Efficacy and safety of second‑generation FLT3 inhibitors in acute myeloid leukemia: A systematic review and meta‑analysis of randomized controlled trials

Abstract

Acute myeloid leukemia (AML) is one of the most frequent forms of acute leukemia and the second most common leukemia subtype in adults. In 2020, the incidence of AML in the United States was estimated to be ~4 cases per 100,000 adults. The FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutation are major prognostic indicators of AML. They are more frequently observed in younger AML patients (aged <60 years), likely due to their association with de novo. Additionally, these mutations have a stronger negative impact on survival in younger patients. Therefore, quizartinib and gilteritinib are second-generation FLT3 inhibitors that are frequently applied for treating patients with AML. However, to the best of our knowledge, few studies have compared the efficacy of second-generation FLT3 inhibitors for AML treatment. Therefore, the present study conducted a comprehensive search for studies on the efficacy and safety of FLT3 inhibitors across PubMed, Embase, the Cochrane Library and ClinicalTrials.gov. The search criteria were limited to randomized controlled trials (RCTs). Subsequently, a meta-analysis was performed on a total of five randomized controlled trials, involving 1,543 participants in total, using a random-effects model. In each RCT, compared to the salvage chemotherapy used in the control group, the groups that received second-generation FLT3 inhibitors experienced significant improvements in overall survival (hazard ratio, 0.717; 95% CI, 0.604-0.850; P<0.001). In addition, overall survival was found to be consistent across the different types of second-generation FLT3 inhibitors used and different types of AML. The risks associated with a prolonged heart-rate corrected QT interval (QTc) interval were next evaluated. Compared with the salvage chemotherapy used in the control group, the second-generation FLT3 inhibitor group exhibited a significantly higher risk of having a prolonged QTc interval (odds ratio, 6.311; 95% CI, 3.061-13.013; P<0.001). In conclusion, these findings suggest that second-generation FLT3 inhibitors can improve the overall survival of patients with AML. However, QTc prolongation is a potential adverse effect that should be monitored.

Keywords: gilteritinib; overall survival; prolonged heart-rate corrected QT interval; quizartinib; second-generation FMS-like tyrosine kinase 3 inhibitors.

Figure 1

Preferred reporting items for systematic reviews and meta-analyses flowchart of the study selection process.

Figure 2

Overview of the quality assessment of included studies, conducted using the Cochrane risk of bias tool for randomized trials, version 2.

Figure 3

Summary of overall survival effect of second-generation FLT3 inhibitors. The relative weight indicates each study's contribution to the overall effect in the meta-analysis. FLT3, FMS-like tyrosine kinase 3.

Figure 4

Sensitivity analysis of second-generation FLT3 inhibitors for the treatment of acute myeloid leukemia. The relative weight indicates each study's contribution to the overall effect in the meta-analysis. FLT3, FMS-like tyrosine kinase 3.

Figure 5

Subgroup analysis of overall survival effects following sorting by second-generation FLT3 Inhibitor. The relative weight indicates each study's contribution to the overall effect in the meta-analysis. FLT3, FMS-like tyrosine kinase 3.

Figure 6

Subgroup analysis of overall survival effects stratified by the form of AML. The relative weight indicates each study's contribution to the overall effect in the meta-analysis. AML, acute myeloid leukemia.

Figure 7

Meta-regression analysis of association between log HR and age. The sizes of each circle represent the relative weight of each study, and the base of the logarithm used was e.

Figure 8

Comparison of the risk of prolonged QTc interval between second-generation FLT3 inhibitor group and control group. The relative weight indicates each study's contribution to the overall effect in the meta-analysis. FLT3, FMS-like tyrosine kinase 3.