Stemler Jannik, de Jonge Nick, Skoetz Nicole, Sinkó János, Brüggemann Roger J, Busca Alessandro, Ben-Ami Ronen, Ráčil Zdeněk, Piechotta Vanessa, Lewis Russell, Cornely Oliver A
Department I of Internal Medicine, Excellence Center for Medical Mycology, University of Cologne and University Hospital Cologne, Cologne, Germany; Translational Research, Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases, University of Cologne and University Hospital Cologne, Cologne, Germany; German Centre for Infection Research, Partner Site Bonn-Cologne, Cologne, Germany.
Department of Haematology, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands.
Lancet Haematol. 2022 May;9(5):e361-e373. doi: 10.1016/S2352-3026(22)00073-4.
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.
基于总体生存率的提高，治疗指南强烈推荐对急性髓系白血病患者在缓解诱导化疗期间进行抗真菌预防。许多新型靶向药物由细胞色素P450代谢，但潜在的药物相互作用（DDIs）及其产生的风险效益比尚未在临床试验中得到评估，导致临床管理存在不确定性。因此，欧洲血液学协会委托传染病、血液学、肿瘤学、临床药理学和方法学领域的专家制定关于抗真菌预防的最新建议以及三唑类抗真菌药物的药代动力学药物相互作用管理。根据Cochrane方法进行了系统的文献综述，并使用推荐分级评估、发展和评价证据到决策框架制定了建议。我们检索了MEDLINE、Embase和Cochrane图书馆，包括对照试验中央注册库，以查找从创刊到2020年3月10日发表的随机对照试验和系统评价。我们排除了非英文发表的研究。对任何已确定的对急性髓系白血病有效的新型药物的证据进行了如下结果的审查：侵袭性真菌病的发生率、住院时间延长、在重症监护病房的天数、侵袭性真菌病导致的死亡率、生活质量以及潜在的药物相互作用。针对急性髓系白血病患者的每种靶向药物和每种特定情况编制了建议和共识声明。为低甲基化药物、米哚妥林以及维奈克拉-低甲基化药物组合制定了基于证据的建议。对于所有其他药物，针对特定治疗情况给出了共识声明，特别是针对复发或难治性急性髓系白血病患者的管理、单药治疗以及与化疗联合使用。在大多数情况下，抗真菌预防以中等强度推荐，如果新型急性髓系白血病药物与强化诱导化疗联合使用，则强烈推荐。对于艾伏尼布、来司替尼、奎扎替尼和维奈克拉，我们适度建议在使用三唑类药物期间调整抗白血病药物的剂量。这是首个支持急性髓系白血病新型靶向药物接受者抗真菌预防临床决策的指南。未来包括治疗药物监测在内的研究将需要确定在与CYP3A4抑制性抗真菌药物同时给药期间，新型抗白血病药物剂量调整在不良反应和缓解状态方面的作用。
