On the basis of improved overall survival, treatment guidelines strongly recommend antifungal prophylaxis during remission induction chemotherapy for patients with acute myeloid leukaemia. Many novel targeted agents are metabolised by cytochrome P450, but potential drug-drug interactions (DDIs) and the resulting risk-benefit ratio have not been assessed in clinical trials, leading to uncertainty in clinical management. Consequently, the European Haematology Association commissioned experts in the field of infectious diseases, haematology, oncology, clinical pharmacology, and methodology to develop up-to-date recommendations on the role of antifungal prophylaxis and management of pharmacokinetic DDIs with triazole antifungals. A systematic literature review was performed according to Cochrane methods, and recommendations were developed by use of the Grading of Recommendations Assessment, Development and Evaluation Evidence to Decision framework. We searched MEDLINE, Embase, and Cochrane Library, including Central Register of Controlled Trials, for randomised controlled trials and systematic reviews published from inception to March 10, 2020. We excluded studies that were not published in English. Evidence for any identified novel agent that is active against acute myeloid leukaemia was reviewed for the following outcomes: incidence of invasive fungal disease, prolongation of hospitalisation, days spent in intensive-care unit, mortality due to invasive fungal disease, quality of life, and potential DDIs. Recommendations and consensus statements were compiled for each targeted drug for patients with acute myeloid leukaemia and each specific setting. Evidence-based recommendations were developed for hypomethylating agents, midostaurin, and the venetoclax-hypomethylating agent combination. For all other agents, consensus statements were given for specific therapeutic settings, specifically for the management of patients with relapsed or refractory acute myeloid leukaemia, monotherapy, and combination with chemotherapy. Antifungal prophylaxis is recommended with moderate strength in most settings, and strongly recommended if the novel acute myeloid leukaemia agent is administered in combination with intensive induction chemotherapy. For ivosidenib, lestaurtinib, quizartinib, and venetoclax, we moderately recommend adjusting the dose of the antileukaemic agent during administration of triazoles. This is the first guidance supporting clinical decision making on antifungal prophylaxis in recipients of novel targeted drugs for acute myeloid leukaemia. Future studies including therapeutic drug monitoring will need to determine the role of dosage adjustment of novel antileukaemic drugs during concomitant administration of CYP3A4-inhibiting antifungals with respect to adverse effects and remission status.

Clinical Trials Centre Cologne Faculty of Medicine University of Cologne and University Hospital Cologne Cologne Germany

Department 1 of Internal Medicine Excellence Center for Medical Mycology University of Cologne and University Hospital Cologne Cologne Germany

Department of Haematology Amsterdam University Medical Centers location AMC Amsterdam Netherlands

Department of Haematology and HSCT South Pest Central Hospital National Institute of Haematology and Infectious Diseases Budapest Hungary

Department of Infectious Diseases Tel Aviv Sourasky Medical Center Tel Aviv Israel

Department of Medical and Surgical Sciences University of Bologna Infectious Diseases IRCCS S Orsola University Hospital Bologna Italy

Department of Pharmacy Radboud University Medical Center Nijmegen Netherlands

Department of Physiology Faculty of Medicine Masaryk University Brno Czech Republic

Evidence based Oncology Department 1 of Internal Medicine Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf University of Cologne and University Hospital Cologne Cologne Germany

German Centre for Infection Research Partner Site Bonn Cologne Cologne Germany

Institute of Hematology and Blood Transfusion Prague Czech Republic

Nijmegen Institute for Health Sciences Radboud University Medical Center Nijmegen Netherlands

Radboudumc Center for Infectious Diseases Radboud University Medical Center Nijmegen Netherlands

Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

Stem Cell Transplant Center Città della Salute e della Scienza Turin Turin Italy

Translational Research Cologne Excellence Cluster on Cellular Stress Responses in Ageing Associated Diseases University of Cologne and University Hospital Cologne Cologne Germany

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