吉妥珠单抗奥唑米星治疗各亚组急性髓系白血病的临床获益与安全性：一项更新的系统评价、Meta分析及网状Meta分析
Clinical Benefits and Safety of Gemtuzumab Ozogamicin in Treating Acute Myeloid Leukemia in Various Subgroups: An Updated Systematic Review, Meta-Analysis, and Network Meta-Analysis.
作者信息
Xu Qingyu, He Shujiao, Yu Li
机构信息
Department of Hematology and Oncology, International Cancer Center, Shenzhen Key Laboratory, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen University Health Science Center, Shenzhen, China.
Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
出版信息
Front Immunol. 2021 Aug 16;12:683595. doi: 10.3389/fimmu.2021.683595. eCollection 2021.
BACKGROUND
Previous trials demonstrated evidence involving the total effects of gemtuzumab ozogamicin (GO), an anti-CD33 humanized antibody, on treating acute myeloid leukemia (AML). In this updated systematic review, meta-analysis, and network meta-analysis (NMA), we aimed to comprehensively explore the clinical benefits and safety of GO in various subtypes of AML.
METHODS
PubMed, Embase, Cochrane, and Chinese databases were filtered to search randomized controlled trials (RCTs) and retrospective cohort studies that compared clinical efficiency and toxicity of GO with non-GO groups in AML. Random-effects models were used to calculate pooled effect sizes and 95% confidence intervals (CIs). Relative risk (RR) was used for estimating complete remission (CR), early death, and toxicity. Hazard risk (HR) was accomplished to evaluate survival.
RESULTS
Fifteen RCTs and 15 retrospective cohort studies were identified (GO: 4,768; Control: 6,466). GO tended to improve CR (RR 0.95, p = 0.084), followed by significantly improved survival (overall survival: HR 0.86, p = 0.003; event-free survival: HR 0.86, p = 0.015; relapse-free survival: HR 0.83, p = 0.001; cumulative incidence of relapse: HR 0.82, p < 0.001). GO benefits of CR and survival were evident in favorable- and intermediate-risk karyotypes (p ≤ 0.023). GO advantages were also associated with nucleophosmin 1 mutations (p ≤ 0.04), wild-type FMS-like tyrosine kinase 3 internal tandem duplication gene (p ≤ 0.03), age of <70 years (p < 0.05), AML (p ≤ 0.017), and CD33(+) (p ≤ 0.021). Both adding GO into induction therapy (p ≤ 0.011) and a lower (<6 mg/m) dose of GO (p ≤ 0.03) enhanced survival. Prognosis of combined regimens with GO was heterogeneous in both meta-analysis and NMA, with several binding strategies showing improved prognosis. Additionally, GO was related to increased risk of early death at a higher dose (≥6 mg/m) (RR 2.01, p = 0.005), hepatic-related adverse effects (RR 1.29, p = 0.02), and a tendency of higher risk for hepatic veno-occlusive disease or sinusoidal obstruction syndrome (RR 1.56, p = 0.072).
CONCLUSIONS
These data indicated therapeutic benefits and safety of GO in AML, especially in some subtypes, for which further head-to-head RCTs are warranted.
SYSTEMATIC REVIEW REGISTRATION
[PROSPERO: https://www.crd.york.ac.uk/prospero/], identifier [CRD42020158540].
背景
先前的试验证明了抗CD33人源化抗体吉妥珠单抗奥唑米星（GO）治疗急性髓系白血病（AML）的总体疗效。在这项更新的系统评价、荟萃分析和网状荟萃分析（NMA）中，我们旨在全面探讨GO在AML各亚型中的临床益处和安全性。
方法
筛选PubMed、Embase、Cochrane和中文数据库，以检索比较GO与非GO组在AML中的临床疗效和毒性的随机对照试验（RCT）和回顾性队列研究。采用随机效应模型计算合并效应量和95%置信区间（CI）。相对危险度（RR）用于估计完全缓解（CR）、早期死亡和毒性。采用风险比（HR）评估生存率。
结果
共纳入15项RCT和15项回顾性队列研究（GO组：4768例；对照组：6466例）。GO倾向于改善CR（RR=0.95，p=0.084），随后显著改善生存率（总生存率：HR=0.86，p=0.003；无事件生存率：HR=0.86，p=0.015；无复发生存率：HR=0.83，p=0.001；复发累积发生率：HR=0.82，p<0.001）。在预后良好和中等风险核型中，GO对CR和生存的益处明显（p≤0.023）。GO的优势还与核磷蛋白1突变（p≤0.04）、野生型FMS样酪氨酸激酶3内部串联重复基因（p≤0.03）、年龄<70岁（p<0.05）、AML（p≤0.017）和CD33(+)（p≤0.021）有关。在诱导治疗中加入GO（p≤0.011）和较低剂量（<6mg/m）的GO（p≤0.03）均可提高生存率。在荟萃分析和NMA中，GO联合方案的预后存在异质性，几种联合策略显示预后改善。此外，高剂量（≥6mg/m）的GO与早期死亡风险增加（RR=2.01，p=0.005）、肝脏相关不良反应（RR=1.29，p=0.02）以及肝静脉闭塞病或窦性阻塞综合征风险增加的趋势（RR=1.56，p=0.072）相关。
结论
这些数据表明GO在AML中具有治疗益处和安全性，尤其是在某些亚型中，对此有必要进行进一步的直接比较RCT。
系统评价注册
[PROSPERO：https://www.crd.york.ac.uk/prospero/]，标识符[CRD42020158540]
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