Prospective randomized multicenter phase III trial of decitabine and Venetoclax administered in combination with all-trans retinoic acid or placebo in patients with acute myeloid leukemia who are ineligible for induction chemotherapy

急性髓性白血病（AML）是一种主要发生在老年人中的癌症，诊断年龄通常为70岁以上。直到最近，这些患者的治疗选择非常有限，因为强化化疗，年轻AML患者的标准，往往会导致不可接受的毒性，而且往往不如年轻患者有效。表观遗传活性药物地西他滨和阿扎胞苷可提供耐受性更好的轻度AML治疗。这些非常密切相关的药物是在门诊基础上给予的，患有合并症的老年患者也耐受良好，并且被认为通过白血病细胞的重编程起作用，因此可能通过与常规化疗不同的作用机制起作用。为了增强这种表观遗传疗法的功效-其本身不会导致AML的治愈-在过去几年中已经对许多药物组合进行了临床测试。通过来自不同德国大学医院的医生的试验网络内的合作，我们可以在多中心临床试验DECIDER（注册号为NCT 00867672）中证明，与地西他滨单独治疗相比，地西他滨输注联合维生素A衍生物（ATRA胶囊）导致老年AML患者（中位年龄76岁）的总生存期增加。在计划的后续研究（DECIDER-2）中，我们的主要目的是证实与不加ATRA的治疗相比，加用ATRA的患者生存期延长。一半的患者将接受ATRA胶囊加地西他滨，另一半将接受安慰剂胶囊代替ATRA与地西他滨联合治疗（双盲随机研究）。此外，所有患者将接受第三种药物（维奈托克胶囊），旨在加速AML细胞的程序性细胞死亡。该研究计划在30多个德国研究中心招募250名患者。虽然最重要的研究问题是找出接受ATRA的患者是否会比接受安慰剂（与其他两种药物联合）的患者活得更长，但第二个重要目标是测量AML治疗前和治疗期间的生活质量。在此，我们希望受益于治疗的患者也能享受生活质量的改善。在伴随的实验室研究中，应使用患者的骨髓和血细胞研究这种新疗法的作用机制，以便能够更好地预测哪种患者将从这种无化疗治疗中获益最多。

Acute myeloid leukemia (AML) is a type of cancer that occurs predominantly in the elderly, with age of diagnosis often 70+ years. Until recently, therapeutic options for these patients were very limited, since intensive chemotherapy, standard for younger AML patients, often led to unacceptable toxicities, and frequently was not as effective as in younger patients. Better tolerated, mild AML therapy is provided by the epigenetically active medicines Decitabine and Azacitidine. These very closely related drugs are given on an outpatient basis, are well tolerated also by elderly patients with comorbidities, and thought to act by reprogramming of the leukemia cells, thus probably by different mechanisms of action than conventional chemotherapy. To enhance the efficacy of this epigenetic therapy - by itself not leading to cure of AML - numerous drug combinations have been clinically tested during the last years. Through a collaboration within a trial network of physicians from different German University Hospitals, we could demonstrate in the multicenter clinical trial DECIDER (registered under NCT00867672) that Decitabine infusions in combination with a vitamin A derivative (ATRA capsules) led to an increase in overall survival of elderly AML patients (median age 76 years) compared to treatment with Decitabine alone. Within the planned successor study (DECIDER-2) our primary objective is to confirm the extension of patient survival with ATRA add-on compared to treatment without ATRA add-on. Half of the patients will receive ATRA capsules in addition to Decitabine, the other half will receive placebo capsules instead of ATRA in combination with Decitabine (double-blind randomized study). All patients will receive, in addition, a third drug (Venetoclax capsules) with the aim to accelerate the programmed cell death in the AML cells. The study is planned to accrue 250 patients at more than 30 German study sites. While the most important study question is to find out whether patients receiving ATRA will live longer than patients receiving placebo (in combination with the other two drugs), a second important objective is the measurement of quality of life before and during this AML therapy. Here we hope that patients benefiting from the treatment will also enjoy an improvement of their quality of life. In accompanying laboratory studies, the mechanism of action of this novel therapy shall be studied using bone marrow and blood cells of the patients, in order to be able to make better predictions about which patient will profit most from such chemotherapy-free treatment.