Comparative Efficacy of Intensive Frontline Regimens in FLT3-Mutated AML: A Bayesian Network Meta-Analysis of Randomized Trials

Comparative Efficacy of Intensive Frontline Regimens in FLT3-Mutated AML: A Bayesian Network Meta-Analysis of Randomized Trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparative Efficacy of Intensive Frontline Regimens in FLT3-Mutated AML: A Bayesian Network Meta-Analysis of Randomized Trials antonella bruzzese, danilo lofaro, Enrica Antonia Martino, Francesco Mendicino, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8529770/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Apr, 2026 Read the published version in Annals of Hematology → Version 1 posted 9 You are reading this latest preprint version Abstract FLT3-mutated acute myeloid leukemia (FLT3mut AML) is associated with poor outcomes. Although FLT3 inhibitors (FLT3is) combined with chemotherapy improve responses, long-term survival remains limited, and the optimal first-line strategy is unclear. We conducted a Bayesian network meta-analysis of eight randomized trials, including 1,793 patients, to compare intensive regimens for overall survival (OS). Treatments studied were 3 + 7 with midostaurin, quizartinib, sorafenib, gemtuzumab ozogamicin (GO), glasdegib, CPX-351, and decitabine. FLT3i-based regimens improved outcomes but showed attenuated effects in this analysis, consistent with prior data. The small population with FLT3 mutation treated with GO + 3 + 7 and CPX-351 provided good outcomes (SUCRA 86.1% and 71.7%), while glasdegib + 3 + 7 and decitabine resulted in less effective strategies. Notably, 3 + 7 + GO showed superior benefit despite limited FLT3mut subgroup evidence. Ongoing studies are exploring CPX-351, GO, and FLT3i combinations, as well as novel strategies. Prospective, mutation-specific trials are needed to define optimal therapy. FLT3mutated (FLT3mut) AML treatment naïve AML OS in AML meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 INTRODUCTION Acute myeloid leukemia (AML) is a biologically and clinically heterogeneous hematologic malignancy characterized by a spectrum of cytogenetic and molecular abnormalities. Among the most frequent genetic lesions (detected in approximately 25–30% of AML), there are mutations in the FMS-like tyrosine kinase 3 (FLT3) gene, the two most frequent ones are internal tandem duplications (FLT3-ITD) in the juxtamembrane domain, and point mutations or small deletions within the tyrosine kinase domain (FLT3-TKD) [1–5]. FLT3-ITD mutations have consistently been associated with an adverse prognosis, including higher relapse rates and reduced overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS) compared to wild-type FLT3-ITD, particularly following chemotherapy or allogeneic stem cell transplantation (alloSCT) [1–2,6–9]. In contrast, the prognostic impact of FLT3-TKD mutations remains less well-defined and may be influenced by co-occurring genetic abnormalities. The therapeutic landscape for FLT3-mutated (FLT3 mut ) has evolved substantially with the introduction of FLT3 inhibitors (FLT3is). The pivotal phase III RATIFY trial demonstrated that the addition of midostaurin to standard induction and consolidation chemotherapy significantly improved complete remission (CR) rates, OS, and RFS with the addition of midostaurin to conventional chemotherapy in newly diagnosed, fit patients with FLT3 mut AML [10]. As a result, given the therapeutic relevance of FLT3 targeting, current European Leukemia Net (ELN) and the National Comprehensive Cancer Network (NCCN) guidelines recommend FLT3 mutation testing at diagnosis in all AML patients, and recommend adding midostaurin to intensive chemotherapy [11–12]. Other FLT3is have also been evaluated in both pre-alloSCT and post-alloSCT settings. Sorafenib has been investigated in phase II trials with conflicting results when added to standard chemotherapy [13–14]. More recently, the phase III QuANTUM-First trial showed that quizartinib, when combined with intensive chemotherapy, led