Clinical Features

Clinical features of the disease include infections, autoimmunity, anemia, pure red cell aplasia, an aggressive transformation, and/or secondary malignancies.

1.3.1. Infections

Infections are the major cause of death in patients with CLL. The basis for the increased susceptibility to infection is multifactorial and relates to both the disease and its treatment. Hypogammaglobulinemia is common, as is defective activation of the complement system and defects in cell-mediated immunity and phagocytosis. Before treatment, the most common pathogens are those that require opsonization for bacterial killing. After treatment, the number of infections with Gram-negative organisms and opportunistic pathogens (especially after treatment with nucleoside analogs) increases (5,6). Infections are the ultimate cause of death in 60-85% of patients with CLL (7).

High-dose, intravenous immunoglobulins have been evaluated for the ability to prevent infections in CLL. Prophylactic use of intravenous immunoglobulins failed to reduce the total number of major infections or incidence of infection, and no improvement in overall survival was reported for patients receiving prophylactic, high-dose, intravenous immunoglobulins (8). Prophylactic antimicrobial regimens are not routinely recommended because the broad spectrum of potential pathogens would require multiple, potentially toxic drugs. Therefore, prophylactic uses of antimicrobial agents or high-dose intravenous immunoglobulins have been restricted to patients with documented, repeated bacterial infections.

1.3.2. Aggressive Transformation

Aggressive transformation of CLL has been reported in 10-15% of patients. The most common transformation (5%) is Richter's syndrome. Transformation is not clearly related to either the nature or extent of primary therapy. Evolution into PLL, acute lymphocytic leukemia (ALL), plasma cell leukemia, multiple myeloma, and Hodgkin's disease (HD) have been reported.

1.3.3. Autoimmunity

Up to 20% of patients may have a positive Coombs' antiglobulin test, although clinical hemolysis occurs in only 50% of these patients. The frequency of immune thrombocytopenia is approx 2%. Autoimmune anemia, or thrombocytopenia, generally responds to a short course of therapy with corticosteroids. In patients unresponsive to corticosteroids, high doses of intravenous immunoglobulin have been used. Splenectomy is an option if systemic approaches fail (9-11).

1.3.4. Anemia and Pure Red Cell Aplasia

Anemia in CLL (defined as hemoglobin [Hb] concentration < 10 g/dL) is frequently observed at presentation (reported incidence of 9-29%) and becomes both more frequent

Table 1

Staging Systems for Chronic Lymphocytic Leukemia


Simplified three-stage system

Clinical features

Median survival (yr)

Modified Rai staging system

Binet staging system A

Lymphocytosis in blood and >10

marrow only

Intermediate Lymphocytosis + lymphadenopathy 7 risk Splenomegaly ± hepatomegaly

Lymphocytosis + anemia 1.5-4


Less than three areas of clinical 12

lymphadenopathy; no anemia or thrombocytopenia Three or more involved node areas; 7

no anemia or thrombocytopenia Hb > 10 g/dL and/or 2-4

platelets < 100 x 109/L

and more pronounced with disease progression (12-14). Anemia in CLL may be caused by autoimmune hemolysis, extensive bone marrow infiltration, hypersplenism, deficiency of hematopoietic cofactors, blood loss, and/or the anemia of chronic disease (ACD). ACD is characterized by the release of cytokines such as interleukin (IL)-1a and -1P, tumor necrosis factor (TNF)-a, transforming growth factor (TGF)-P, and IL-6, which inhibit endogenous erythropoietin (EPO) production, diminish the responsiveness of erythroid progenitors to EPO, and impair iron utilization (15-19).

Pure red cell aplasia is an uncommon complication characterized by severe anemia without a reticulocyte response or bone marrow normoblast, in the absence of neu-tropenia or thrombocytopenia. Chemotherapy that effects a clinical response increases the hematocrit in most treated patients. Corticosteroids and cyclosporin may induce responses (20).

1.3.5. Secondary Malignancies

Secondary malignancies occur with increased frequency in patients with CLL and have been attributed both to the immune defects associated with CLL and to iatrogenic consequences of treatment.

1.4. Staging

Patients with CLL exhibit a highly variable course, probably reflecting the underlying molecular heterogenicity of the disease (21). Two staging systems are available and are widely accepted: the Rai classification (commonly used in the United States), and the Binet system (commonly used in Europe). In both systems, increasing incidence and severity of anemia is associated with disease progression (Table 1). Clinical stage is the strongest predictor of outcome, but significant clinical heterogeneity exists within stages of both systems. The Rai system initially identified five stages but has been simplified into a three-stage system. Both systems are cited in the literature.

0 0

Post a comment