A double-blind trial on prophylactic voriconazole (VRC) or placebo during induction chemotherapy for acute myelogenous leukaemia (AML)

Abstract

Objectives: Invasive fungal infections remain a frequent cause of morbidity and mortality in long-term neutropenic patients. The availability of tolerable broad-spectrum antifungals like voriconazole stimulated the discussion about optimal timing of antifungal therapy. We conducted a trial to analyze the efficacy and safety of voriconazole in the prevention of lung infiltrates during induction chemotherapy for acute myelogenous leukaemia (AML).

Methods: This was a prospective, randomised, double-blind, placebo-controlled phase III trial in AML patients undergoing remission induction chemotherapy. Oral voriconazole 200 mg twice daily or placebo was administered until detection of a lung infiltrate or end of neutropenia. Primary efficacy parameter was the incidence of lung infiltrates until day 21 after initiation of chemotherapy. Secondary objectives were incidence of infections, length of stay in hospital, time to antifungal treatment, time to first fever, and drug safety.

Results: A total of 25 patients were randomly assigned to receive voriconazole (N=10) or placebo (N=15). Incidence of lung infiltrates until day 21 was 0 (0%) in the voriconazole and 5 (33%) in the placebo group (P=0.06). Average length of stay in hospital was shorter in the voriconazole group (mean 31.9 days) than in the placebo group (mean 37.3 days, P=0.09). Four patients were diagnosed with hepatosplenic candidiasis until a 4 week follow-up, all in the placebo group (P=0.11). Adverse events and toxicity did not differ between the two treatment groups. The trial was stopped prematurely when another trial demonstrated reduced mortality by antifungal prophylaxis with posaconazole, thus rendering further randomisation against placebo unethical.

Conclusion: In AML patients undergoing induction chemotherapy, prophylactic oral voriconazole 200 mg twice daily resulted in trends towards reduced incidences of lung infiltrates and hepatosplenic candidiasis. Voriconazole was safe and well tolerated.