Defects in Phagocytic Cell

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Impairment in monocyte and neutrophil function have been detected in CLL patients, but these seem to have no important consequences. Neutropenia from the disease or its therapy is of overriding importance in predisposing to infection. In the absence of neutrophils, many of the defects in humoral immunity have little significance, since their function is to facilitate phagocytosis.

2.1.1. Defects in Phagocytic Cell Function

Defects in both granulocytes and monocytes have been detected in CLL patients. Deficiencies in glucuronidase, lysozyme, and myeloperoxidase but not in neutral proteases and alkaline phosphatase have been found in the neutrophils of some, but not all, CLL patients (4). Some studies have found that neutrophil function is normal in untreated patients (1). Monocytes from CLL patients have been found to be deficient in glucuronidase, lysozyme, and myeloperoxidase (4). Some patients have a scarcity of large mature monocytes. These functional abnormalities appear to be reversible if patients achieve disease remission (4). Adrenal corticosteroids are often incorporated into therapeutic regimens for CLL. If given at high doses or for prolonged periods, they interfere with the fungicidal activity of monocytes. For example, the cells are able to ingest Aspergillus spores but are not able to kill them in vitro (5).

Inhibitory factors directed against neutrophils have been found in the sera of some CLL patients. The phagocytic and bactericidal activity of neutrophils has been inhibited in vitro by sera from CLL patients (6). CLL cells also may release into the serum a chemotactic inhibitory factor

Table 2

Important Deficiencies in Host Defenses in Chronic Lymphocytic Leukemia

Deficiencies associated with the disease process Hypogammaglobulinemia Neutrophil inhibitory factors Neutropenia

Complement deficiencies Impaired antibody response Decreased CD4+ lymphocytes Skin anergy

Decreased interferon-y, interleukin-4 (IL-4), IL-2

Deficiencies associated with conventional chemotherapy Neutropenia

Impaired macrophage function Lymphopenia

Inhibition of antibody production Skin anergy

Deficiencies associated with purine analog chemotherapy Neutropenia

Decreased CD4+ lymphocytes

Decreased CD8+ lymphocytes

Decreased natural killer cells

Impaired macrophage function

Inhibition of cytokine function_

directed against neutrophils (7). The presence of this factor did not correlate with the stage of disease or lymphocyte count. Infections were significantly more common among patients who had this factor than in those without it. All the infections involved the respiratory tract, and respiratory infections have been associated with impaired leukocyte migration. CLL patients with recurrent infection exhibited impaired function and chemoluminescence of neutrophils in vitro compared with CLL patients without infections (8).

2.1.2. Defects in Numbers of Phagocytic Cells

Neutropenia may be caused by replacement of the bone marrow by CLL cells, suppression by tumor products, or, most often, myelosuppressive chemotherapy. Although alkylating agents cause myelosuppression, resulting in neutropenia, most conventional regimens usually do not cause severe or prolonged neutropenia (9). Although not studied in CLL patients specifically, the risk of infection is inversely related to the degree of neutropenia and is directly related to its duration (10). Also, the risk of hematogenous dissemination is related to the degree of neutropenia. Neutropenia is a pre-eminent factor in predisposing to most bacterial infections and also to systemic Candida and mold infections. Furthermore, response to appropriate therapy, especially in fungal infections, is largely dependent on neutrophil recovery.

Purine analogs (fludarabine, cladribine, and pentostatin) can cause severe myelosuppression. During 201 courses of fludarabine, the absolute neutrophil count fell below 500 cells/^L in 22% and to less than 1000 cells/mL in 46% of courses (11). In a large study comparing fludarabine alone with chlorambucil and with the combination, neutropenia occurred in 27, 19, and 43%, respectively (12). Severe neutropenia (<500 cells/^L) was greater with fludarabine than with chlorambucil. In one study neutropenia occurred in about 20% of patients receiving cladribine ± prednisone, whereas it occurred more frequently in other studies (13). Cladribine also causes transient monocytopenia. Severe neutropenia occurs in about 20% of patients receiving pentostatin (14).

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