在提高总生存率的基础上,治疗指南强烈建议在缓解期诱导化疗期间对急性髓系白血病患者进行抗真菌预防.许多新型靶向药物被细胞色素P450代谢,但潜在的药物-药物相互作用(DDI)和由此产生的风险-收益比尚未在临床试验中评估。导致临床管理的不确定性。因此,欧洲血液学协会委托传染病领域的专家,血液学,肿瘤学,临床药理学,和方法,以制定有关三唑类抗真菌剂的抗真菌预防和药代动力学DDIs管理的最新建议。根据Cochrane方法进行了系统的文献综述,和建议是通过使用建议分级评估来制定的,开发和评估决策证据框架。我们搜索了MEDLINE,Embase,和Cochrane图书馆,包括中央受控试验登记册,从开始到2020年3月10日发表的随机对照试验和系统评价。我们排除了没有以英文发表的研究。对任何已确定的有效抗急性髓系白血病的新型药物的证据进行了审查,以了解以下结果:侵袭性真菌病的发生率,延长住院时间,在重症监护室度过的日子,由侵袭性真菌病引起的死亡率,生活质量,和潜在的DDI。针对急性髓性白血病患者的每种靶向药物以及每种特定情况,编制了建议和共识声明。针对低甲基化药物制定了循证建议,Midostaurin,和维奈托克-低甲基化剂组合。对于所有其他特工来说,针对特定的治疗环境给出了共识声明,特别是对于复发或难治性急性髓系白血病患者的管理,单一疗法,并结合化疗。在大多数情况下,建议使用中等强度的抗真菌预防,并强烈建议如果新型急性髓性白血病药物与强化诱导化疗联合使用。对于ivosidenib来说,列妥替尼,quizartinib,和维尼托克,我们建议在使用三唑类药物期间调整抗白血病药的剂量。这是第一个支持急性髓性白血病新型靶向药物受体抗真菌预防的临床决策的指南。包括治疗药物监测在内的未来研究将需要确定在CYP3A4抑制抗真菌药物的伴随给药期间新型抗白血病药物的剂量调整在不良反应和缓解状态方面的作用。
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.