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Background  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.    Methods  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  FLT3 (+) patients, or demonstrating the efficiency of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in  FLT3 (+) 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).    Results  After addressing all criteria, 39 studies were eventually analyzed. Better CR was accomplished by FLT3i in untreated AML (RR 0.88,  p  = 0.04) and refractory and relapsed  FLT3 (+) AML (rrAML) (RR 0.61,  p  < 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  p  < 0.01;  FLT3 (+) rrAML: OS, HR 0.60,  p  < 0.01; RFS, HR 0.40,  p  = 0.01). In addition, allo-HSCT improved survival in  FLT3 (+) AML (OS, HR 0.53; EFS, HR 0.50; RFS, HR 0.57; CIR, HR 0.26; all  p  < 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  p  < 0.01). Additionally, FLT3i consistently improved OS (p < 0.05) regardless of  FLT3-ITD  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 ( p  < 0.05). In NMA, gilteritinib showed the highest probability for improved prognosis.    Conclusions  FLT3i safely improved prognosis in induction/reinduction stage of  FLT3 (+) 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.

frontiers in oncology

Clinical Benefits and Safety of FMS-Like Tyrosine Kinase 3 Inhibitors in Various Treatment Stages of Acute Myeloid Leukemia: A Systematic Review, Meta-Analysis, and Network Meta-Analysis