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

Abstract

BackgroundPrevious 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.AimThe 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 methodsPubMed, 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.ResultsA 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).ConclusionOur 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.

FLT3 inhibitors in acute myeloid leukaemia: assessment of clinical effectiveness, adverse events and future research—a systematic review and meta-analysis

“…In our review, FLT3 mutation was not assessed in relation to OS due to lack of data; however, a recent metaanalysis which included non-randomised data has concluded that patients with FLT3-ITD-positive mutations are more sensitive to FLT3 inhibitor treatment, thereby achieving a better CR (OR = 1.89, 95% CI 1.06 to 3.37, p= 0.03) and ORR (OR = 3.07, 95% CI 2.13 to 4.43, p < 0.001) [26].…”

Development of UHPLC-MS/MS Method for Indirubin-3′-Oxime Derivative as a Novel FLT3 Inhibitor and Pharmacokinetic Study in Rats

“…AML usually occurs in elderly patients [1,2]. The FMS-like receptor tyrosine kinase 3 (FLT3), a member of the receptor tyrosine kinase family, is an important target in the field of AML drug development [3]. FLT3 activates the intracellular tyrosine kinase domain, which dimerizes and autophosphorylates upon binding of the FLT3 ligand and causes phosphorylation of downstream molecules [4].…”

A Novel T-Cell Engaging Bi-specific Antibody Targeting the Leukemia Antigen PR1/HLA-A2

“…Targeted therapy has been revolutionary for the treatment of certain leukemias and have recently made an impact on AML patient treatment (2). Clinical trials evaluating FLT3 inhibitors were recently evaluated in a meta-analysis, and showed in combination with chemotherapy, FLT3 inhibitors increased patient overall survival (3, 4). Recently, the re-introduction and FDA approval of targeted therapies such as gemtuzumab ozogamicin (5), a CD33-targeting antibody conjugate, and other novel immunotherapies have expanded treatment possibilities for patients with AML (6).…”