Chapter 55: Chronic Lymphocytic Leukemia and Related Diseases

DEFINITION

• Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells characterized by blood and marrow lymphocytosis. Varying degrees of lymphadenopathy, splenomegaly, and blood cytopenias develop as the neoplasm progresses.

EPIDEMIOLOGY

• CLL is the most prevalent adult leukemia in Western societies.

• The prevalence of CLL in the United States in 2014 was 126,553 patients. There are approximately 15,700 new cases annually.

• CLL is uncommon before age 40 years and is extremely rare in children or young adults.

• The incidence of the disease increases logarithmically after age 45 years.

• Median age at diagnosis is approximately 70 years.

• CLL is uncommon in Asian countries and in Asians immigrants to the Americas or Europe.

ETIOLOGY AND PATHOGENESIS

Environmental Factors

• Radiation or chemotherapy has not been shown to be a risk factor for developing CLL.

• Exposure to occupational chemicals, such as solvents, paints, or pesticides, has not been established to be a risk factor for CLL.

• There is a higher frequency of living or working on a farm in patients with CLL compared to those without the disease.

Hereditary Factors

• Familial occurrence is most evident in CLL compared with other leukemias.

  — Multiple cases of CLL are found within a single family with greater frequency.

  — Up to 10% of patients with CLL have a first- or second-degree relative with CLL.

  — First-degree relatives of patients with lymphoplasmacytic lymphoma or Waldenström macroglobulinemia (Chap. 69) have a greater than threefold increased risk of developing CLL.

• Genetic factors contribute to increased incidence of CLL.

  — Polymorphisms in the gene encoding CD5 (located at chromosome 11q13), CD38 (located at chromosome 4p15), or tumor necrosis factor-α, and other genes mapping to chromosome 13q21.33-q22.2.

Disease Biology

• CLL cells typically express CD5, CD19, CD23, and low levels of CD20.

• CLL cells have surface immunoglobulins reactive with self-antigens.

• CLL cells have defective apoptosis supported by the microenvironment.

• CLL cells overexpress BCL-2.

• CLL is characterized by dysregulation in both cellular and humoral immunity.

• CLL cells depend on constitutive activation of the B-cell receptor pathway for survival; the survival signals are transduced through LYN, PI3K, SYK, and BTK pathways.

Monoclonal B-Cell Lymphocytosis

• CLL has an initial phase referred to as monoclonal B-cell lymphocytosis. In most cases, this is not apparent at diagnosis because it is asymptomatic and is detected by flow cell analysis of blood lymphocytes.

• Patients have no lymphadenopathy; no splenomegaly; otherwise normal blood counts; and no fever, night sweats, or unexplained weight loss.

• The incidence of monoclonal B-cell lymphocytosis increases dramatically after 40 years of age.

• Approximately 15% of healthy individuals, who have first-degree relatives with two or more family members with CLL, have blood monoclonal B cells of the CLL B-cell immunophenotype.

• The immunophenotype of the monoclonal B cells may be ...