Leukemia, Chronic Lymphocytic

Key Features

Essentials of Diagnosis

• Most patients are asymptomatic at presentation

• B-cell lymphocytosis with CD19 expression > 5000/mcL

• Mature morphologic appearance of lymphocytes

• Coexpression of CD19, CD5

General Considerations

• A clonal malignancy of B lymphocytes

• The course is usually indolent, with slowly progressive accumulation of long-lived small lymphocytes that are immunoincompetent

• Results in immunosuppression, bone marrow failure, and organ infiltration with lymphocytes

• Immunodeficiency also related to inadequate antibody production by abnormal B cells

• In severe disease, may cause damage by direct tissue infiltration

• Prognostically useful staging system (Rai system)

  • Stage 0, lymphocytosis only

  • Stage I, lymphocytosis plus lymphadenopathy

  • Stage II, organomegaly (spleen, liver)

  • Stage III, anemia

  • Stage IV, thrombocytopenia

Demographics

• Chronic lymphocytic leukemia (CLL) occurs mainly in older patients

  • 90% of cases occur in persons over age 50

  • Median age at presentation is 70

Clinical Findings

Symptoms and Signs

• Incidentally discovered lymphocytosis in many patients

• Fatigue

• Diffuse lymphadenopathy in 80%

• Hepatomegaly or splenomegaly in 50%

Differential Diagnosis

• Atypical lymphocytosis due to bacterial or viral infection or pertussis

• Lymphoma in its leukemic stage, especially mantle cell lymphoma

• Hairy cell leukemia

• Waldenström macroglobulinemia

• Monoclonal B-cell lymphocytosis (MBL) characterized by < 5000/mcL B-cells is considered a precursor to B-CLL

Diagnosis

Laboratory Tests

• White blood cell count is usually > 20,000/mcL (20 × 10⁹/L) and may be markedly elevated to several hundred thousand

• Differential: usually 75–98% of circulating cells are lymphocytes

• Hematocrit and platelet count usually normal at presentation

• On peripheral smear, lymphocytes are usually morphologically indistinguishable from normal small lymphocytes

• Larger and more immature cells are found in prolymphocytic leukemia (PLL)

• CLL is diagnosed by coexpression of B-lymphocyte lineage marker CD19 with T-lymphocyte marker CD5

• CLL is distinguished from mantle cell lymphoma by

  • Expression of CD23

  • Low expression of surface immunoglobulin and CD20

  • Absence of overexpression of cyclin D1

• High expression of CD38 or ZAP-70 is correlated with more aggressive course

• Fluorescence in-situ hybridization (FISH) assesses genomic changes

• Hypogammaglobulinemia is found in half of CLL patients, becomes more common with advanced disease

• Serum protein electrophoresis: IgM paraprotein may be present

Diagnostic Procedures

• Bone marrow is variably infiltrated with small lymphocytes

• Lymph node biopsy shows same pathologic changes as in diffuse small lymphocyte lymphoma

Treatment

Medications

• Most patients with early stage disease do not require treatment for months or years

• Initial treatment options include

  • Ibrutinib or venetoclax in combination with anti-CD20 antibody therapy

  • Choice between these agents is based on toxicity as well as preference

• Ibrutinib

  • A ...