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INTRODUCTION

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Chronic lymphocytic leukemia (CLL) is a neoplastic disease characterized by the accumulation of monoclonal lymphocytes in blood, bone marrow, and lymphoid tissues. These lymphocytes are small, mature-appearing B cells typically expressing CD19, CD5, and CD23. It is generally a disease of older people and prognosis ranges widely from a few years to many years, but it is not considered curable outside of the bone marrow transplant setting. At times these neoplastic cells predominate in lymph nodes leading to the classification as a lymphoma. Hence, the WHO in 2008 has defined this neoplasm as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (1).

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EPIDEMIOLOGY

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CLL is the most common form of leukemia among adults of Western societies and accounts for 30% of all leukemias. In the United States, 16,060 new cases or 4.2 per 100,000 persons and 4580 deaths are projected for 2012 (2, 3). The male-to-female ratio is approximately 3:2. CLL accounts for 1% of all cancers, and is a disease of older adults with a median age of 72 years; only 10% of patients are <50 year old. The disease tends to run in families. When multiple members of a family have CLL, a detectable clone of CLL cells can be found by flow cytometry in 13.5% of apparently healthy first-degree relatives of patients. Also, among normal individuals >40 years of age, a clone of B cells consistent with CLL can be found by multiparameter flow cytometry in 3.5% of subjects (4). It is uncertain whether these individuals will progress to clinically significant disease. CLL is uncommon in Asia.

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BIOLOGY

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CAUSE

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The cause is unknown. Environmental factors such as exposure to radiation, sunlight, chemical toxins, or viruses are not associated with an increased incidence of the disease. HLA haplotype is not associated with disease susceptibility.

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MOLECULAR DEFECT

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CLL cells are characterized by a defective B-cell receptor (CD79a and CD79b) that does not respond properly to antigen engagement but is associated with constitutive signaling intracellularly through immuno-receptor tyrosine-based activation motifs (ITAMs) to activate a cascade of kinases including Lyn and Syk leading to proliferation, inhibition of apoptosis, or, on occasion, promotion of apoptosis (5, 6). These changes lead to an accumulation of CLL cells in G0. CLL cells derive from antigen-experienced B lymphocytes and have the phenotype of activated cells.

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During an immune response, normal B cells encountering antigen will travel to a germinal center and undergo a series of point mutations in the immunoglobulin genes, which result in a more snug fit for the antigen in its binding site. These somatic mutations can be detected by sequencing the immunoglobulin heavy-chain variable-region (IgVH) genes. Patients with CLL cells that contain somatic mutations in their Ig genes (a little over 50%) will have a much better prognosis than patients with CLL cells containing germline Ig sequences. Two surrogate markers for mutational status are more easily obtainable than mutational analysis: CD38, a cell-surface enzyme involved in regulating B-cell activation, and ZAP-70, the 70-kD zeta-associated protein normally found in T ...

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