Pre-emptive versus empirical antifungal therapy in patients with febrile neutropenia with acute leukaemia: a GIMEMA study

Objectives: To compare the efficacy of pre-emptive antifungal therapy (PAT) and empirical antifungal therapy (EAT) in patients with febrile neutropenic acute leukaemia (AL) with/without anti-mold prophylaxis. Methods: We included 92 patients with AL and neutropenia with fever unresponsive to empiric antibiotics, stratified by posaconazole prophylaxis to receive EAT (n = 40) or PAT (n = 52). In the PAT group, a standardized diagnostic workup for the detection of invasive fungal infection (IFI) was performed. The study endpoints were antifungal therapy initiation, IFI documentation, safety, and cost. Results: Posaconazole prophylaxis was equally distributed among the patients (overall 55.4%). Antifungal therapy was started in 58% of the patients in the PAT group versus 100% in the EAT group (P < 0.01; 95% CI: 0.42 [0.28-0.55]). In the EAT and PAT groups, overall proven/probable IFI rates were 2% and 17%, respectively (P = 0.02; 95%CI: -0.14 [-0.26 to -0.03]) and 4% and 10% in patients with posaconazole prophylaxis, respectively (P = 0.3; 95% CI: -0.06 [-0.20-0.07]). At hospital discharge, mortality was 19% in the EAT and 5% in the PAT groups (P = 0.02; 95% CI: -0.14 [-0.26 to -0.03]), unrelated to the use of posaconazole prophylaxis, and no IFI-related death was observed. The mean costs per patient were €7681 and €3344 in the EAT and PAT groups, respectively (P = 0.003; 95% CI: €4337 [€1814-6860]). Adverse reactions to antifungals were similar between the groups. Conclusions: In patients with persistently febrile neutropenic AL, PAT was safe and effective and reduced the use and costs of antifungals, irrespective of anti-mold prophylaxis, compared with empirical treatment.