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Chronic lymphocytic leukemia (CLL) is an indolent lymphoid disorder involving a clonal expansion of CD5-positive B cells. Nucleoside analogs in combination with alkylating agents and/or monoclonal antibodies have produced marked improvement in remission rates. There is now evidence of an improvement in survival with chemoimmunotherapy.

CLL is the most common leukemia in the Western hemisphere, accounting for 20% of all leukemias in the United States. This disease is uncommon in the Asian population, and accounts for only 2.5% of all leukemias in Japan. The incidence is age-dependent, with an increase from 5.2 per 100,000 persons older than 50 years to 30.4 per 100,000 persons older than 80 years. The male-to-female ratio is 1.5:1.

Cell of Origin

Surface Antigen Phenotype

CLL is a clonal B-cell lymphoid leukemia. Morphologically, CLL cells resemble small mature lymphocytes arrested in an intermediate stage of the B-cell differentiation pathway. The hallmark of CLL cells are that they express CD5, an antigen commonly found on T cells. CD5-positive B cells can be found in the mantle zone of lymphoid follicles, but they constitute a minor fraction of the B-cell population. CD19, CD20, and CD23 are other B-cell markers expressed on CLL cells. Surface immunoglobulin, FMC7, CD22, CD11c, and CD79b are either weakly expressed or negative in CLL. Based on the antigen expression profile, CLL appears to arise from an "activated" B cell (1).

Somatic Hypermutation of Immunoglobulin Variable Gene

Assessment for somatic hypermutation of immunoglobulin variable gene (IgV) defines two subsets of CLL. Recombination of variable (V), diversity (D), and joining (J) genes and insertion of nontemplated nucleotides at the V–D and D–J junction occurs in the pregerminal phase of B-cell development. Somatic hypermutations are introduced in the V(D)J rearrangement in normal B cells in the germinal center in response to antigen presented by follicular dendritic cells (2). Approximately, 50% of CLL cases have somatic hypermutation of the IgV gene (3) and thus appear to arise from postgerminal B cells, while the subset of CLL lacking IgV gene hypermutation appear to arise from naive B cells. The mutation status of CLL cells seems fixed, and mutational status is not gained or lost during the course of disease. It has been demonstrated that the mutational status provides significant prognostic information.


Using conventional chromosome banding techniques, cytogenetic abnormalities can be detected in up to 50% of CLL cases. These techniques are hampered by the low mitotic activity of CLL cells; B-cell mitogens may be used to enhance this activity. In addition, metaphases obtained for karyotyping may also arise from normal T cells in the sample, as indicated by sequential immuno-typing followed by karyotypic analysis (4).

Fluorescent in situ hybridization (FISH) using genomic DNA probes has greatly enhanced the ability to detect molecular ...

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