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Use of FLT3 inhibitors in acute myeloid leukemia remission induction or salvage therapy: systematic review and meta-analysis.

ABSTRACT: Background:Previous studies showed that FLT3 inhibitors played an important role in acute myeloid leukemia (AML) therapy. However, discrepancies remain regarding the association between FLT3 inhibitors use and prognosis of AML patients in clinical trials. Aim:The aim of this study was to evaluate the effect of FLT3 inhibitors on the treatment of AML in a systematic review and meta-analysis. Materials and methods:PubMed, Embase, and Cochrane Library databases were searched for studies published before August 2017 that used FLT3 inhibitors in AML. Fixed- and random-effect models were used, and between-study heterogeneity was assessed. Results:A total of 26 studies fitting our inclusion and exclusion criteria were included. The FLT3 status of patients and main treatment outcomes including overall survival (OS), event-free survival (EFS), relapse-free survival (RFS), complete remission (CR), and overall response rate (ORR) after therapy were extracted. Five studies comparing addition of FLT3 inhibitors and placebo or blank control to chemotherapy were analyzed in Part I, showing improved OS (hazard ratio [HR]=0.86, 95% confidence interval [CI]=0.75-0.99, P=0.03) in the FLT3 inhibitor group but without a significant improvement on EFS (HR=0.86, 95% CI=0.62-1.21, P=0.39) and ORR (odds ratio [OR]=1.10, 95% CI=0.89-1.35, P=0.38). Twenty-one studies evaluating the benefit of using FLT3 inhibitors in different FLT3-type AML patients were analyzed in Part II, showing that FLT3-internal tandem duplication (ITD)-positive patients were more sensitive to FLT3 inhibitor treatment and achieved better CR (OR=1.89, 95% CI=1.06-3.37, P=0.03) and ORR (OR=3.07, 95% CI=2.13-4.43, P<0.001). Conclusion:Our study showed that combined use of FLT3 inhibitors improved OS and that the FLT3 status of AML patients could affect their sensitivity to FLT3 inhibitors in terms of CR and ORR.

SUBMITTER: Yang M

PROVIDER: S-EPMC6097505 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Use of FLT3 inhibitors in acute myeloid leukemia remission induction or salvage therapy: systematic review and meta-analysis.

Yang Minglei M Zhao Jian J Liu Tielong T Yang Xinghai X Wei Haifeng H Xu Wei W Xiao Jianru J

Cancer management and research 20180814

<h4>Background</h4>Previous studies showed that FLT3 inhibitors played an important role in acute myeloid leukemia (AML) therapy. However, discrepancies remain regarding the association between FLT3 inhibitors use and prognosis of AML patients in clinical trials.<h4>Aim</h4>The aim of this study was to evaluate the effect of FLT3 inhibitors on the treatment of AML in a systematic review and meta-analysis.<h4>Materials and methods</h4>PubMed, Embase, and Cochrane Library databases were searched f ...[more]

PMID: 30147364

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Project description:Mutations in the fms-like tyrosine kinase 3 (FLT3) gene are detected in approximately one-third of patients with newly diagnosed acute myeloid leukemia (AML). These consist of the more common FLT3-internal tandem duplication (ITD) in approximately 20-25% of AML cases, and point mutations in the tyrosine kinase domain (TKD) in approximately 5-10%. FLT3 mutations, especially FLT3-ITD, are associated with proliferative disease, increased risk of relapse, and inferior overall survival when treated with conventional regimens. However, the recent development of well tolerated and active FLT3 inhibitors has significantly improved the outcomes of this aggressive subtype of AML. The multikinase inhibitor midostaurin was approved by the United States Food and Drug Administration (US FDA) in April 2017 for the frontline treatment of patients with FLT3-mutated (either ITD or TKD) AML in combination with induction chemotherapy, representing the first new drug approval in AML in nearly two decades. In November 2018, the US FDA also approved the second-generation FLT3 inhibitor gilteritinib as a single agent for patients with relapsed or refractory FLT3-mutated AML. Promising phase I and II efficacy data for quizartinib is likely to lead to a third regulatory approval in relapsed/refractory AML in the near future. However, despite the significant progress made in managing FLT3-mutated AML, many questions remain regarding the best approach to integrate these inhibitors into combination regimens, and also the optimal sequencing of different FLT3 inhibitors in various clinical settings. This review comprehensively examines the FLT3 inhibitors currently in clinical development, with an emphasis on their spectra of activity against different FLT3 mutations and other kinases, clinical safety and efficacy data, and their current and future roles in the management of AML. The mechanisms of resistance to FLT3 inhibitors and potential combination strategies to overcome such resistance pathways are also discussed.

Dataset Information

Use of FLT3 inhibitors in acute myeloid leukemia remission induction or salvage therapy: systematic review and meta-analysis.

Publications

Use of FLT3 inhibitors in acute myeloid leukemia remission induction or salvage therapy: systematic review and meta-analysis.

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