The therapy of CLL has changed dramatically with the introduction of the purine analogs. Unfortunately, although these agents are highly efficacious, they are associated with substantial risks of infection even for prolonged periods after cessation of therapy. Fludarabine has been combined with prednisone, which proved to be no more effective than fludarabine alone but was associated with a higher risk of infections (11). What is most impressive and probably related to reduced CD4+ lymphocyte numbers, is the increased frequency of infections that are also seen in AIDS patients such as Pneumocystis carinii, cytomegalovirus, herpesviruses, and Listeria monocytogenes infections (46).
3.3.1. Infections Associated With Fludarabine Therapy
The largest amount of information on infectious complications following purine analog therapy has been obtained from CLL patients receiving fludarabine. Early studies focused on the increased frequency of L. monocytogenes and P. carinii infections (47). Subsequently, a variety of infections, most of which are typically associated with defects in cellular immunity were reported, primarily as single case reports or only small series. These include infections caused by Legionella species, atypical Mycobacterium species, Nocardia species, and Cryptococcus neoformans (46). Viral infections have included herpes simplex, herpes zoster, cytomegalovirus, adenoviruses, JC virus, respiratory syncytial virus, and astrovirus (48,49). An association between fludarabine therapy may be spurious in some cases, since only single cases have been reported.
The largest review of infections associated with fludarabine included 402 CLL patients who received the drug alone or with prednisone (46). The frequency of infection was 58% among prior treated patients vs 34% among those who had no prior therapy. More than 50% were pneumonias, and 12% were herpes zoster infections. Among the 158 patients who had CD4+ lymphocyte counts determined, herpes zoster occurred in 26%, with CD4+ lymphocyte counts of less than 50 cells/^L compared with 6% of those with CD4+ lymphocyte counts greater than 50 cells/^L. Mucocutaneous herpes simplex infection was three times more frequent in the former group. Cytomegalovirus and mycobacterial infection also occurred in patients with low CD4+ lymphocytes counts. L. monocytogenes and P. carinii infections only occurred in patients who received fludarabine plus prednisone.
Another large study examined the frequency of fever and infection among 518 previously untreated CLL patients who were randomly assigned to fludarabine, chlorambucil, or the combination (50). The frequency of all types of infection was highest among those receiving the combination and lowest among those receiving chlorambucil, although the duration of follow-up was substantially shorter for the latter group. Considering only the 188 patients who received fludarabine alone, 77% experienced at least one febrile episode, and 29% developed a major infection. The most frequent sites of infection were the lower respiratory tract (14% of patients) and skin and soft tissue (7% of patients). The most frequent infections were herpes zoster, occurring in 13% of patients, followed by herpes simplex (10%), Gram-positive cocci (8%), Gram-negative bacilli (5%), Candida species (3%), and P. carinii (0.5%). Only 19% of major infections occurred when patients were neutropenic, and none of them died of infection.
In a study of fludarabine administered by continuous infusion, more than 30% of patients developed major infections; 60% were respiratory infections and more than 50% were fatal (51). In a randomized study comparing fludarabine with chlorambucil with the combination in previously untreated patients, the frequency of infection was 16, 9, and 28%, respectively (12). The proportions of the infections requiring hospitalization were 29, 17, and 45%, respectively.
In a study examining the long-term effects of fludarabine ± prednisone therapy, 43% of all fatalities were owing to infection (52). There were 94 episodes of infection in 137 patients who achieved complete or partial remission, although the frequency was less for those in complete remission. The most common infections were sinopulmonary (41%), localized herpes zoster (20%), and urinary tract (9%) infections. There was no correlation between the CD4+ lymphocyte count at the end of therapy and risk of subsequent infection.
3.3.2. Infections Associated With Cladribine Therapy
Infections during cladribine therapy may be caused by neutropenia or lymphopenia. In one study of patients with hematological malignancies, 68% of patients who developed neutropenia had fever or infection. The frequency of infection among patients with hematological malignancies almost doubled during the 6 mo following the first course of cladribine compared to the previous 6 mo (53). In another study, half of the infections were caused by viruses, predominantly herpes simplex (36). About 20% of cases were pneumonias and septicemias. Organisms responsible for infection included Gram-positive and Gram-negative bacteria, L. monocytogenes, P. carinii, adenoviruses, cytomegalovirus, Candida species, and Aspergillus species (3). In a study of 378 CLL patients, 123 received cladribine alone and 255 received cladribine + prednisone (13). Fever and infection was higher among previously treated patients (49% vs 38%) and, surprisingly, lower among those receiving prednisone (36% vs 58%). The most common site of infection was the respiratory tract, and over 20% had reactivation of herpes zoster or herpes simplex infection. There were no cases of listeriosis or pneumocystosis. Infection was responsible for 54% of deaths, predominantly owing to pneumonia and septic shock.
3.3.3. Infections Associated With Pentostatin Therapy
Infection has occurred in about 25% of CLL patients receiving pentostatin at appropriate dosage schedules (14). Infections occur predominantly during the first few weeks of therapy and include bacterial (especially L. monocytogenes), P. carinii, Toxoplasma gondii, Candida species, and Aspergillus species infections. Herpes simplex and herpes zoster infections were especially common, including several cases of disseminated zoster (37). A substantial number of pneumonias occurred, associated with a high fatality rate. As many as 70% of patients were not neutropenic at the onset of their infection.
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