to improved CR rates, OS, and EFS compared to chemotherapy alone in patients with FLT3-ITD AML [15]. In parallel with the development of FLT3is, several other agents have been explored in the frontline treatment of newly diagnosed AML irrespective of FLT3 mut [16–21]. While several of these studies included patients with FLT3 mutations, most were not specifically powered to assess efficacy in this subgroup. Furthermore, no head-to-head randomized trials have directly compared different FLT3is combined with chemotherapy, nor have studies systematically evaluated the addition of FLT3is to alternative intensive regimens. The present network meta-analysis aims to synthesize available evidence on the comparative efficacy of intensive strategies in newly diagnosed, fit patients with FLT3 mut AML. By integrating data from randomized trials, this analysis seeks to inform optimal first-line therapeutic approaches in this molecularly defined subgroup. METHODS Search strategy A systematic literature review was conducted to identify randomized controlled trials (RCTs) evaluating first-line treatments in newly diagnosed (treatment-naïve, TN) AML patients harboring FLT3 mutations. Both published and unpublished studies, including congress abstracts, were considered eligible provided that they reported sufficient methodological and outcome data. Eligibility Criteria Studies were eligible for inclusion if they met the following criteria: (i) randomized controlled design, regardless of blinding status; (ii) enrolled adult patients with TN FLT3 mut AML; (iii) investigated novel or non-standard first-line regimens in the experimental arms, with standard induction therapy as comparator; and (iv) reported at least one efficacy outcome, including OS, specifically for the FLT3-mutated subgroup. Studies were excluded if they were non-randomized or non-prospective, lacked relevant outcome data for the FLT3-mutated subgroup, had unclear or incomplete methodology, or evaluated treatments outside the first-line. Data extraction and quality assessment Two reviewers (A.B. and M.G.) independently screened titles and abstracts, assessed full-text articles for eligibility, and extracted data using a standardized form. Extracted data included: i) study identifiers (first author, publication year); study design characteristics, patient demographics, patient FLT3 mutation status, treatment details, and reported hazard ratios (HRs) for OS in the FLT3-mutated population. Each reviewer maintained a separate database; results were compared, and discrepancies were resolved by discussion. Duplicates were removed following cross-checking. Risk of bias assessment The risk of bias for included studies was evaluated using the Cochrane Risk of Bias 2 (RoB 2) tool [22], which assesses bias across the five domains: randomisation process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of the reported result. Each study was independently assessed by two reviewers. Any disagreements were resolved through discussion or consultation with a third reviewer, if necessary. Studies were classified as having ‘Low risk’, ‘Some concerns’, or ’High risk’ of bias. Summary results were visualized using traffic‑light plots and a bar chart. Statistical Analysis A Bayesian random‑effects contrast‑based network meta‑analysis (NMA) was performed to compare the efficacy of different intensive first-line regimens in FLT3 mut AML. The outcome analysed was the HR of the OS contrast. Non-informative normal priors (mean 0, large variance) were applied to basic treatment effects, while a wide Uniform prior was used for the between-study standard deviation (τ). Robustness was assessed using a moderately informative half-Normal prior for τ. Four parallel Markov chains were run (40,000 iterations; burn-in = 20,000; thinning = 10). Convergence was confirmed visually and with Brooks-Gelman-Rubin diagnostics (all potential scale-reduction factors ≤ 1.05). Model adequacy was judged by the posterior mean residual deviance and the