BACKGROUND: Empiric antifungal therapy is considered the standard of care for high-risk neutropenic patients with persistent fever. The impact of a preemptive, diagnostic-driven approach based on galactomannan screening and chest computed tomography scan on demand on survival and on the risk of invasive fungal disease (IFD) during the first weeks of high-risk neutropenia is unknown. METHODS: Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and allogeneic hematopoietic cell transplant recipients were randomly assigned to receive caspofungin empirically (arm A) or preemptively (arm B), while receiving fluconazole 400 mg daily prophylactically. The primary end point of this noninferiority study was overall survival (OS) 42 days after randomization. RESULTS: Of 556 patients recruited, 549 were eligible: 275 in arm A and 274 in arm B. Eighty percent of the patients had AML or MDS requiring high-dose chemotherapy, and 93% of them were in the first induction phase. At day 42, the OS was not inferior in arm B (96.7%; 95% confidence interval [CI], 93.8%-98.3%) when compared with arm A (93.1%; 95% CI, 89.3%-95.5%). The rates of IFDs at day 84 were not significantly different, 7.7% (95% CI, 4.5%-10.8%) in arm B vs 6.6% (95% CI, 3.6%-9.5%) in arm A. The rate of patients who received caspofungin was significantly lower in arm B (27%) than in arm A (63%; P < .001). CONCLUSIONS: The preemptive antifungal strategy was safe for high-risk neutropenic patients given fluconazole as prophylaxis, halving the number of patients receiving antifungals without excess mortality or IFDs. Clinical Trials Registration. NCT01288378; EudraCT 2010-020814-27.

Department of Hematology Algemeen Ziekenhuis St Jan Brugge Belgium

Department of Hematology Caen University Hospital Caen France

Department of Hematology Centre Hospitalier Universitaire Henri Mondor Créteil France

Department of Hematology Centre Hospitalier Universitaire Limoges Limoges France

Department of Hematology Gustave Roussy Cancer Campus Villejuif France

Department of Hematology Masaryk University Brno and Institute of Hematology and Blood Transfusion Prague Czech Republic

Department of Hematology Oncology Caritas Hospital Bad Mergentheim Germany

Department of Hematology Oncology Faculty of Medicine and Medical Centre University of Freiburg Freiburg Germany

Department of Hematology Radboud University Medical Center Nijmegen The Netherlands

Department of Hematology University Hospitals Leuven Leuven Belgium

Department of Hematology University of Liège and University Hospital of Liège Liège Belgium

Department of Infection Immunity and Biochemistry Cardiff University Cardiff United Kingdom

Department of Infectious Diseases Ensemble Hospitalier de la Côte Morges Switzerland

Department of Internal Medicine 2 Universitaetsklinikum Würzburg Germany

Department of Internal Medicine Infectious Diseases Cliniques Universitaires St Luc Brussels Belgium

Department of Internal Medicine Institut Jules Bordet Brussels Belgium

Department of Medicine Lausanne University Hospital Lausanne Switzerland

Department of Oncohematology Comenius University and National Cancer Institute Bratislava Slovakia

European Organisation for Research and Treatment of Cancer Headquarters Brussels Belgium

Merck and Co Inc Kenilworth New Jersey USA

Service des maladies du sang Centre Hospitalier Régional Universitaire Lille Lille France

Translational Health Economics Network Bordeaux University Hospital Bordeaux France

Zobrazit více v PubMed

EORTC International Antimicrobial Therapy Cooperative Group . Empiric antifungal therapy in febrile granulocytopenic patients. Am J Med 1989; 86:668–72. PubMed

Pizzo P, Robichaud KJ, Gill FA, Witebsky FG. Empirical antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. Am J Med 1982; 72:101–11. PubMed

Freifeld AG, Bow EJ, Sepkowitz KA, et al. . Clinical practice guidelines for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011; 52:427–31. PubMed

Marchetti O, Cordonnier C, Calandra T. Empirical antifungal therapy in neutropaenic cancer patients with persistent fever. Eur J Cancer 2007; 5:32–42.

Walsh TJ, Finberg RW, Arndt C, et al. . Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med 1999; 340:764–71. PubMed

Walsh TJ, Teppler H, Donowitz GR, et al. . Caspofungin vs liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 2004; 351:1391–402. PubMed

Bretagne S, Marmorat-Khuong A, Kuentz M, Latge JP, Bart-Delabesse E, Cordonnier C. Serum Aspergillus galactomannan antigen testing by sandwich ELISA: practical use in neutropenic patients. J Infect 1997; 35:7–15. PubMed

Maertens J, Van Eldere J, Verhaegen J, Verbeken E, Verschakelen J, Boogaerts M. Use of circulating galactomannan screening for early diagnosis of invasive aspergillosis in allogeneic stem cell transplant recipients. J Infect Dis 2002; 186:1297–306. PubMed

Maertens J, Verhaegen J, Demuynck H, et al. . Autopsy-controlled prospective evaluation of serial screening for circulating galactomannan by a sandwich enzyme-linked immunosorbent assay for haematological patients at risk for invasive aspergillosis. J Clin Microbiol 1999; 37:3223–8. PubMed PMC

