13-30: Chronic Lymphocytic Leukemia

ESSENTIALS OF DIAGNOSIS

GENERAL CONSIDERATIONS

CLL is a clonal malignancy of B lymphocytes. The disease is usually indolent, with slowly progressive accumulation of long-lived small lymphocytes. These cells are immune-incompetent and respond poorly to antigenic stimulation.

CLL is manifested clinically by immunosuppression, bone marrow failure, and organ infiltration with lymphocytes. Immunodeficiency is also related to inadequate antibody production by the abnormal B cells. With advanced disease, CLL may cause damage by direct tissue infiltration.

CLL usually pursues an indolent course, but some subtypes behave more aggressively; a variant, prolymphocytic leukemia, is more aggressive. The morphology of the latter is different, characterized by larger and more immature cells. In 5–10% of cases, CLL may be complicated by autoimmune hemolytic anemia or autoimmune thrombocytopenia. In approximately 5% of cases an aggressive large-cell lymphoma (Richter syndrome) can develop.

Information about CLL is evolving rapidly, with new findings in biology and new treatment options; outcomes are improving significantly.

CLINICAL FINDINGS

A. Symptoms and Signs

CLL is a disease of older patients, with 90% of cases occurring after age 50 years and a median age at presentation of 70 years. Many patients will be incidentally discovered to have lymphocytosis. Others present with fatigue or lymphadenopathy. On examination, 80% of patients will have diffuse lymphadenopathy and 50% will have enlargement of the liver or spleen.

The long-standing Rai classification system remains prognostically useful: stage 0, lymphocytosis only; stage I, lymphocytosis plus lymphadenopathy; stage II, organomegaly (spleen, liver); stage III, anemia; stage IV, thrombocytopenia. These stages can be collapsed into low risk (stages 0–I), intermediate risk (stage II), and high risk (stages III–IV).

B. Laboratory Findings

The hallmark of CLL is isolated lymphocytosis. The WBC count is elevated and may be markedly abnormal (elevated to several hundred thousand). Usually 75–98% of the circulating cells are lymphocytes. Lymphocytes appear small and mature, with condensed nuclear chromatin, and are morphologically indistinguishable from normal lymphocytes, but smaller numbers of larger and activated lymphocytes may be seen. The hematocrit and platelet count are usually normal at presentation. The bone marrow is variably infiltrated with small lymphocytes (eFigures 13–30 and 13–31). The immunophenotype of CLL demonstrates coexpression of the B lymphocyte lineage marker CD19 with the T lymphocyte marker CD5; this finding is commonly observed only in CLL and mantle cell lymphoma. CLL is distinguished from mantle cell lymphoma by the expression of CD23, CD200, and LEF-1, low expression of surface immunoglobulin and CD20, and the absence of a translocation or overexpression of cyclin D1. Patients whose CLL cells have pathogenic variants of the immunoglobulin gene (IgVH somatic mutation) ...