Xu Qingyu, He Shujiao, Yu Li
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.
Front Oncol. 2021 Jun 3;11:686013. doi: 10.3389/fonc.2021.686013. eCollection 2021.
Given the controversial roles of FMS-like tyrosine kinase 3 inhibitors (FLT3i) in various treatment stages of acute myeloid leukemia (AML), this study was designed to assess this problem and further explored which FLT3i worked more effectively.
A systematic review, meta-analysis and network meta-analysis (NMA) were conducted by filtering PubMed, Embase, Cochrane library, and Chinese databases. We included studies comparing therapeutic effects between FLT3i and non-FLT3i group in AML, particularly (+) patients, or demonstrating the efficiency of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in (+) AML. Relative risk (RR) with 95% confidence intervals (CI) was used for estimating complete remission (CR), early death and toxicity. Hazard ratio (HR) was used to assess overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) and cumulative incidence of relapse (CIR).
After addressing all criteria, 39 studies were eventually analyzed. Better CR was accomplished by FLT3i in untreated AML (RR 0.88, = 0.04) and refractory and relapsed (+) AML (rrAML) (RR 0.61, < 0.01) compared to non-FLT3i arm, followed by improved survival (untreated AML: OS, HR 0.76; EFS, HR 0.67; RFS, HR 0.72; all < 0.01; (+) rrAML: OS, HR 0.60, < 0.01; RFS, HR 0.40, = 0.01). In addition, allo-HSCT improved survival in (+) AML (OS, HR 0.53; EFS, HR 0.50; RFS, HR 0.57; CIR, HR 0.26; all < 0.01), which was further prolonged by FLT3i administrated after allo-HSCT (OS, HR 0.45; RFS, HR 0.34; CIR, HR 0.32; all < 0.01). Additionally, FLT3i consistently improved OS (p < 0.05) regardless of ratio, when compared to non-FLT3i group. Besides, FLT3i showed significantly increased risk of thrombocytopenia, neutropenia, anemia, skin- and cardiac-related adverse effects, increased alanine aminotransferase, and increased risk of cough and dyspnea ( < 0.05). In NMA, gilteritinib showed the highest probability for improved prognosis.
FLT3i safely improved prognosis in induction/reinduction stage of (+) AML and further boosted survival benefits from allo-HSCT as maintenance therapy, suggesting better prognosis if FLT3i is combined before and after allo-HSCT. In NMA, gilteritinib potentially achieved the best prognosis, which should be identified in direct trials.
鉴于FMS样酪氨酸激酶3抑制剂（FLT3i）在急性髓系白血病（AML）各治疗阶段的作用存在争议，本研究旨在评估这一问题，并进一步探究哪种FLT3i疗效更佳。
通过筛选PubMed、Embase、Cochrane图书馆和中文数据库进行系统评价、荟萃分析和网状荟萃分析（NMA）。我们纳入了比较FLT3i组与非FLT3i组在AML，特别是（+）患者中的治疗效果，或证明异基因造血干细胞移植（allo-HSCT）在（+）AML中的疗效的研究。采用95%置信区间（CI）的相对风险（RR）来估计完全缓解（CR）、早期死亡和毒性。采用风险比（HR）评估总生存期（OS）、无事件生存期（EFS）、无复发生存期（RFS）和复发累积发生率（CIR）。
在满足所有标准后，最终分析了39项研究。与非FLT3i组相比，FLT3i在初治AML（RR 0.88， = 0.04）和难治/复发（+）AML（rrAML）（RR 0.61， < 0.01）中实现了更好的CR，随后生存期得到改善（初治AML：OS，HR 0.76；EFS，HR 0.67；RFS，HR 0.72；均 < 0.01；（+）rrAML：OS，HR 0.60， < 0.01；RFS，HR 0.40， = 0.01）。此外，allo-HSCT改善了（+）AML的生存期（OS，HR 0.53；EFS，HR 0.50；RFS，HR 0.57；CIR，HR 0.26；均 < 0.01），allo-HSCT后给予FLT3i可进一步延长生存期（OS，HR 0.45；RFS，HR 0.34；CIR，HR 0.32；均 < 0.01）。此外，与非FLT3i组相比，无论 比值如何，FLT3i均持续改善OS（p < 0.05）。此外，FLT3i显示血小板减少、中性粒细胞减少、贫血、皮肤和心脏相关不良反应、丙氨酸转氨酶升高以及咳嗽和呼吸困难风险增加（ < 0.05）。在NMA中，吉瑞替尼改善预后的概率最高。
FLT3i安全地改善了（+）AML诱导/再诱导阶段的预后，并进一步提高了allo-HSCT作为维持治疗的生存获益，提示在allo-HSCT前后联合使用FLT3i预后更佳。在NMA中，吉瑞替尼可能实现最佳预后，这应在直接试验中得到验证。
