Overview

Chronic lymphocytic leukemia (CLL) is a disease characterized by high numbers of circulating abnormal lymphocytes (B-Cells) in the peripheral blood. The disease often involves enlargement of lymph nodes in various parts of the body as well as enlargement of the spleen. In CLL the marked elevation of lymphocytes in the blood is partially due to a prolonged survival of abnormal lymphocytes compared to normal lymphocytes.

CLL typically occurs in individuals between 65 and 70 years of age.  Historically, it has been diagnosed at an advanced stage that typically involves the lymph nodes and bone marrow. More recently, however, the disease has frequently been detected in routine blood tests, allowing for earlier diagnosis. As a result, more patients are presenting with early-stage asymptomatic disease.

CLL is the most common adult leukemia with over 15,000 new cases per year in the United States and almost 5,000 deaths. CLL is not a rapidly growing cancer, but the abnormal cells accumulate in blood, bone marrow, lymph nodes and spleen, resulting in enlargement of these organs and decreased bone marrow and immune function. This disease interferes with the normal production of antibodies and immunoglobulins, so the body cannot properly fight infections.

Chronic lymphocytic leukemia has unique features that are not present in other kinds of leukemia, such as immune-mediated destruction of red blood cells and platelets. These are referred to as autoimmune-mediated cytopenias. Patients with CLL may also experience repeated infections from low levels of normal immunoglobulin production.

CLL is a heterogeneous disease with survival times measured in months or many years depending on risk factors at the time of diagnosis. The diagnosis of CLL is usually confirmed by tests for specific characteristics of B-cells in individuals with an absolute lymphocyte count above 5,000.

Monoclonal B-Cell Lymphocytosis

Some individuals will have all the characteristics of CLL in a blood test but have a lymphocyte count of less than 5,000. This is known as monoclonal B-cell lymphocytosis.1 Such low levels of CLL cells are detected in approximately 3% of the general population. Chromosomal abnormalities are frequently detected in this group of apparently normal patients. It is estimated that 1-2% of patients per year with monoclonal B-cell lymphocytosis will progress to CLL and require treatment. Monoclonal B-cell lymphocytosis occurs predominantly in elderly individuals and requires periodic monitoring but not necessarily treatment.

Staging of CLL

There are two staging systems in use: Rai and Binet.

The Rai system has five stages:

• Stage 0: Stage 0 CLL is characterized by absolute lymphocytosis (high lymphocyte count) without lymphadenopathy (enlarged lymph nodes), hepatosplenomegaly (enlarged liver and spleen), anemia (low red blood cell count), or thrombocytopenia (low platelet count).
• Stage I: Stage I CLL is characterized by absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia.
• Stage II: Stage II CLL is characterized by absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy.
• Stage III: Stage III CLL is characterized by absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or splenomegaly.
• Stage IV: Stage IV CLL is characterized by absolute lymphocytosis and thrombocytopenia (<100,000/mm³) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia.

The Binet staging system has three stages:

• Clinical Stage A*: Clinical Stage A CLL is characterized by no anemia or thrombocytopenia and fewer than three areas of lymphoid involvement (Rai Stages 0, I, and II).
• Clinical stage B*: Clinical Stage B CLL is characterized by no anemia or thrombocytopenia with three or more areas of lymphoid involvement (Rai Stages I and II).
• Clinical Stage C: Clinical Stage C CLL is characterized by anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement (Rai Stages III and IV).

*Lymphoid areas include cervical, inguinal and spleen.

The original staging systems were based on clinical examination and blood tests which may not be accurate enough for determination of need for treatment. For instance, researchers have found that 27% of patients with RAI Stage 0 will have abnormal abdominal computed tomography (CT) scans.2 These authors found that an abnormal abdominal CT correlated with increased bone marrow infiltration, higher lymphocyte count, increased ZAP-70 expression (a marker for poor prognosis) and a short lymphocyte doubling time. Patients with an abnormal CT also had a median time to disease progression of 3.5 years while for patients without an abnormal CT scan the median time to disease progression was longer.

One of the most important factors that affects the decision to treat or not to treat is whether or not patients with CLL have symptoms of their disease. Some of the symptoms of CLL include: fever, frequent infections, night sweats, swollen and painful lymph nodes and significant weight loss.

Although all patients should be accurately staged with one of the above staging systems, for treatment purposes patients are divided into two groups: asymptomatic patients with early-stage disease (usually Binet Stage A and RAI Stage 0, I, and II) and symptomatic patients who usually have advanced-stage disease (Binet Stage B and C and RAI Stage III and IV). The goal of staging is to determine which patients have early and which have advanced-stage CLL.

There have been tremendous advances in the treatment of CLL over the past decade, especially over the past five years. CLL was once described as a chronic disease with treatment being predominantly palliative (with the exception of allogeneic stem cell transplantation). Now, complete molecular remissions and long-term disease-free survival can sometimes be achieved with one of several combination treatment regimens. It has therefore become important to determine when patients should be treated and how aggressively. A comprehensive approach to treating patients with CLL now involves risk stratification for newly diagnosed patients, adherence to supportive care guidelines, attention to quality of care issues specific to patients with CLL and consideration of age, other health conditions, and quality of life in selection of therapy and disease management.

In order to learn more about the most recent information available concerning the treatment of CLL, click on the appropriate stage:

• Early Asymptomatic CLL (usually Binet Stage A or RAI Stage 0-II)
• Symptomatic CLL (usually Binet Stages B and C or RAI Stage III-IV)
• Relapsed/Refractory CLL (the cancer has persisted or returned following treatment)

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