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Infections in Patients with Chronic Lymphocytic Leukemia Treated with Fludarabine

Elias J. Anaissie, MD; Dimitrios P. Kontoyiannis, MD; Susan O'Brien, MD; Hagop Kantarjian, MD; Lester Robertson, MD; Susan Lerner, RRA; and Michael J. Keating, MD
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Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1998;129(7):559-566. doi:10.7326/0003-4819-129-7-199810010-00010
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Background: Fludarabine, a purine analogue with activity in chronic lymphocytic leukemia, is usually well tolerated. Although serious infections after fludarabine therapy have been described, a systematic analysis of the risk factors for such infections in chronic lymphocytic leukemia is lacking.

Objective: To determine the risk factors for major infection in patients with chronic lymphocytic leukemia treated with fludarabine.

Design: Retrospective review of medical records.

Setting: Cancer center.

Patients: 402 patients with chronic lymphocytic leukemia not previously treated or treated with chlorambucil (with or without prednisone) who received fludarabine (30 mg/m2 of body surface area per day for 5 days) with or without prednisone at 4-week intervals.

Results: Infections occurred more often in previously treated (144 of 248 [58%]) than in previously untreated (53 of 154 [34%]) patients (P < 0.001). Listeriosis or pneumocystosis occurred in 12 of 170 (7%) previously treated patients receiving fludarabine plus prednisone, 0 of 78 previously treated patients receiving fludarabine alone, and 2 of 154 (1%) previously untreated patients receiving fludarabine plus prednisone (P = 0.003). Univariate analysis identified previous chemotherapy, advanced disease, failure to respond to fludarabine, elevated serum β2-microglobulin level (P < 0.001), low serum albumin level (P = 0.024), elevated serum creatinine concentration (P = 0.008), and low granulocyte count (P = 0.003) as risk factors for infection. Multivariate analysis identified Rai stage III or IV (odds ratio, 1.98 [95% CI, 1.17 to 3.94]), previous treatment (odds ratio, 2.24 [CI, 1.43 to 3.51]), and elevated serum creatinine concentration (odds ratio, 1.98 [CI, 1.09 to 3.67]) as statistically significant independent risk factors for major infection. A baseline granulocyte count of more than 1000 cells/µL was protective (odds ratio, 0.54 [CI, 0.29 to 0.99]). Five (26%) of 19 patients with a CD4 count less than 50 cells/mL developed cutaneous zoster compared with 9 (6%) of 139 patients with a CD4 count greater than 50 cells/mL (P = 0.01).

Conclusions: Fludarabine used in previously treated patients with chronic lymphocytic leukemia may be associated with infections involving T-cell dysfunction, such as listeriosis, pneumocystosis, mycobacterial infections, and opportunistic fungal and viral infections. Prophylaxis or presumptive therapy should be initiated in the appropriate setting.


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Figure 1.
Infection prophylaxis in patients with chronic lymphocytic leukemia treated with fludarabine.
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Figure 2.
Management of infectious complications in patients with chronic lymphocytic leukemia treated with fludarabine.Pneumocystis carinii

BAL = bronchoalveolar lavage; CMV = cytomegalovirus; CSF = cerebrospinal fluid; CT = computed tomography; LP = lumbar puncture; MRI = magnetic resonance imaging; PCP = pneumonia; PCR = polymerase chain reaction; TMP-SMX = trimethoprim-sulfamethoxazole; VZV = varicella-zoster virus.

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