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KEY POINTS
■ Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the Western world. About three-quarters of cases are diagnosed in persons 55 to 84 years old.
■ The diagnosis of CLL requires the presence of at least 5,000 B lymphocytes per microliter in the peripheral blood. Immunophenotyping by flow cytometry is mandatory for diagnosis.
■ The Rai and Binet staging systems offer limited prognostic information in early-stage disease, but analysis of chromosomal aberrations using the fluorescence in situ hybridization (FISH) technique is helpful.
■ At some point, approximately three-quarters of patients with CLL require treatment with chemotherapy directed at control of disease symptoms. A variety of chemotherapeutic combinations are available for treatment.
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the Western world. The incidence is about 2 to 6 cases per 100,000 per year.1 Risk increases with age, and in the past CLL was considered to be a disease of the elderly. In 2003-2007, the median age at diagnosis was 72 years; roughly 75% of cases are diagnosed in persons 55 to 84 years old. Although CLL is being identified more frequently in younger persons, the disease is quite unusual before age 44 years (less than 2% of cases). The lifetime risk of developing chronic lymphocytic leukemia is approximately 1 in 210 (0.48%).2 CLL is slightly more prevalent in males than females, with a ratio of 1.5-2 to 1.1,2 For 1999-2006, the 5-year survival of patients with CLL was 78.4%; survival was highest in white women (81.1%) and lowest in African American men (62.4%).2 There appears to be a genetic predisposition in approximately 5% to 10% of patients with CLL based on finding two or more cases within the same family tree; however, most persons afflicted do not have familial predisposition. The risk appears to be increased 2- to 7-fold in first-degree relatives of those with CLL.1
MAKING THE DIAGNOSIS
Chronic lymphocytic leukemia is considered to be a chronic lymphoproliferative disorder; by definition, it is a clonal/neoplastic proliferation of mature B lymphocytes. An isolated lymphocytosis may be the only presenting sign, and this is often an incidental finding. The diagnosis of CLL requires the presence of at least 5,000 B lymphocytes per microliter in the peripheral blood.3 On a peripheral blood smear, an increased number of small- to medium-sized mature lymphocytes with regular cytoplasmic contours and clumped nuclear chromatin are seen. Prolymphocytes—which are larger lymphocytes, often with a discernable nucleolus (central clearing in the nucleus)—may accompany the CLL populations; in typical CLL, the number is always less than 10% (Figure 1).4 Gumprecht nuclear shadows, called smudge cells, are lysed CLL lymphocytes and are a characteristic finding on the peripheral smear.3,4
Immunophenotyping by flow cytometry is mandatory for the diagnosis of CLL. Flow cytometry, a technique used to sort and classify cells by their surface markers, establishes clonality (versus a reactive cause) and distinguishes CLL from the other disorders within the differential diagnosis.4 The classical immunophenotype of CLL expresses CD5, CD19, CD20 (dim), and CD23. In addition, the CLL cells dimly express surface immunoglobulin (either kappa or lambda).3 The differential diagnosis of CLL includes B-cell prolymphocytic leukemia, B-cell lymphomas in leukemic phase, mantle cell lymphoma, follicular lymphoma, and hairy cell leukemia.4 A bone marrow aspirate and biopsy are not required for diagnosis of CLL.5
The clinical manifestations of chronic lymphocytic leukemia arise secondary to the accumulation of the clonal lymphocyte population in the lymphoid tissues, bone marrow, and blood.4 Patients who present with lymphadenopathy/splenomegaly alone without a peripheral blood lymphocytosis are considered to have small lymphocytic lymphoma (SLL). These patients have usually undergone lymph node biopsy to confirm tissue morphology and immunophenotype of CLL/SLL. CLL and SLL are considered biologically and clinically alike.1
STAGING IN CLL
Patients with chronic lymphocytic leukemia may present with peripheral blood lymphocytosis alone or a combination of extramedullary disease and evidence of cytopenias. In 1975, Dr. Kanti Rai developed a clinical staging system, called the Rai staging system, which is still widely used. The original staging system includes five tiers (Table 1). Lymphadenopathy need not be present in stages II, III, or IV but is usually present. The Rai staging system is based on physical examination alone used at the time of diagnosis.6 In addition, this staging system does not differentiate between cytopenias due to marrow suppression and those due to autoimmune causes. However, the prognosis for patients with cytopenias due to autoimmune causes may be more favorable than for those with advanced (Rai stage III or IV) disease.7
The Rai staging system predicts survival and offers prognostic information (Table 2). For instance, patients who presented with Rai stage 0 disease had an average survival of greater than 150 months, whereas those who presented with stage IV disease had an overall survival of approximately 19 months. Additionally, the Rai staging system predicts the time to first treatment; patients with advanced-stage disease required therapy sooner than those with earlier-stage disease. Based on Rai's data, approximately 25% of patients will present with low-risk disease (stage 0), 50% with intermediate-risk disease (stage I/II), and 25% with high-risk disease (stage III/IV).6
The Binet staging system deserves mention as it is the predominant staging system used in Europe (Table 3). In the Binet system, patients are evaluated based on palpable adenopathy and on their baseline hemoglobin level and platelet count.5
ADDITIONAL PROGNOSTIC MARKERS IN CLL
The Rai and Binet staging systems offer limited prognostic information for patients who present with early-stage disease (Rai stage 0-II); the clinical course in these patients is quite variable.8 In 2000, Döhner published data showing that the chromosomal aberrations seen in CLL lymphocytes using the fluorescence in situ hybridization (FISH) technique are useful for prognostication of early-stage disease.9 Samples from 325 patients with CLL were evaluated by interphase FISH. Approximately 80% of patients had an abnormality (Table 4). Most patients had a deletion (del) of the long arm of chromosome 13. In addition, the probability of survival was predicted by the abnormality by FISH analysis. Patients with a sole abnormality of del (13q) had the longest overall survival, with average survival of 133 months from time of diagnosis. The findings of del (11q) and del (17p) portended a poorer outcome, with average survival for 79 and 32 months, respectively.9
