BACKGROUND Addition of the BCL2 inhibitor venetoclax to lower intensity therapy has been shown to improve overall survival in older (aged 75 years or older) and unfit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to investigate the activity of venetoclax combined with intensive chemotherapy in patients aged 65 years or younger with acute myeloid leukaemia. METHODS This cohort study was done at the MD Anderson Cancer Center in the USA, as part of the single-centre, single arm, phase 2, CLIA trial. Here we report on the independent cohort investigating the safety and activity of venetoclax added to intensive chemotherapy (the CLIA regimen [cladribine, high-dose cytarabine, idarubicin]). Eligible patients were aged 18-65 years with a new diagnosis of acute myeloid leukaemia, mixed phenotype acute leukaemia, or high-risk myelodysplastic syndrome (≥10% blasts or International Prognostic Scoring System ≥2 [intermediate]), who received no previous potentially curative therapy for leukaemia. Patients received cladribine (5 mg/m2) and cytarabine (1·5 g/m2 for patients aged <60 years, 1 g/m2 for patients aged ≥60 years) intravenously on days 1-5 and idarubicin (10 mg/m2) intravenously on days 1-3. Consolidation was cladribine (5 mg/m2) and cytarabine (1 g/m2 for patients aged <60 years and 0·75 g/m2 for patients aged ≥60 years) on days 1-3 and idarubicin (8 mg/m2) on days 1-2. Venetoclax (400 mg) was given on days 2-8 with each course. Patients with a known FLT3-ITD or FLT3-TKD mutation received midostaurin or gilteritinib. The primary outcome was composite complete response (complete response plus complete response with incomplete blood count recovery). Secondary outcomes were overall response, duration of response, event-free survival, overall survival, and safety. This trial was registered with ClinicalTrials.gov, NCT02115295. FINDINGS Between Feb 25, 2019, and March 23, 2021, 77 patients were assessed for eligibility, 50 of whom were enrolled. Median age was 48 years (IQR 37-56). 47 (94% [95% CI 83-98]) patients had composite complete response, with the same proportion also having an overall response; two (4% [1-14]) patients did not respond, and one (2% [0-11]) patient died during induction. 37 (82% [95% CI 68-92]) of 45 patients had undetectable measurable residual disease (MRD). At a median follow-up of 13·5 months (IQR 6·4-19·5), the median duration of response, event-free survival, and overall survival were not reached. At 12 months, the estimated duration of response was 74% (95% CI 60-92), event-free survival was 68% (54-85), and overall survival was 85% (75-97). The most common adverse events of grade 3 or worse were febrile neutropenia (42 [84%] patients), infection (six [12%]), and alanine aminotransferase elevations (six [12%]). There was one death during induction in a patient treated with CLIA-venetoclax plus a FLT3 inhibitor. Two patients died of infectious complications while in complete response in consolidation cycles, both of whom had FLT3-mutated acute myeloid leukaemia and were receiving combined therapy with a FLT3 inhibitor. No deaths were deemed to be treatment related. INTERPRETATION Venetoclax added to CLIA was safe and active in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, producing high rates of durable MRD-negative remissions and encouraging event-free survival and overall survival. FUNDING MD Anderson Cancer Center.

中文翻译：

---

Venetoclax 联合克拉屈滨、伊达比星和阿糖胞苷对新诊断的急性髓性白血病或高危骨髓增生异常综合征患者的强化化疗：来自单中心、单臂、2 期试验的队列。

背景 已证明在低强度治疗中加入 BCL2 抑制剂 venetoclax 可提高新诊断的急性髓性白血病老年（75 岁或以上）和不健康患者的总体生存率。本研究的目的是调查 venetoclax 联合强化化疗对 65 岁或以下急性髓系白血病患者的疗效。方法 这项队列研究是在美国 MD 安德森癌症中心完成的，作为单中心、单臂、2 期 CLIA 试验的一部分。在这里，我们报告了独立队列研究加入强化化疗（CLIA 方案 [克拉屈滨、大剂量阿糖胞苷、伊达比星]）的 venetoclax 的安全性和活性。符合条件的患者年龄在 18-65 岁之间，新诊断为急性髓性白血病、混合表型急性白血病、或高危骨髓增生异常综合征（≥10% 原始细胞或国际预后评分系统≥2 [中间]），之前未接受过白血病的潜在治愈性治疗。患者在第 1-5 天静脉内接受克拉屈滨（5 mg/m2）和阿糖胞苷（1·5 g/m2，年龄<60 岁，1 g/m2，年龄≥60 岁）和伊达比星（10 mg/m2）在第 1-3 天静脉注射。第 1-3 天使用克拉屈滨（5 mg/m2）和阿糖胞苷（1 g/m2，年龄<60 岁的患者，0·75 g/m2，年龄≥60 岁的患者）和伊达比星（8 mg/m2）第 1-2 天。在每个疗程的第 2-8 天给予 Venetoclax (400 mg)。具有已知 FLT3-ITD 或 FLT3-TKD 突变的患者接受米多司他林或 gilteritinib。主要结果是复合完全缓解（完全缓解加上完全缓解伴血细胞计数恢复不完全）。次要结果是总反应、反应持续时间、无事件生存期、总生存期和安全性。该试验已在 ClinicalTrials.gov 注册，NCT02115295。2019 年 2 月 25 日至 2021 年 3 月 23 日期间，77 名患者接受了资格评估，其中 50 人入组。中位年龄为 48 岁（IQR 37-56）。47 (94% [95% CI 83-98]) 患者有复合完全缓解，同样比例的患者也有总体缓解；两名 (4% [1-14]) 患者没有反应，一名 (2% [0-11]) 患者在诱导期间死亡。45 名患者中有 37 名 (82% [95% CI 68-92]) 有无法检测到的可测量残留病 (MRD)。中位随访 13·5 个月（IQR 6·4-19·5），未达到中位反应持续时间、无事件生存期和总生存期。在 12 个月时，估计反应持续时间为 74% (95% CI 60-92)，无事件生存率为 68% (54-85)，总生存率为 85% (75-97)。最常见的 3 级或更严重的不良事件是发热性中性粒细胞减少症（42 名 [84%] 患者）、感染（6 名 [12%]）和丙氨酸氨基转移酶升高（6 名 [12%]）。一名接受 CLIA-venetoclax 加 FLT3 抑制剂治疗的患者在诱导期间有 1 例死亡。两名患者在巩固周期中完全缓解时死于感染性并发症，他们都患有 FLT3 突变的急性髓性白血病，并正在接受 FLT3 抑制剂的联合治疗。没有死亡被认为与治疗有关。解释 CLIA 中添加的 Venetoclax 对新诊断的急性髓性白血病或高危骨髓增生异常综合征患者是安全且有效的，产生高持久 MRD 阴性缓解率，​​并鼓励无事件生存和总生存。资助 MD 安德森癌症中心。