deviance-information criterion (DIC). A forest plot was used to display pooled posterior HRs and 95% credible intervals (CrIs) for each regimen versus the reference regimen. Treatment ranking was summarised with surface under the cumulative ranking curve (SUCRA) and reported alongside posterior medians and 95% CrIs for every pairwise contrast. Sensitivity analyses were carried out to assess robustness of the results, in particular: i) an NMA limited to trials that enrolled only FLT3-mutated patients (excluding subgroup data); ii) leave-one-treatment-out (NMAs leaving out one treatment each time) analyses to eventually identify influential studies; iii) Bayesian meta-regressions incorporating median age, an indicator for “older-patient-only” trials and an indicator of subgroups derived results, to explore potential effect modification and violations of NMA assumptions. All analyses were conducted in R 4.5.0 [23], with NMA models implemented in JAGS, via the gemtc [24] and rjags R packages [25]. The present network meta-analysis was not registered in the PROSPERO international prospective register of systematic reviews. RESULTS Study selection The study selection process is summarized in the PRISMA flow diagram (Fig. 1 ). From an initial pool of 4,317 records, identified between 2012 and 2025—including full articles and conference abstracts—1,881 review articles were excluded, yielding 2,436 potentially eligible studies. After title and abstract screening, 2,078 reports were excluded due to irrelevance or ineligible design, leaving 358 clinical trials for further evaluation. Among these, 244 studies were excluded owing to the absence of a suitable comparator arm. Full-text review was conducted on 114 studies, of which 106 were excluded for methodological limitations or lack of data specific to FLT3-mutated AM. Ultimately, eight trials, including 1,793 TN FLT3 mut AML patients, were deemed eligible for inclusion in the network meta-analysis (Table 1 ). Table 1 Main characteristics of clinical trials included in the meta-analysis. Trial (Authors) Publication Year Treatment arms Randomized patients FLT3-mutated RATIFY ( Stone et al.) 2017 Midostaurin + 3 + 7 3 + 7 360 357 360 357 QuANTUM First ( Erba et al.) 2023 Quizartinib + 3 + 7 3 + 7 268 271 268 271 SORAML ( Rolling et al.) 2021 Sorafenib + 3 + 7 3 + 7 134 133 23 23 Study by ALLG ( Loo et al.) 2023 Sorafenib + 3 + 7 3 + 7 35 33 35 33 ALFA-0701 ( Castaigne et al.) 2012 GO + 3 + 7 3 + 7 140 140 22 27 NCT02172872 ( Lübbert et al.) 2023 10day-DEC 3 + 7 303 303 32 22 BRIGHT AML 1019 ( Sekeres et al.) 2023 Glasdegib + 3 + 7 3 + 7 201 203 12 14 Study 301 ( Lancet et al.) 2021 CPX-351 3 + 7 153 156 22 21 Abbreviations: GO - Gentuzumab + Ozogmamicin; DEC - Decitabin Risk of bias assessment Risk of bias was assessed for all included studies using the Cochrane RoB2 tool (Fig. 2 ). Nine randomised controlled trials encompassing eight distinct treatment regimens were included in the network meta-analysis. Overall, three trials were judged to be at low risk of bias, while five of the remaining were rated as having some concerns; no study was classified as being at high risk. The most frequent source of concern related to Domain 2 (deviations from intended interventions) is primarily due to open-label study designs. However, given that overall survival was the primary outcome, these deviations were unlikely to materially influence effect estimates. Additional concerns were identified in Domain 5 (selection of the reported result) for five trials, as HR estimates for overall survival were derived from subgroup analyses of FLT3-mutated patients that were not pre-specified in the original study protocols. This raised the potential for selective outcome reporting, although no clear evidence of systematic reporting bias was observed. Network Meta-analysis of Overall Survival The evidence network included eight strategies configured in a star-shaped topology, with standard 3 + 7 induction chemotherapy as the common comparator (Fig. 3 ). Direct