Objectives

The study is designed as a Phase III, randomized, double-blind, multicenter, prospective, comparative study of fluconazole versus voriconazole for the prevention of fungal infections in allogeneic transplant recipients.

Background

Allogeneic blood and marrow transplant patients are highly susceptible to invasive fungal infection prior to engraftment, due to neutropenia and mucosal injury. After engraftment, an impairment of cell mediated immunity from graft-versus-host disease (GVHD) and the use of aggressive immunosuppressive therapies, such as corticosteroids, leave patients vulnerable to invasive fungal infections. Recipients of alternate donor transplants are especially susceptible due to slow reconstitution of cell mediated immunity.
Fluconazole prophylaxis in prospective randomized trials of both autologous and allogeneic transplant recipients has previously been demonstrated to reduce invasive fungal infections prior to engraftment (NEJM 326:845, 1992; Clin Inf Dis 28:331, 1999). A prolonged course of fluconazole given during the first 75 days (to cover the early post-engraftment period of risk) was highly effective in preventing yeast infections (J Inf Dis 171:1545, 1985). This translated into a survival benefit. An analysis of long-term outcomes of these individuals demonstrated a continuing benefit beyond the course of prophylaxis with a further benefit in survival (Blood 96:12055, 2000). In another study of various factors associated with survival after matched unrelated donor transplants, fluconazole prophylaxis was an independent predictor for overall survival in a multivariate analysis (NEJM 338:962, 1998). Fluconazole prophylaxis has been found to be effective and safe with few substantive drug interactions and has been widely adopted by transplant clinicians.

Participants

A total of 600 patients were randomized into the trial. Subjects were ≥ 2 years of age undergoing related or unrelated allogeneic HCT after myeloablative conditioning regimen for the treatment of a hematological malignancy. Patients were excluded if they had prior invasive yeast infection within 8 weeks of study entry, mold infection within 4 months of study entry, or a viral or bacterial infection not controlled at time of registration.

Design

BMT CTN 0101 was a Phase III, randomized, double-blind, multicenter, prospective, comparative study of fluconazole versus voriconazole for the prevention of invasive fungal infections (IFI) in allogeneic transplant recipients. The trial was conducted in 35 centers participating in the Blood and Marrow Transplant Clinical Trials Network. Recipients were stratified by center and donor type (sibling vs. unrelated) and randomized to either the fluconazole or voriconazole arm in a 1:1 ratio. Subjects who meet all entry criteria were assigned randomly to voriconazole or fluconazole within 72 hours of Day 0. Participants began the study drug on Day 0 (after completion of the conditioning regimen). Day 0 was defined as the day infusion of the stem cell product was completed. The study drug continued until Day 100 following transplant or until one or more criteria for early withdrawal was met. The development of any fungal infection during prophylaxis was classified according to protocol definitions. All subjects were monitored in structured program by clinical and galactomannan screening.

Conclusions

This study demonstrated that in the context of intensive monitoring and structured empiric antifungal therapy, 6-month fungal-free survival and overall survival did not differ in allogeneic HCT recipients given prophylactic fluconazole or voriconazole.

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