Comparative safety and efficacy of first- and second-generation FLT3 inhibitors in newly diagnosed and relapsed AML: A meta-analysis stratified by molecular biomarkers

Abstract Background: FMS-like tyrosine kinase 3 (FLT3) mutation, including tyrosine kinase domain mutation and internal tandem duplications, occurs in ~30% of AML cases and is associated with poor prognosis. First-generation (sorafenib and midostaurin) and second-generation (gilteritinib, quizartinib, and crenolanib) FLT inhibitors demonstrated efficacy and safety across disease stages and are now used as a standard of treatment for FLT3-mutated AML. Stratification by biomarker, including FLT-ITD allelic ratio and mutations like nucleophosmin 1 (NPM1), influences therapeutic response. Objectives To analyze the therapeutic response rate, overall survival (OS), and individual toxicity profile of first and second-generation FLT inhibitors in newly diagnosed and relapsed AML patients, stratified by FLT3 mutation site, allelic ratio, and NPM1 co-mutation.Methods A systematic search was conducted using Medline-PubMed, Experta Medical Database (EMBASE), and Cochrane Database. Seventeen eligible studies (randomized trials and observational cohorts reporting FLT3 inhibitors) were included in the meta-analysis. Pooled hazard ratio (HR) analysis for overall survival (OS) and risk ratio (RR) for complete response/complete response incomplete (CR/CRi) were calculated with a random effect model. Toxicity rates were analyzed. Subgroup analysis using FLT-ITD allelic ratio and NPM1 mutation status. Risk of bias was assessed using the Cochrane RoB 2 tool. Results Seventeen studies (n = 5,214 patients) were included in the meta-analysis. Pooled overall survival using midostaurin was HR 0.78 (95% CI, 0.65-0.94), and gilteritinib was HR 0.64 (0.95% CI, 0.52-0.79). Overall CR rates/CRi rates using first-generation agents were RR=1.11 (95% CI, 1-1.22), and second-generation agents had a pooled RR of 1.38 (95% CI, 1.27-1.5). The significant cardiac toxicity of QTc prolongation was seen mostly in second-generation inhibitors with a pooled odds ratio of 6.31 (95% CI, 3.06-13). Among newly diagnosed FLT3-AML, midostaurin yields aCR/CRi rate of 59.1% with a median OS of 74.7 months vs 25.6 months (HR 0.78:95% CI, 0.65-0.94). The most significant toxicities were 92.7% Grade ¾ toxicity, 14.1% rash, and 5.6% nausea. Quzartinib leads to 71.6%, with a median OS of 31.9 months vs 15.1 months (HR, 0.78; 95% CI, 0.62-0.98). The QTc prolongation rates were 17% with a 42.3% neutropenia rate. In relapsed-refractory AML, gilteritinib had CR/CRi rates of 54.3% with median OS rates of 9.3 months vs 5.6 months in standard of care (HR, 0.64; 95% CI, 0.52-0.79). The elevated liver enzyme rate was 22.1%, and the QTC prolongation, 12.4%. Sorafenib was with CR/CRi rates of ~30% with a median OS rate of 5.6 months. The hypertension rate was 14.2% and dermatologic toxicity was 28.7% In biomarker stratification, a high FLT3-ITD allelic ratio >0.5 results in reduced rates of therapeutic response to gilteritinib, with GI50 increasing with p 0.36. FLT3-ITD allelic ratio: There is no therapeutic difference in efficacy across the allelic ratio groups in patients treated with quizartinib. Co-occurrence with NPM1 is associated with higher GI50 values across the inhibitors, suggestive of poor target engagement and reduced sensitivity despite FLT targeting. Conclusions Second-generation FLT inhibitors exhibit enhanced efficacy in relapsed-refractory AML scenarios and comparable outcomes to first-generation inhibitors in newly diagnosed AML.Stratification using ITD allelic ratio and NPM1 co-mutation is emerging as a critical factor. In light of these findings, it's imperative to integrate second-generation inhibitors in salvage settings and Biomarker-guided treatment decisions in front-line FLT3 mutant-AML