Chapter 56: The Chronic Lymphocytic Leukemias

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 estimated prevalence of CLL in the United States in 2020 was 186,422 patients. Approximately 16,000 new cases occur annually.

• CLL is uncommon before age 40 years and is extremely rare in children or young adults. The median age at diagnosis is 70 years.

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

• CLL is more common in men, especially in those presenting at age less than 65 years.

• CLL is uncommon in Asian countries and in Asian 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, although there appears to be a higher incidence in hairdressers and those living or working on farms.

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. 70) have a greater than threefold increased risk of developing CLL.

• Genetic factors contribute to increased incidence of CLL.

  — Multiple gene polymorphisms have an increased frequency in CLL, but functional studies proving pathogenesis are lacking. Of note, some of these genes convey prognostic information (see below).

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

  — CLL cells have a distinct methylation profile that corresponds to the differentiation stage in normal cells at which neoplastic transformation occurred.

  — CLL is not a stem cell disease, but the stem cells in some patients may be primed to develop CLL.

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 overexpress BCL-2.

• CLL cells have defective apoptosis.

• 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 the LYN, PI3K, SYK, and BTK kinases and their downstream pathways.

Monoclonal B-Cell Lymphocytosis

• CLL has an initial phase referred to as monoclonal B-cell ...