live for 10 to 20 years. About half of all patients are in between these two extremes. Researchers have developed the Rai system to stage the disease, assess prognosis and the need for treatment. Originally Rai assigned stages of 0-IV, but it was determined that there were only three groups for the purposes of prognosis, so the system was modified to include low, intermediate and high risk. (See table below)
In Europe, the Binet staging system is more widely used. This system incorporates prognostic factors such as hemoglobin, platelet count and lymph node involvement to group patients into groups based on prognosis. (see below)
There are a few other features that help clinicians determine poorer prognosis and the need for treatment. The presence of CD38 on the surface of CLL cells is a predictor of poorer prognosis. Following the lymphocyte count over time determines lymphocyte doubling time, which is the time it takes for the count to double. Taking longer than 12 months to double is considered lower risk, faster than this is considered higher risk disease. The extent to which the bone marrow is involved can be prognostic, and while bone marrow biopsy is not a necessary test to evaluate disease, many practitioners use it to decide on treatment. CT scans, or other radiology tests, are not routinely done in CLL unless progressive disease (called Richter's syndrome) is suspected.
How is CLL treated?
The decision to treat or not is an important one. People with early stage or less aggressive disease can actually have better outcomes if treatment is not started until disease related symptoms or rapid doubling time occur. For years, clinicians thought that patients would experience significant psychological distress from "watching and waiting", but this did not prove true in studies, therefore the standard approach for a stage 0 CLL is observation.
Once a decision to treat has been reached, there are no set in stone regimens. A chemotherapy drug called fludarabine is considered standard first line therapy, but several studies have shown decreased disease progression when it is combined with another agent such as cyclophosphamide, so combination therapy is often used. Chlorambucil is an oral chemotherapy that was considered the standard before fludarabine and is still a good choice for first or second line therapy. Despite the many clinical trials of various drugs, none has clearly shown longer survival time over the others (they have shown less disease progression, but this may not translate to longer life).
Monoclonal antibodies (alemtuzumab, rituximab) are a group of medications that are designed to target a specific type of cell (in this case, B-cell leukemia) and are being studied in CLL. Antibodies, which are normally found in the body, are developed by the immune system to destroy foreign things (such as a germ). These medications are antibodies that are made in a laboratory, with the goal of stimulating the patient's immune system to attack the leukemia cells.
Recently, at the Hospital of the University of Pennsylvania, a trial involving the infusion of autologous T cells genetically modified with a "chimeric antigen receptor" (or CAR) targeting a CD19 protein found on most B-cell CLL cells. This treatment takes the patient's own T cells and modifies them to include an antibody that recognizes CD 19. Once these cells are given back to the patient, they are able to seek out the CLL cells, which have the CD19 protein on their surface, and stimulate the immune system to attack and kill these cells. Although only a handful of patients with CLL have been treated, the results are promising and these T cells were able to kill off large quantities of the leukemia cells. Research continues into this treatment.
What precautions do people with CLL need to take?
CLL affects a person's ability to fight infection and precautions must be taken to prevent infection. The number one way to prevent infection is through hand washing, both the patient and those they come into contact with. Avoiding large crowds, like a shopping mall the day before Christmas! The lack of a properly functioning immune system means that the common cold, flu or pneumonia can spell real trouble, and can even be life threatening, for a person with CLL. Unfortunately, the same dysfunction in the immune system makes vaccines, such as the flu vaccine, much less effective in people with CLL. Patients should discuss the need for vaccines and when to receive them (in relation to treatments) with their healthcare team. Some studies have shown that giving the pneumococcal vaccine (protects against the most common type of pneumonia) early in CLL may improve its effectiveness.
People with low hemoglobin counts (also called anemia) can experience fatigue, shortness of breath or appear pale. Talk with your healthcare team about ways to treat anemia. Low platelet count (also called thrombocytopenia) can lead to bleeding. This can be as small as gums bleeding when brushing the teeth or a nosebleed to dangerous bleeding, such as a stroke. Patients should avoid contact sports, shaving (electric razor is okay), or any activities that increase the risk of bleeding or bruising. Patients should always inform their healthcare team if they have symptoms of anemia or thrombocytopenia.
What is Richter's Syndrome?
In 3-15% of patients, CLL "transforms" into an aggressive form of lymphoma, which is called Richter's syndrome. There is no way to predict which patients this will occur in, but the prognosis with transformation is very poor. Patients with Richter's syndrome will have increasing swelling of the lymph nodes, spleen and liver; develop fever, abdominal pain and weight loss. Blood counts typically worsen, with anemia, thrombocytopenia and a rapid increase in the lymphocyte count. A lymph node biopsy can diagnose the lymphoma.
Are there other types of CLL?
Yes, there are two other types of B cell leukemias called prolymphocytic leukemia and hairy cell leukemia. T cell leukemias are quite rare, accounting for only 2% of all CLL cases. These include: mycosis fungoides, T-PLL, adult T-cell leukemia, NK (natural killer) cell leukemia (NK cells are a part of the immune system) and large granular lymphocytosis.
Prolymphocytic leukemia (PLL) tends to occur in older persons and most are diagnosed with advanced stage disease. While PLL also affects B cells, they are less mature than those affected in CLL. PLL tends to respond poorly to chemotherapy and the median survival is about 3 years (median means this is the time when half of the patients have died, but half are still living; it is not the same as an average).
Hairy cell leukemia (HCL) occurs in about 600-800 people each year in the United States and is more common in men, by a rate of 4 to 1. It is named for the "hairy" appearance of the B cells under the microscope. Patients most commonly present with recurrent infections, fatigue, enlarged spleen (splenomegaly) or liver (hepatomegaly), low blood counts and the presence of "hairy" cells in the blood stream.
Many patients with HCL will not require treatment, which is only initiated if the disease progresses. When treatment is necessary, cladribine and pentostatin are chemotherapy agents, which can achieve remission in 90% of patients, though the treatment is not curative. Other medications used to treat HCL include interferon alpha and Rituxan. Patients with HCL were often treated by removal of the spleen (splenectomy) until the early 1980's, when it was determined that this did not change the course of the disease. Splenectomy may still be performed in patients who do not respond to other therapy.
References & Further Reading
Abeloff, M., Armitage, J., Niederhuber, J., Kastan, M. & McKenna, G. (Eds.): Clinical Oncology (2004). Elsevier, Philadelphia, PA.
Chiorazzi N, Rai KR, Ferrarini M (2005). "Chronic lymphocytic leukemia". NEJM. 352 (8): 804–15
Eichhorst, B et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol (2010)21(suppl 5):v162-v164.
Hoffman, R et al. (Eds): Hematology Basic Principles and Practice (2005). Elsevier, Philadelphia, PA.
National Cancer Institute "Chronic Lymphocytic Leukemia"
The Leukemia & Lymphoma Society
Palma, M et al. The biology and treatment of chronic lymphocytic leukemia. Annals of Oncology 17 (Supplement 10): x144–x154, 2006.
Porter D, Levine B, Kalos M, et al (2011). Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia. NEJM. 365(8): 725-733.