The Alfred Hospital, Melbourne, VIC, Australia.
Leukaemia Translational Research, Central Clinical School, Monash University, Melbourne, VIC, Australia.
Blood. 2020 Jun 11;135(24):2137-2145. doi: 10.1182/blood.2020004856.
Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. Adults age ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international phase 3 randomized double-blind placebo-controlled trial. Patients (N = 211) were randomized 2:1 to venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1 to 10. Primary end point was overall survival (OS); secondary end points included response rate, transfusion independence, and event-free survival. Median age was 76 years (range, 36-93 years), 38% had secondary AML, and 20% had received prior hypomethylating agent treatment. Planned primary analysis showed a 25% reduction in risk of death with venetoclax plus LDAC vs LDAC alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.52-1.07; P = .11), although not statistically significant; median OS was 7.2 vs 4.1 months, respectively. Unplanned analysis with additional 6-month follow-up demonstrated median OS of 8.4 months for the venetoclax arm (HR, 0.70; 95% CI, 0.50-0.98; P = .04). Complete remission (CR) plus CR with incomplete blood count recovery rates were 48% and 13% for venetoclax plus LDAC and LDAC alone, respectively. Key grade ≥3 adverse events (venetoclax vs LDAC alone) were febrile neutropenia (32% vs 29%), neutropenia (47% vs 16%), and thrombocytopenia (45% vs 37%). Venetoclax plus LDAC demonstrates clinically meaningful improvement in remission rate and OS vs LDAC alone, with a manageable safety profile. Results confirm venetoclax plus LDAC as an important frontline treatment for AML patients unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352.
对于不能耐受强化化疗的急性髓系白血病（AML）患者，有效的治疗选择有限。本国际 3 期随机双盲安慰剂对照试验纳入了年龄≥18 岁、新诊断为不适合强化化疗的 AML 成人患者。患者（N=211）按 2:1 随机分组，分别接受维奈妥拉（n=143）或安慰剂（n=68）治疗，联合低剂量阿糖胞苷（LDAC）治疗，第 1-10 天用药。主要终点为总生存期（OS）；次要终点包括缓解率、输血独立性和无事件生存期。中位年龄为 76 岁（范围 36-93 岁），38%为继发性 AML，20%曾接受过去甲基化药物治疗。计划的主要分析显示，维奈妥拉联合 LDAC 与 LDAC 单药相比，死亡风险降低了 25%（风险比[HR]，0.75；95%置信区间[CI]，0.52-1.07；P=0.11），尽管未达到统计学显著性；中位 OS 分别为 7.2 个月和 4.1 个月。在未计划的分析中，增加了 6 个月的随访时间，维奈妥拉组的中位 OS 为 8.4 个月（HR，0.70；95%CI，0.50-0.98；P=0.04）。维奈妥拉联合 LDAC 组的完全缓解（CR）加不完全血细胞计数恢复的 CR 率分别为 48%和 13%，LDAC 单药组分别为 48%和 13%。≥3 级不良事件（维奈妥拉 vs LDAC 单药）分别为发热性中性粒细胞减少症（32% vs 29%）、中性粒细胞减少症（47% vs 16%）和血小板减少症（45% vs 37%）。维奈妥拉联合 LDAC 可显著提高缓解率和 OS，与 LDAC 单药相比，安全性可控。结果证实维奈妥拉联合 LDAC 是不适合强化化疗的 AML 患者的一种重要一线治疗方法。该试验在 www.clinicaltrials.gov 上注册，编号为 #NCT03069352。
