Chronic lymphocytic leukemia (CLL) is a clonal hematopoietic disorder involving expansion of CD5-positive B cells. Chemoimmunotherapy (CIT) has been the standard first-line treatment for patients with CLL (1). In the last several years, major strides have been made in understanding the disease biology of CLL, and, fortunately, several of these discoveries are making their way into the clinic.
Chronic lymphocytic leukemia is the most common leukemia in the Western Hemisphere, accounting for about 25% of all leukemias in the United States. The estimated number of new CLL cases for 2015 was 14,620, with 8,140 occurring in men and 6,480 in women. Chronic lymphocytic leukemia is uncommon in the Asian population and accounts for only 2.5% of all leukemias in Japan. The incidence is age-related, 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. Population studies have not identified specific occupational or environmental risk factors for developing CLL (2). The risk of CLL is not increased in Asians settled in Western countries, indicating that genetic factors play a part in CLL risk (3). Up to 15% to 20% of patients with CLL have a family member with CLL or a related lymphoproliferative disorder (4). Genome-wide association studies identified several single nucleotide polymorphisms associated with increased risk of CLL (5,6).
Surface Antigen Phenotype
Chronic lymphocytic leukemia is a clonal B-cell lymphoid leukemia. Chronic lymphocytic leukemia cells morphologically resemble small mature lymphocytes arrested in an intermediate stage of the B-cell differentiation pathway. The hallmark of CLL cells is that they are monoclonal and 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 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.
Somatic Hypermutation of Immunoglobulin Heavy-Chain Variable Gene
Normal B-cell development involves an antigen-independent phase and an antigen-dependent phase. During the antigen-independent phase, B cells undergo rearrangement of the variable (V), diversity (D), and joining (J) genes in the bone marrow. Somatic mutation of the heavy- and light-chain variable gene occurs after encounter with antigen in the germinal center. Assessment for somatic hypermutation of immunoglobulin heavy-chain variable gene (IGHV) defines two subsets of CLL. Approximately 50% of CLL cases have somatic hypermutation (>2% deviation from germline sequence) of the IGHV gene and thus appear to arise from postgerminal B cells, whereas the subset of CLL lacking IGHV gene hypermutation (≤2% deviation ...