comparisons were available only between each experimental regimen and 3 + 7; no closed loops were present, precluding statistical assessment of inconsistency. Between-study heterogeneity was moderate, with a posterior median between-study standard deviation (τ ) of 0.43 (95%CrI 0.02–1.14, log-HR scale). Overall model fit was acceptable (DIC = 15.0). Comparative Efficacy Versus Standard Induction (3 + 7) Figure 4 presents posterior median HRs and 95% CrIs for each experimental treatment versus standard 3 + 7. The combination of GO with 3 + 7 showed the most favourable point estimate (HR = 0.30, 95%CrI 0.06–1.46), followed by CPX-351 (0.51, 0.12–2.15) and Sorafenib + 3 + 7 (0.67, 0.24–1.85). Combinations involving Midostaurin and Quizartinib yielded HRs clustered around 0.8. In contrast, Decitabine and Glasdegib + 3 + 7 were associated with numerically higher HRs (1.40 and 1.98, respectively), suggesting a trend toward inferior outcomes relative to the control. However, all CrIs overlapped the null value (HR = 1), reflecting substantial uncertainty, largely attributable to the reliance on subgroup-level data for five of the seven experimental regimens. Treatment ranking Treatment ranking based on SUCRA values is illustrated in Fig. 5 . Despite the limited number of patients with FLT3 mutation treated with the first 2 regimens, the GO + 3 + 7 regimen demonstrated the highest probability of being the most effective (SUCRA 86.1%), followed by CPX-351 (71.7%), Sorafenib + 3 + 7 (60.3%), Midostaurin + 3 + 7 (52.3%), and Quizartinib + 3 + 7 (51.5%). Standard 3 + 7 ranked in the lower half of the distribution (SUCRA 33.0%), whereas Decitabine and Glasdegib + 3 + 7 had the lowest probabilities of benefit (SUCRA 24.9% and 20.2%, respectively). Pairwise contrasts All 28 indirect pairwise contrasts between treatments were directionally consistent with the SUCRA rankings, but lacked statistical significance. CrI for all comparisons crossed unity, reflecting wide uncertainty intervals (Table 2 ). These findings underscore a key limitation of the network’s star-shaped configuration, wherein all regimens are compared only to the common comparator (3 + 7), with no direct head-to-head trials between experimental treatments. Table 2 Pairwise relative treatment effects comparison as HR (95% CrI). Gemtuzumab Ozogamicin 0.57 (0.07–5.24) CPX-351 0.44 (0.06–2.87) 0.76 (0.14–4.33) Sorafenib 0.38 (0.05–2.86) 0.67 (0.09–4.21) 0.87 (0.16–4.35) Midostaurin 0.38 (0.05–2.72) 0.66 (0.09–4.58) 0.87 (0.17–4.36) 0.99 (0.16–6.32) Quizartinib 0.30 (0.06–1.46) 0.52 (0.12–2.15) 0.68 (0.24–1.85) 0.78 (0.21–2.95) 0.78 (0.21–2.86) 3 + 7 0.21 (0.02–2.03) 0.37 (0.04–3.06) 0.48 (0.08–3.02) 0.56 (0.08–4.08) 0.56 (0.08–4.12) 0.72 (0.16–3.19) Decitabin 0.15 (0.01–1.95) 0.26 (0.02–3.20) 0.34 (0.04–3.38) 0.40 (0.04–4.49) 0.40 (0.04–4.73) 0.52 (0.07–3.92) 0.71 (0.05–9.01) Glasdegib Sensitivity analyses Multiple sensitivity analyses were undertaken to assess the robustness of the results and to identify potential violations of model assumptions. First, restricting the analysis to trials exclusively enrolling FLT3 mut patients [12,14–15] yielded consistent SUCRA rankings (Supplementary Tables 1, 2), with 3 + 7 consistently ranked lowest. Effect sizes from the original trials showing statistically significant OS benefit (e.g., RATIFY and QuANTUM-First) were attenuated in the network model. While point estimates remained similar (HR = 0.78), the 95% CrIs widened and crossed unity in both cases: Midostaurin (HR = 0.78; 95% CrI, 0.52–3.00) and Quizartinib (HR = 0.78; 95% CrI, 0.52–1.17). Leave-one-treatment-out analyses demonstrated minimal impact on SUCRA rankings and pairwise HRs (Supplementary Figs. 1 and 2). Removal of any single treatment did not alter the top three ranked therapies, and the absolute percentage change in HRs did not exceed ~ 3%. In addition, we performed a dedicated sensitivity analysis excluding decitabine from the network. After removal of decitabine, the relative positioning of the main regimens