Mennink-Kersten MA, Donnelly JP, Verweij PE. Detection of circulating galactomannan for the diagnosis and management of invasive aspergillosis. Lancet Infect Dis 2004; 4:349–57. PubMed

Caillot D, Couaillier JF, Bernard A, et al. . Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol 2001; 19:253–9. PubMed

Heussel CP, Kauczor HU, Heussel GE, et al. . Pneumonia in febrile neutropenic patients and in bone marrow and blood stem-cell transplant recipients: use of high-resolution computed tomography. J Clin Oncol 1999; 17:796–805. PubMed

Maertens J, Theunissen K, Verhoef G, et al. . Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis 2005; 41:1242–50. PubMed

Aguilar-Guisado M, Espigado I, Cordero E, et al. . Empirical antifungal therapy in selected patients with persistent febrile neutropenia. Bone Marrow Transplant 2010; 45:159–64. PubMed

Dignan FL, Evans SO, Ethell ME, et al. . An early CT-diagnosis based treatment strategy for invasive fungal infection in allogeneic transplant recipients using caspofungin first line: an effective strategy with low mortality. Bone Marrow Transplant 2009; 44:51–6. PubMed

Pagano L, Caira M, Nosari A, et al. . The use and efficacy of empirical vs preemptive therapy in the management of fungal infections: the HEMA e-Chart Project. Haematologica 2011; 96:1366–70. PubMed PMC

Tan B, Low J, Chlebicka N, et al. . Galactomannan-guided preemptive vs. empirical antifungals in the persistently febrile neutropenic patient: a prospective randomized study. Int J Infect Dis 2011; 15:e350–6. PubMed

Blenow O, Remberger M, Klingspor L, et al. . Randomized PCR-based therapy and risk factors for invasive fungal infection following reduced-intensity conditioning and hematopoietic SCT. Bone Marrow Transplant 2010; 45:1710–8. PubMed

Cuenca-Estrella M, Meije Y, Diaz-Pedroche C, et al. . Value of serial quantification of fungal DNA by a real-time PCR based technique for early diagnosis of invasive aspergillosis in patients with febrile neutropenia. J Clin Microbiol 2009; 47:379–84. PubMed PMC

Halliday C, Hoile R, Sorrell T, et al. . et al. Role of prospective screening of blood for invasive aspergillosis by polymerase chain reaction in febrile neutropenic recipients of haematopoietic stem cell transplants and patients with acute leukaemia. Br J Haematol 2005; 132:478–86. PubMed

Morissey O, Chen S, Sorrell T, et al. . Galactomannan and PCR vs culture and histology for directing use of antifungal treatment for invasive aspergillosis in high-risk hematology patients: a randomised controlled trial. Lancet Infect Dis 2013; 13:519–28. PubMed

Girmenia C, Micozzi A, Gentile G, et al. . Clinically driven diagnostic antifungal approach in neutropenic patients: a prospective feasibility study. J Clin Oncol 2010; 28:667–74. PubMed

Cordonnier C, Pautas C, Maury S, et al. . Empirical vs preemptive antifungal therapy for high-risk, febrile, neutropenic patients: a randomized, controlled trial. Clin Infect Dis 2009; 48:1042–51. PubMed

Kimura SI, Murata T, Akahoshi Y, et al. . Economic evaluation of a preemptive treatment strategy for invasive fungal infection in neutropenic patients with hematological diseases. Eur J Clin Microbiol Infect Dis 2015; 34:951–61. PubMed

Severens J, Donnelly J, Meris J, De Pauw B, Verweij P. Two strategies for managing invasive aspergillosis: a decision analysis. Clin Infect Dis 1997; 25:1148–54. PubMed

Transplantation ESfBaM. MED-AB FORMS MANUAL: A guide to the completion of the EBMT HSCT Med-AB forms. The European Society for Blood and Marrow Transplantation.

De Pauw B, Walsh T, Donnelly JP, et al. . Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46:1813–21. PubMed PMC

Cornely OA, Maertens J, Winston DJ, et al. . Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356:348–59. PubMed

Ascioglu S, Rex JH, de Pauw B, et al. . Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 2002; 34:7–14. PubMed

Even C, Bastuji-Garin S, Hicheri Y, et al. . Impact of invasive fungal disease on the chemotherapy schedule and event-free survival in acute leukemia patients who survived fungal disease: a case-control study. Haematologica 2011; 96:337–41. PubMed PMC

Donnelly J, Cordonnier C, Cuenca-Estrella M, et al. . A European period prevalence study to estimate the rate of invasive pulmonary mould disease (PIMDA Study). Barcelona, Spain: ECCMID, 2014.

Robin C, Cordonnier C, Sitbon K, et al. . Mainly post-transplant factors are associated with invasive aspergillosis after allogeneic stem cell transplantation: a study from the Surveillance des Aspergilloses Invasives en France and Société Francophone de Greffe de Moelle et de Thérapie Cellulaire. Biol Blood Marrow Transplant 2019; 25:354–61. PubMed

Duarte RF, Sánchez-Ortega I, Cuesta I, et al. . Serum galactomannan-based early detection of invasive aspergillosis in hematology patients receiving effective antimold prophylaxis. Clin Infect Dis 2014; 59:1696–702. PubMed

Zobrazit více v PubMed

ClinicalTrials.gov
NCT01288378