Differential Diagnosis

Few syndromes can be confused with chronic lymphocytic leukemia. Viral infections producing lymphocytosis should be obvious from the presence of fever and other clinical findings. Other lymphoproliferative diseases such as Waldenstrom’s Waldenström’s macroglobulinemia, hairy cell leukemia, or lymphoma in the leukemic phase are distinguished on the basis of the morphology of circulating lymphocytes and bone marrow.

Treatment

Most cases of early indolent chronic lymphocytic leukemia require no specific therapy. Indications for treatment include progressive fatigue, troublesome lymphadenopathy, or the development of anemia or thrombocytopenia. These patients have either symptomatic and progressive stage II disease or stage III/IV disease. Initial therapy is with chlorambucil, 0.6–1 mg orally every 3 weeks. Complications such as autoimmune hemolytic anemia or immune thrombocytopenia may be treated with high-dose prednisone but often require splenectomy for control. Fludarabine is a new agent which is useful in treating disease refractory to other agents. As initial therapy, fludarabine produces faster and more complete responses than chlorambucil, and the duration of remissions is considerably longer. However, fludarabine causes long-term immunosuppression, and it remains to be determined if it should be used as primary therapy or reserved for use later in the disease. The rare young patient (age under 50) with aggressive disease may be a candidate for allogeneic bone marrow transplantation.

Prognosis

Median survival is approximately 6 years, and 25% of patients live more than 10 years. Patients with stage 0 or I disease have a median survival of 10 years. It is important to reassure these patients that despite the frightening diagnosis of “leukemia” they can live a normal life for many years. Patients with stage III or IV disease have a median survival of less than 2 years. Chronic lymphocytic leukemia is managed in palliative fashion. Patients with advanced disease benefit only briefly from intensive therapy.

Clinical Findings
A. Symptoms and Signs: Chronic lymphocytic leukemia is a disease of the elderly, with 90% of cases occurring after age 50 and a median age at presentation of 65. Many patients will be incidentally discovered to have lymphocytosis. Others present with fatigue or lymphadenopathy. On examination, 80% of patients will have lymphadenopathy and half will have enlargement of the liver or spleen.

A prognostically useful staging system has been developed as follows: stage 0, lymphocytosis only; stage I, lymphocytosis plus lymphadenopathy; stage II, organomegaly; stage III, anemia; stage IV, thrombocytopenia.

Chronic lymphocytic leukemia usually pursues an indolent course but occasionally will present as a rapidly progressive disease. These patients usually have larger, less mature-appearing lymphocytes and are said to have “prolymphocytic” leukemia. In 5–10% of cases, chronic lymphocytic leukemia may be complicated by autoimmune hemolytic anemia or autoimmune thrombocytopenia. In approximately 5% of cases, while the systemic disease remains stable, an isolated lymph node will be transformed into an aggressive large cell lymphoma (Richter’s syndrome).

B. Laboratory Findings: The hallmark of chronic lymphocytic leukemia is isolated lymphocytosis. The white blood count is usually greater than 20,000/mL and may be markedly elevated. Usually 75–98% of the circulating cells are lymphocytes. Lymphocytes appear small and “mature,” with condensed nuclear chromatin, and are morphologically indistinguishable from normal small lymphocytes. The hematocrit and platelet count are usually normal at presentation. The bone marrow is variably infiltrated with small lymphocytes. (See Supplemental Figures 13–28 and 13–29.) The malignant cells weakly express surface immunoglobulin, and the monoclonal nature of the cells can be demonstrated by the finding of a single light chain type on the surface. The immunophenotype of CLL is unique in that it co-expresses B lymphocyte lineage markers such as CD19 with the T lymphocyte marker CD5. Other B cell malignancies do not express CD5.

Hypogammaglobulinemia is present in half of cases and becomes more common with advanced disease. In some instances, a small amount of IgM paraprotein is present in the serum. Pathologic changes in lymph nodes are the same as in diffuse small cell lymphocytic lymphoma.

Chronic lymphocytic leukemia (CLL) a B lymphocyte (rarely T lymphocytes) clonal malignancy. The disease is usually indolent, with slowly progressive accumulation of long-lived small lymphocytes. These cells are immunoincompetent and respond poorly to antigenic stimulation.

Chronic lymphocytic leukemia is manifested clinically by immunosuppression, bone marrow failure, and organ infiltration with lymphocytes. Immunosuppression, bone marrow failure, and infiltration of organs account for most clinical manifestations. Immunodeficiency is also related to inadequate antibody production by the abnormal B cells. With advanced disease, chronic lymphocytic leukemia may cause damage by direct tissue infiltration.