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Immediate versus deferred empirical antifungal (IDEA) therapy in high-risk patients with febrile neutropenia: a randomized, double-blind, placebo-controlled, multicenter study

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Abstract

Empirical antifungal therapy is widely used in high-risk neutropenic hematology patients with fever persisting for more than 4 days. This clinical trial assessed whether immediate empirical therapy with voriconazole could lower the rates of invasive fungal infections (IFIs) compared with this approach. In a double-blind, placebo-controlled, multicenter study, patients with acute leukemia undergoing chemotherapy or allogeneic hematopoietic stem cell transplantation (HSCT) recipients were randomized to broad-spectrum antibacterial therapy plus voriconazole (immediate) or placebo (deferred) after the onset of neutropenic fever. If fever persisted for 96 h, patients were switched to open-label intravenous voriconazole; oral treatment was permitted after 96 h. The primary endpoint was the rate of proven/probable IFIs between Days 2 and 28 after fever onset in the modified intent-to-treat (mITT) complete-case population. One hundred and forty-seven patients were randomized to immediate (n = 81) or deferred (n = 66) voriconazole. In the mITT population, six patients in the immediate group and nine in the deferred group developed proven/probable IFI between Days 2 and 28 (p = 0.258). The safety profiles were similar in both groups. While immediate empirical therapy with voriconazole appears to be safe in febrile neutropenic high-risk patients, it was not associated with a significant reduction in IFIs compared with therapy deferred for 96 h after fever onset.

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Notes

  1. Disclaimer: voriconazole is not specifically licensed for empirical antifungal therapy in febrile neutropenic patients.

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Acknowledgments

This study was sponsored by Pfizer Inc.

The authors would like to thank Peter Cooper and Fiona Brock (Quanticate, Hitchin, UK) for conducting the statistical analyses for this paper. The authors would also like to thank Dietmar Pfründer, who was with Pfizer at the time this study was started, for his support during the initial stages of this study.

The study protocol was initiated and developed by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology.

Manuscript preparation

Editorial support was provided by Leigh Prevost and Dominik Wolf of PAREXEL and was funded by Pfizer International Operations.

Potential conflicts of interest

G.M. has served as a consultant for Gilead Sciences, Merck/MSD, and Pfizer, and has been on the speakers’ bureau for Cephalon, Gilead Sciences, Merck/MSD, and Pfizer. W.J.H. has served as a consultant for Merck/MSD and Pfizer, and has been on the speakers’ bureau for Cephalon, Gilead Sciences, Merck/MSD, and Pfizer. B.H. has no conflicts of interest to declare. H.-A.H. has no conflicts of interest to declare. C.R. has no conflicts of interest to declare. T.W. has no conflicts of interest to declare. O.A.C. is supported by the German Federal Ministry of Research and Education (BMBF grant 01KN1106) and has served as a consultant for Astellas, Basilea, F2G, Gilead, Merck/Schering, Optimer, and Pfizer; he has received research grants from Astellas, Basilea, Gilead, Merck/Schering, Optimer, and Pfizer; and lecture honoraria from Astellas, Gilead, Merck/Schering, and Pfizer. J.L. has no conflicts of interest to declare. M.R. has been a paid advisory board member and has received lecture honoraria, including service on speakers’ bureaus, from Essex, MSD, Pfizer, Gilead, Astellas, and Novartis; he has also received research grants/grants pending from Pfizer, MSD, and Deutscher Stifterverband, and payment for the development of educational presentations from Pfizer.

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Authors and Affiliations

  1. Klinikum Ernst von Bergmann, Charlottenstrasse 72, 14467, Potsdam, Germany

    G. Maschmeyer

  2. Universitätsklinikum Würzburg, Würzburg, Germany

    W. J. Heinz & J. Löffler

  3. Klinikum Bremen Mitte, Bremen, Germany

    B. Hertenstein

  4. Universität Kiel, Kiel, Germany

    H.-A. Horst

  5. Universität Erlangen-Nürnberg, Erlangen, Germany

    C. Requadt

  6. Universitätsklinikum Schleswig-Holstein (Campus Lübeck), Lübeck, Germany

    T. Wagner

  7. 1st Department of Internal Medicine; ZKS Köln, BMBF 01KN1106; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

    O. A. Cornely

  8. Charité Universitätsmedizin (Campus Mitte), Berlin, Germany

    M. Ruhnke

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Voriconazole is not specifically licensed for empirical antifungal therapy in febrile neutropenic patients.

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Appendix

Appendix

In addition to the authors, the following principal investigators participated in the IDEA study: Dr. Walter E. Aulitzky (Robert-Bosch-Krankenhaus, Stuttgart, Germany), Dr. Hartmut Bertz (Medizinische Universitätsklinik und Poliklinik, Freiburg, Germany), Dr. Claudia Binder (Georg-August-Universität, Göttingen, Germany), Dr. Stefanie Buchholz (Medizinische Hochschule Hannover, Hannover, Germany), Dr. Axel A. Fauser (Klinik für KMT und Hämatologie/Onkologie, Idar-Oberstein, Germany), Dr. Mathias Hänel (Klinikum Chemnitz, Chemnitz, Germany), Dr. Wolfgang Heit (Ev. KKH Essen-Werden, Essen, Germany), Dr. Martin Hoffmann (Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany), Dr. Meinolf Karthaus (Klinikum Neuperlach, München, Germany), Dr. Ulrich Keller (Klinikum Rechts der Isar der TU München, München, Germany), Dr. Michael G. Kiehl (Klinikum Frankfurt/Oder, Frankfurt/Oder, Germany), Dr. Wolf-Dieter Ludwig (Helios-Klinikum Berlin Buch, Berlin, Germany), Dr. Rolf Mahlberg (Klinikum Mutterhaus der Borromärinnen, Trier, Germany), Dr. Stefan Neuburger (Charité Universitätsmedizin, Campus Virchow-Klinikum, Berlin, Germany), Dietger Niederwieser (Universitätsklinikum Leipzig, Leipzig, Germany), Dr. Michael Pfreundschuh (Universitätsklinikum des Saarlandes, Homburg/Saar, Germany), Dr. Günther Schlimok (Zentralklinikum Augsburg, Augsburg, Germany), Dr. Norbert Schmitz (AK St. Georg, Hamburg, Germany), Dr. Ulrich S. Schuler (Universitätsklinikum Carl Gustav Carus, Dresden, Germany), Dr. Rainer Schwerdtfeger (Stiftung Deutsche Klinik f. Diagnostik GmbH, Wiesbaden, Germany), Dr. Kambiz Tagizadeh (Evangelisches Johannes-Krankenhaus Bielefeld, Bielefeld, Germany), Dr. Eckhard Thiel (Charité Universitätsmedizin, Campus Benjamin Franklin, Berlin, Germany), Dr. Andrew J. Ullmann (Klinikum der Johannes Gutenberg Universität Mainz, Mainz, Germany), Dr. Axel Zander (Universitätskrankenhaus Hamburg-Eppendorf, Hamburg, Germany).

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Maschmeyer, G., Heinz, W.J., Hertenstein, B. et al. Immediate versus deferred empirical antifungal (IDEA) therapy in high-risk patients with febrile neutropenia: a randomized, double-blind, placebo-controlled, multicenter study. Eur J Clin Microbiol Infect Dis 32, 679–689 (2013). https://doi.org/10.1007/s10096-012-1794-4

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