复发性或难治性 (R/R) 急性髓系白血病 (AML) 是一种具有挑战性、高风险的临床情况，结果令人沮丧。最近对驱动克隆进展的遗传、表观遗传和代谢事件的见解以及新疗法的出现导致在 R/R 环境中单独或组合地结合了几种新的靶向疗法，目的是提高反应率和生存。在此，我们回顾了非免疫治疗方法治疗 R/R AML 的当前挑战和未来机遇。FLT3 和 IDH 1/2 抑制剂现已获得 FDA 批准用于患有 R/R 疾病和相应突变的患者。这些药物还与强化和低强度平台结合使用，试图提高反应和生存率。目前正在早期试验中单独或组合测试几种靶向药物。其中包括针对细胞凋亡途径的药物、干扰 R/R 白血病细胞关键生存途径的药物以及针对白血病骨髓微环境的疗法。 Menin 抑制剂是治疗 NPM1 和 KMT2A 重排 AML 的一类很有前途的活性药物。关键信息：几种新的免疫学和非免疫学靶向疗法正在研究中，并正在进入临床前和临床管道。剩下的重大挑战包括开发适合患者特定生物学和临床背景的协同联合疗法，以及重新定义同种异体移植在 R/R 疾病患者中的作用和时机。作者。由巴塞尔 S. Karger AG 出版。

Relapsed or refractory (R/R) acute myeloid leukemia (AML) is a challenging, high-risk, clinical scenario with a dismal outcome. Recent insights on the genetic, epigenetic, and metabolic events that drive clonal progression and the advent of novel therapies resulted in the incorporation of several new targeted therapies, alone or in combination, in the R/R setting with the aim of improving response rates and survival. Herein we review current challenges and future opportunities with non-immunotherapeutic approaches to treat R/R AML.Inhibitors of FLT3 and IDH 1/2 are now FDA-approved for patients with R/R disease and corresponding mutations. These agents are also used in combination with intensive and low-intensity platforms in an attempt to improve response and survival. Several targeted agents are currently being tested alone or in combination in early-phase trials. These include drugs that target apoptotic pathways, drugs that interfere with key survival pathways of the R/R leukemic cell as well as therapies aimed towards the leukemia marrow microenvironment. Menin inhibitors are a promising class of active drugs in NPM1 and KMT2A-rearranged AML. Key-messages: Several new targeted therapies, immunologic and non-immunologic are being studied and are moving through pre-clinical and clinical pipelines. Significant remaining challenges include the development of synergistic combination therapies tailored to the specific biology and clinical context of the patient, and re-defining the role and timing of allogeneic transplantation in patients with R/R disease.The Author(s). Published by S. Karger AG, Basel.