Frequency and type of serious infections in fludarabine-refractory B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma - Implications for clinical trials in this patient population

BACKGROUND. Treatments for fludarabine-refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) are limited. Most new therapies being examined in fludarabine-refractory patients have shown a high frequency of serious infection. Little data exist regarding the frequency of infections in this population treated with noninvestigational best supportive care therapies. METHODS. The infectious courses of 27 patients with fludarabine-refractory CLL/ SLL were retrospectively reviewed. Fludarabine-refractoriness was defined as either relapse within six months of completion of or failure to respond to fludarabine treatment. Infections were documented after patients met National Cancer Institute criteria for further treatment. Serious infections were defined as infections mandating admission to the hospital for intravenous antibiotics. RESULTS. Patient characteristics included: median age 67 years (range, 40-83), median 3 chemotherapy treatments (range, 1-8), and hypogammaglobulinemia in 73% of patients. Pneumocystis carinii prophylaxis was given to 89% of patients. Serious infections developed in 24 out of 27 patients (89%). Patients had a median of 2 admissions (range, 0-11) for serious infection occurring at a median of 4 months (range, 0-21) from onset of fludarabine-reftactoriness. The median frequency of admission for infection was 0.17 per month. Most common sites for infection in decreasing frequency were: respiratory tract, urinary tract, blood/ sepsis, and soft tissues. Bacteria caused 69 out of 88 infections (78.4%); viruses (varicella-zoster and herpes simplex) caused 11 out of 88 (12.5%); fungi caused 4 out of 88 (4.5%); and opportunistic infections caused 4 out of 88 (4.5%). Median survival was 13.0 months (range, 1-44+). CONCLUSIONS. The frequency of serious infections in patients with fludarabine-refractory CLL/SLL is high. These findings are relevant to trials with new and highly effective agents for which the incidence of serious infections after treatment might otherwise appear to be prohibitively high.