of interest remained substantially unchanged. The corresponding SUCRA profiles showed only minor redistribution across adjacent ranks, without inversion of the relative ordering of top-ranked treatments (Supplementary Table 3). Consistently, the pairwise HR estimates involving 3 + 7 + GO and CPX-351 remained stable, with differences well within the range observed in the leave-one-treatment-out analyses (absolute changes < 3%). Meta-regression Analyses Exploratory meta-regression analyses were conducted to explore the potential influence of study-level covariates (Supplementary Table 4). Incorporating median age as a continuous covariate did not meaningfully modify the treatment effect estimated (HR ratio = 0.99 per 10-year increase; 95% CrI 0.02–21.18). Model fit improved only marginally (DIC = 13.4 versus 15.0), and τ remained stable. Similarly, the introduction of a binary covariate for trials restricted to older populations yielded null findings. A third model assessing whether dedicated FLT3 mut trials differed from subgroup-based analyses also showed no significant effect modification (HR ratio = 0.89; 95% CrI, 0.19–6.12), although this model introduced slightly greater residual heterogeneity (τ = 0.55) and a modest increase in DIC (15.6). These findings suggest that variation in patient age and trial design does not significantly confound treatment effect estimates within the network. DISCUSSION For nearly four decades, the combination of cytarabine and an anthracycline (commonly referred to as the 3 + 7 regimen) has represented the standard of care for patients with AML eligible for intensive chemotherapy. However, growing insights into the genetic and molecular heterogeneity of AML have facilitated a shift toward more personalized treatment approaches. This shift is reflected in recent classifications, such as the International Consensus Classification (ICC), which underscore the complexity of AML subtyping and highlight the challenges of individualized treatment selection [1]. In the subset of AML patients harboring FLT3 mut —a group comprising approximately 25–30% of adult AML—therapeutic advances have been largely driven by the development of FLT3is. These agents have shown efficacy both as monotherapies and in combination with intensive regimens. Despite this progress, outcomes remain suboptimal, with median RFS around 30 months, and CR rates approximately 70% in clinical trials, suggesting that FLT3i-based triplet regimens may still be improved [10,15]. In the present NMA, when restricted to trials enrolling exclusively FLT3 mut patients treated with 3 + 7 plus a FLT3i, no substantial differences in efficacy emerged among the experimental regimens. SUCRA values were comparable, and standard 3 + 7 consistently ranked lowest, suggesting a reduced probability of being the most effective regimen. Notably, effect sizes from pivotal trials, such as RATIFY (midostaurin) and QuANTUM-First (quizartinib), which had reported statistically significant improvements in OS, were attenuated in the NMA [10,14–15]. This attenuation reflects the application of a random-effects prior, which accounts for between-study heterogeneity and incorporates hierarchical shrinkage, thereby widening credible intervals when few studies inform a comparison. These findings are consistent with a prior meta-analysis by Molica et al., which similarly found no significant OS differences among FLT3is [26]. A retrospective analysis also suggested improved RFS and OS with FLT3is, particularly in lower-intensity treatment settings [27]. Emerging FLT3is, such as crenolanib, may offer further therapeutic gains [28]. Despite important limitations in our star-shaped network—specifically the lack of direct head-to-head comparisons between experimental regimens—and the small sample sizes of included trials, the combinations of 3 + 7 + GO and CPX-351 ranked highest. Most FLT3 mut cases fall into the intermediate-risk category, potentially benefiting from GO [16,17], while others with secondary AML may