Fluconazole Prophylaxis of Fungal Infections in Patients with Acute Leukemia: Results of a Randomized Placebo-Controlled, Double-Blind, Multicenter Trial

Infections continue to be common causes of morbidity and mortality in neutropenic patients undergoing chemotherapy for acute leukemia [1, 2]. Although bacteria are usually the primary pathogens in neutropenic patients, most bacterial infections can now be treated successfully with currently available antibacterial drugs [3, 4]. In contrast, fungal infections, often documented only at autopsy, are increasing in frequency in patients with acute leukemia and are now responsible for most fatal infections [5-7]. Candida species are the predominant fungal pathogens, followed by Aspergillus species, the zygomycetes, and several newly recognized opportunistic fungi. Survival from invasive fungal infections has generally been poor in neutropenic patients with acute leukemia. In many cases, this poor survival can be linked to delays in diagnosis. Obstacles to the rapid diagnosis of invasive fungal infection include difficulty in isolation of fungi in cultures, inability to perform biopsies or other invasive diagnostic procedures in patients with disorders of coagulation, and the nonavailability of reliable serologic tests [8]. Because of these difficulties, amphotericin B is frequently administered empirically to patients with neutropenia and persistent fever refractory to antibacterial therapy [3, 9, 10]. This approach, however, is limited by the toxicity of amphotericin B, especially in patients receiving other nephrotoxic drugs. The problems associated with effective therapy of serious fungal infections in neutropenic patients with acute leukemia have been the stimulus for using antifungal drugs for prophylaxis. Unfortunately, prophylaxis with oral agents such as nystatin, clotrimazole, and ketoconazole has produced inconsistent results either due to lack of efficacy or poor patient compliance [11]. Similarly, prophylaxis with parenteral drugs like intravenous miconazole or amphotericin B has been used only on a limited basis because of concerns about toxicity and overall effectiveness [12, 13]. Thus, there is currently no uniformly accepted or proven approach for prevention of fungal infections in neutropenic patients with acute leukemia. Fluconazole is a new triazole antifungal agent with activity against many common fungal pathogens causing infection in patients with acute leukemia [14]. Fluconazole has a favorable pharmacokinetic profile that includes a long serum half-life, making once-daily administration possible, more consistent absorption from the gastrointestinal tract than that of ketoconazole, excellent penetration into the cerebrospinal fluid, and elimination predominantly by renal mechanisms. Significant side effects related to fluconazole have been uncommon and occur less frequently than those associated with amphotericin B. Fluconazole is currently approved for treatment of Candida and cryptococcal infections [15, 16]. Studies in neutropenic animal models also suggest that fluconazole may be effective for prevention of Candida infection and for treatment of invasive aspergillosis when given at high doses [17, 18]. Similar studies in neutropenic bone marrow transplants found that prophylactic fluconazole prevents both systemic and superficial fungal infections [19]. For these reasons, we did a double-blind, placebo-controlled trial of prophylactic fluconazole in neutropenic patients undergoing chemotherapy for acute leukemia. Methods Patients Patients were eligible for the study if they satisfied the following criteria: 1) undergoing chemotherapy for acute leukemia or the blast crisis of chronic myelogenous leukemia; 2) 13 years of age or older; 3) anticipated neutropenia of less than 500 neutrophils per mm3 for 7 or more days; 4) no clinical evidence of fungal infection at time of study entry; 5) no systemic antifungal therapy within the 2 weeks before randomization; and 6) no allergy to the imidazoles or azoles. Patients with moderate or severe liver disease (aspartate aminotransferase [AST], alanine aminotransferase [ALT], or alkaline phosphatase greater than five times the upper limit of normal or a total bilirubin greater than 43 mol/L) and patients with renal insufficiency (creatinine clearance of less than 0.83 mL/s) were excluded from the study. Our trial involved 18 oncology centers. Informed consent approved by the institutional review board at each center was obtained from each patient. Study Drugs Eligible patients were randomly assigned to receive either prophylactic fluconazole or placebo in a double-blind fashion. The fluconazole or placebo was begun at the time of initiation of chemotherapy and administered in identically appearing capsules. A capsule contained 100 mg of fluconazole, and each patient received four capsules (400 mg) as a single daily dose. For patients unable to tolerate oral capsules, the fluconazole or placebo was administered intravenously. The intravenous dose of fluconazole was 200 mg