Antifungal prophylaxis in adult patients with acute myeloid leukaemia treated with novel targeted therapies: a systematic review and expert consensus recommendation from the European Hematology Association.

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.

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Declaration of interests JSt has received research grants from the German Ministry of Education and Research and Basilea Pharmaceuticals, speaker honoraria from Pfizer, and travel grants from German Society for Infectious Diseases and Meta-Alexander Foundation. NdJ has received a consultation fee from Gilead. NS has received grants from the European Hematology Association within this study. JSi reports having received consultations fees, honoraria for lectures, and support for attending scientific meetings from Merck/MSD, Pfizer, and Gilead. RJB has received grants from Gilead and Pfizer; received consulting fees from Gilead, Pfizer, Astellas, Mundipharma, Cidara, and Amplyx; received lecture honoraria or served for the speaker's bureau of Gilead and Pfizer; and participated on advisory boards of Pfizer, Gilead, Astellas, Mundipharma, Cidara, and Amplyx. AB has received honoraria from Gilead Sciences, Merck/MSD, Novartis, Pfizer, and Jazz Pharmaceuticals and travel support from Biotest. RBA has received grants from the Israel Science Foundation and the Israel Ministry of Science and Technology, received speaker honoraria from Gilead and Teva, and served on advisory boards for Pfizer and Merck/MSD. ZR has received speaker honoraria from and been part of advisory boards for Pfizer, Astellas, Novartis, and Abbvie. VP declares no competing interests. RL reports grants from Merck/MSD and Gilead and has received speaking fees or compensation for consultancy for Gilead, Pfizer, Anvir, Cidara Therapeutics, and F2G. OAC reports grants or contracts from Amplyx, Basilea, the German Ministry of Education and Research, Cidara, German Centre for Infection Research, EU Directorate-General for Research and Innovation (101037867), F2G, Gilead, Matinas, MedPace, Merck/MSD, Mundipharma, Octapharma, Pfizer, and Scynexis; consulting fees from Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, Matinas, MedPace, Menarini, Molecular Partners, Mycoses Study Group-Education and Research Consortium, Noxxon, Octapharma, PSI, Scynexis, and Seres; honoraria for lectures from Abbott, Al-Jazeera Pharmaceuticals, Astellas, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, and Pfizer; payment for expert testimony from Cidara; participation on a data safety monitoring board or advisory board from Actelion, Allecra, Cidara, Entasis, IQVIA, Jannsen, MedPace, Paratek, PSI, Shionogi; a pending patent for a device that allows a safer and more tolerable bronchoscopy for patients is currently being reviewed at the German Patent and Trade Mark Office; is chair of the Infectious Diseases Working Party at the German Society for Hematology and Oncology, advisory committee member for the German Infectious Society for Infectious Diseases, educational officer for the European Confederation of Medical Mycology, treasurer for the International Society for Human and Animal Mycology, member of the board of directors for the Mycoses Study Group-Education and Research Consortium, and editor-in-chief for Mycoses.