be candidates for CPX-351. Importantly, no randomized trial has specifically evaluated these regimens in FLT3 mut AML despite a plausible biological and clinical rationale. Interestingly, the only 49 FLT3 mut patients enrolled in the ALFA-0701 trial showed no substantial differences in performance status or cytogenetic risk compared to the patients enrolled in the other trials considered for the present meta-analysis. Moreover, patients would not had recived a better supportive treatments considering that ALFA-0701 was among the oldest trials analyzed [16, 17]. Furthermore, a small retrospective study involving 11 FLT3 mut patients reported a CR rate of 91% with the combination of GO, midostaurin, and intensive chemotherapy [29]. In line with these results, the SAL-MODULE phase I study investigated a four-drug regimen (3 + 7 + GO + midostaurin) in 12 patients (10 with FLT3 mutations), achieving a CR rate of 75% and an overall response rate (ORR) of 92% [30]. Conversely, another phase I study enrolling a similar patient population reported a composite CR rate of 76% and OS rates of 79%, 65%, and 39% at 6 months, 1 year, and 2 years, respectively, with frequent grade ≥ 3 cytopenias [31]. The phase III study 301, which included 43 FLT3 mut patients, also demonstrated promising outcomes with CPX-351, despite a population characterized by older age, secondary disease, and adverse cytogenetics. Post hoc analyses revealed increased sensitivity of FLT3-ITD blasts to CPX-351, including enhanced drug uptake and cytotoxicity compared to FLT3-wild-type blasts [32]. Although robust data are lacking on combining CPX-351 with FLT3is, preliminary results are encouraging. A phase I study of CPX-351 + gilteritinib in relapsed/refractory AML reported a composite CR/CRi rate of 46.2% and median OS of 11.9 months, with manageable toxicity [33]. The phase Ib V-FAST trial explored CPX-351 + midostaurin in newly diagnosed FLT3 mut AML, showing CR rates of 82% (FLT3-ITD) and 83% (FLT3-TKD) [34]. Several ongoing trials are evaluating combinations of CPX-351, GO, and FLT3is. One such phase III trial (NCT04293562) is randomizing newly diagnosed AML patients to receive chemotherapy with or without GO, with the addition of gilteritinib for FLT3-mutated patients. Beyond the small sample size of FLT3 mut patients enrolled in most of the analysed trials, another important limitation of the present study are lack of prospective stratification by FLT3 status and the lack of data on alloSCT. Among the analyzed trials, the exact percentage of patients that received alloSCT and their outcomes are available only for patients enrolled in the ALFA 0701 and QUANTUM-first; for the other studies, data are incomplete. Moreover, comparing the percentage of transplanted patients in ALFA 0701 and QUANTUM-first, it is notable that only 1/3 of patients in ALFA0701 underwent alloSCT compared to 50% of QUANTUM-first, reflecting the different approaches to alloSCT in AML patients in a 10year period [15–17]. Moreover, data on therapeutic options for post-transplant relapses are limited, as data comparing consolidation strategies (alloSCT or FLT3is). Another important limitation to take into consideration is that our NMA focuses on OS that is influenced not only by the efficacy and safety of chemotherapy but also by the optimization of supportive care and possible post relapse salvage strategies, whose data are not comparable in the selected studies. FLT3is are also being explored in less intensive regimens. Preclinical synergy between FLT3is and BCL-2 inhibitors has led to studies combining venetoclax with FLT3is, yielding promising early results and potentially more durable responses [41–43]. Although decitabine did not improve outcomes versus standard induction in FLT3 mut AML [19], further research is needed to evaluate whether FLT3i combinations with hypomethylating agents may enhance therapeutic response. In conclusion, FLT3 mut AML represents a biologically distinct and therapeutically challenging subset of the