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

急性髓系白血病(AML)是一种主要发生在老年人的癌症，确诊年龄通常为70岁。直到最近，这些患者的治疗选择非常有限，因为年轻AML患者的标准强化化疗往往会导致不可接受的毒性反应，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替丁提供了耐受性更好的轻度急性髓细胞白血病治疗。这些密切相关的药物是在门诊基础上服用的，患有合并症的老年患者也很耐受，被认为是通过白血病细胞的重新编程发挥作用，因此可能通过不同于传统化疗的作用机制。为了提高这种表观遗传疗法的疗效--本身并不能治愈AML--许多药物组合在过去几年里进行了临床测试。通过来自不同德国大学医院的医生在试验网络中的合作，我们可以在多中心临床试验决策人(注册编号为NCT00867672)中证明，与单独使用地西他滨治疗相比，地西他滨联合维生素A衍生物(ATRA胶囊)可以提高老年AML患者(中位年龄76岁)的总存活率。在计划中的后续研究(Decider-2)中，我们的主要目标是证实与不使用ATRA附加剂的治疗相比，使用ATRA附加剂可以延长患者的生存期。一半的患者将在地西他滨的基础上接受全反式维甲酸胶囊，另一半的患者将接受安慰剂胶囊，而不是全反式维甲酸联合地西他滨(双盲随机研究)。此外，所有患者都将接受第三种药物(万托克拉克斯胶囊)，目的是加速AML细胞的程序性细胞死亡。这项研究计划在德国30多个研究地点招收250名患者。虽然最重要的研究问题是查明接受ATRA治疗的患者是否比接受安慰剂(与其他两种药物联合使用)的患者活得更长，但第二个重要目标是在接受AML治疗之前和期间测量生活质量。在这里，我们希望受益于治疗的患者也能享受到生活质量的改善。在同时进行的实验室研究中，应利用患者的骨髓和血细胞来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不含化疗的治疗中获益最多。

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.