every 12 hours and was infused over 1 hour. The daily dose of fluconazole was reduced in patients who developed renal failure [20]. Prophylaxis with the study drug was continued through the course of chemotherapy and neutropenia and until 7 days after the neutrophil count reached 1000 cells per mm3 or greater. The maximum duration of prophylaxis was 10 weeks. Prophylaxis was discontinued if one of the following events occurred: 1) development of a documented invasive fungal infection; 2) initiation of empiric systemic antifungal therapy (amphotericin B) for clinically suspected invasive fungal infection; 3) adverse side effects related to the study drug; or 4) patient's inability to continue in the study due to noncompliance or death. Patients who developed a documented superficial fungal infection could be treated with topical clotrimazole while continuing to receive the study drug. Laboratory Procedures Complete blood counts, prothrombin times, blood urea nitrogen levels, serum creatinine and electrolyte determinations, urinalyses, and liver function studies (AST, ALT, alkaline phosphatase, and total bilirubin) were obtained at the time of study entry, once or twice weekly during the study, and at the end of prophylaxis to assess patients for drug-related side effects. Patients were also examined at least twice weekly for clinical symptoms and signs of adverse effects related to the study drugs. A serum pregnancy test was done on all women of child-bearing potential before the study began. Surveillance cultures of the nasopharynx, oropharynx, axillae, urine, perirectal area, and stool were done at the time of study entry, once weekly during the study, and at the end of prophylaxis to determine the presence of fungal colonization. Cultures of blood and other suspected sites of fungal infection were obtained during the study whenever a patient's clinical condition suggested the possibility of fungal infection. Amphotericin B therapy was initiated in accordance with previously established guidelines when a reasonable clinical suspicion of systemic fungal infection existed [3, 9, 10]. Definition of Fungal Colonization and Infection Fungal colonization was defined as the presence of a fungus in one or more surveillance cultures in the absence of any clinical symptoms or signs of infection. Superficial fungal infections were diagnosed by the isolation of a fungus from the skin, oropharynx, or gastrointestinal tract in association with signs of inflammation, ulcerations, plaques, or exudates not explainable by other pathogens. Invasive fungal infections were diagnosed by the presence of fungus in the blood, pulmonary tissue or secretions, sinuses, soft tissues, or other organ structures in association with symptoms and signs of infection not explainable by other pathogens. Data Collection and Statistical Analysis Data required by the study protocol were collected and recorded in case report forms by the investigators at each oncology center. Barton and Polansky Associates independently reviewed all case report forms for accuracy and compliance with the protocol by comparing the case report forms with patients' medical and pharmacy records. The case report forms were then submitted to clinical research personnel at Pfizer Central Research for review and entry of data into computer programs. All reviews, classifications of infections, and data entry were done blindly before the statistical analyses were performed. Proven fungal infections were required to meet the definitions of infection established by the protocol and approved by the Federal Drug Administration before the study. There was no interim analysis. All statistical tests were performed as two-tailed tests. The Fisher exact test was used to compare differences in proportions, whereas the equality of two distributions was compared by the Wilcoxon rank-sum test. Univariate comparisons of times to specific events were performed by using Kaplan-Meier estimates of survival distributions and the Gehan generalized Wilcoxon test [21]. The SAS procedure LIFETEST was used for these comparisons [22]. The Cochran-Mantel-Haenszel chi-square test was used to check the equality of mean scores of ordinal response variables adjusted for center effect. Except for one placebo patient who did not receive the study drug and one fluconazole patient with invasive fungal infection at baseline, all patients were included in the efficacy analysis (intent-to-treat analysis). Center by treatment interactions were tested by using the Breslow-Day test of homogeneity of odds ratio [23]. Results Patient Characteristics Two hundred fifty-seven patients were enrolled into the study. One patient randomized to the placebo group did not receive the study drug and was excluded from all analyses. The characteristics of the other 256 patients are summarized in Table 1. One hundred thirty-two patients received placebo, and 124 patients were given fluconazole. The two groups of patients were similar in terms of age, sex, underlying disease, and baseline fungal colonizatio