Empirical Versus Pre-Emptive Antifungal Therapy in High-Risk Febrile Neutropenic Patients: A Prospective Randomized Study.
Authors: Cordonnier Catherine , Pautas Cecile , Maury Sebastien , Vekhoff Anne , Farhat Hassan , Suarez Felipe , Basile Maria , Isnard Francoise , Ades Lionel , Kuhnoski Frederique , Reman Oumady , Chehata Sami , De Revel Thierry , Lepretre Stephane , Raffoux Emmanuel , Bretagne Stephane , Schwarzinger Michael 
Published: October 2019

Abstract
Empirical (E) antifungal therapy (ATF) is a standard of care in febrile neutropenic patients under broad-spectrum antibiotics. However, the safety and cost-effectiveness of the E strategy are challenged, due to better diagnostic methods including galactomannan antigenemia (GM Ag) and efficient therapies for invasive fungal infection (IFI). Previous open studies have evaluated the feasibility of a pre-emptive (PE) strategy where ATF is restricted to patients with clinical symptoms and/or mycological criteria of IFI. This study is the first prospective, randomized trial comparing E vs PE strategy.
Objective: The primary objective of the study was to show that a PE strategy was not inferior to a E strategy for overall survival.
Patients: 293 adult patients with hematologic malignancies (acute leukemia: 199; lymphoma: 65; others:29), including 91 with autologous stem cell transplant (ASCT) and an expected neutropenia (<500 PMN) of ≥ 10 days following chemotherapy were randomized between E or PE strategy with polyens. All were screened 2/w for GM Ag. E patients were given ATFs in case of persistent or recurrent fever, whatever the accompanying symptoms, while PE patients were given ATFs only in case of pneumonia, severe mucositis, septic shock, sinusitis, or skin lesions evocative of filamentous infection, aspergillus colonization, or positive GM Ag.
Methods: This is a multicenter open-label randomized non-inferiority trial. Randomization was stratified according to center, induction vs. consolidation or ASCT, and antifungal prophylaxis. The primary endpoint was the proportion of patients alive either 14 days after recovery from neutropenia or 60 days after inclusion in case of persistent neutropenia or severe complication. Non-inferiority was concluded if survival difference was above the threshold of −8% in intention-to-treat (ITT) and per protocol (PP) analyses. The secondary endpoint was the proportion of patients with IFI (EORTC-MSG definitions).
Results: Among the 150 patients of the E group, and the 143 of the PE group, the mean (std) age was 52 (14) y. The mean (std) duration of neutropenia was 21 (11) days (min: 5; max: 69). Survival was not inferior in the PE group (136/143) as compared to the E group (147/150) with a survival difference of −2.9% [95% CI, −6.4% to 0.6%] in ITT (n=293) and −2.9% [95% CI, −6.8% to 0.1%] in PP (n=266) above the threshold of −8%. The IFI-related mortality was not significantly different in the PE group (3/150) and the E group (0/143) (p=0.12). However, significantly more IFI were diagnosed in the PE group (13/143) when compared to the E group (4/150) (p<0.02). The PE patients received significantly less ATFs than the E group (46% v. 66% of patients, p<0.001).
Conclusion: A PE strategy based on clinical symptoms and GM Ag did not reduce the overall survival of prolonged neutropenic patients when compared to a E strategy. Although we observed significantly more IFI in the PE than in the E group, this did not translate in a higher fungal-related mortality (Grants: PHRC 2002 AOR02028)