disease. This network meta-analysis suggests that 3 + 7 + GO and CPX-351 may be effective in the treatment of FLT3 mut patients; however, definitive conclusions are limited by small sample sizes and a lack of direct comparative trials. Future studies should focus on integrating FLT3is with additional targeted agents and optimizing treatment intensity based on individual molecular and clinical profiles. The continued development of rational combinations tailored to FLT3 mut AML has the potential to significantly improve long-term outcomes in this high-risk population. Declarations Author Contributions: All authors contributed to the manuscript and were involved in revisions and proofreading. All authors approved the submitted version. Conflicts of Interest: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. Data availability statement: Data sharing does not apply to this article, as no new data were generated or analyzed in this study. Human Ethics and Consent to Participate declarations: not applicable. Funding Declaration: no funding. References Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, Wang SA, Bagg A, Barbui T, Branford S, Bueso-Ramos CE, Cortes JE, Dal Cin P, DiNardo CD, Dombret H, Duncavage EJ, Ebert BL, Estey EH, Facchetti F, Foucar K, Gangat N, Gianelli U, Godley LA, Gökbuget N, Gotlib J, Hellström-Lindberg E, Hobbs GS, Hoffman R, Jabbour EJ, Kiladjian JJ, Larson RA, Le Beau MM, Loh ML, Löwenberg B, Macintyre E, Malcovati L, Mullighan CG, Niemeyer C, Odenike OM, Ogawa S, Orfao A, Papaemmanuil E, Passamonti F, Porkka K, Pui CH, Radich JP, Reiter A, Rozman M, Rudelius M, Savona MR, Schiffer CA, Schmitt-Graeff A, Shimamura A, Sierra J, Stock WA, Stone RM, Tallman MS, Thiele J, Tien HF, Tzankov A, Vannucchi AM, Vyas P, Wei AH, Weinberg OK, Wierzbowska A, Cazzola M, Döhner H, Tefferi A. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022 Sep 15;140(11):1200-1228. doi: 10.1182/blood.2022015850. PMID: 35767897; PMCID: PMC9479031. Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, Bejar R, Berti E, Busque L, Chan JKC, Chen W, Chen X, Chng WJ, Choi JK, Colmenero I, Coupland SE, Cross NCP, De Jong D, Elghetany MT, Takahashi E, Emile JF, Ferry J, Fogelstrand L, Fontenay M, Germing U, Gujral S, Haferlach T, Harrison C, Hodge JC, Hu S, Jansen JH, Kanagal-Shamanna R, Kantarjian HM, Kratz CP, Li XQ, Lim MS, Loeb K, Loghavi S, Marcogliese A, Meshinchi S, Michaels P, Naresh KN, Natkunam Y, Nejati R, Ott G, Padron E, Patel KP, Patkar N, Picarsic J, Platzbecker U, Roberts I, Schuh A, Sewell W, Siebert R, Tembhare P, Tyner J, Verstovsek S, Wang W, Wood B, Xiao W, Yeung C, Hochhaus A. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022 Jul;36(7):1703-1719. doi: 10.1038/s41375-022-01613-1. Epub 2022 Jun 22. PMID: 35732831; PMCID: PMC9252913. Cancer Genome Atlas Research Network; Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, Hoadley K, Triche TJ Jr, Laird PW, Baty JD, Fulton LL, Fulton R, Heath SE, Kalicki-Veizer J, Kandoth C, Klco JM, Koboldt DC, Kanchi KL, Kulkarni S, Lamprecht TL, Larson DE, Lin L, Lu C, McLellan MD, McMichael JF, Payton J, Schmidt H, Spencer DH, Tomasson MH, Wallis JW, Wartman LD, Watson MA, Welch J, Wendl MC, Ally A, Balasundaram M, Birol I, Butterfield Y, Chiu R, Chu A, Chuah E, Chun HJ, Corbett R, Dhalla N, Guin R, He A, Hirst C, Hirst M, Holt RA, Jones S, Karsan A, Lee D, Li HI, Marra MA, Mayo M, Moore RA, Mungall K, Parker J, Pleasance E, Plettner P, Schein J, Stoll D, Swanson L, Tam A, Thiessen N, Varhol R, Wye N, Zhao Y, Gabriel S, Getz G, Sougnez C, Zou L, Leiserson MD, Vandin F, Wu HT, Applebaum F, Baylin SB, Akbani R, Broom BM, Chen K, Motter TC, Nguyen K, Weinstein JN, Zhang N, Ferguson ML, Adams C, Black A, Bowen J, Gastier-Foster J, Grossman T, Lichtenberg T, Wise L, Davidsen T, Demchok JA, Shaw KR, Sheth M, Sofia HJ, Yang L, Downing JR, Eley G. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013 May 30;368(22):2059-74. doi: 10.1056/NEJMoa1301689. Epub 2013 May 1. Erratum in: N Engl J Med. 2013 Jul 4;369(1):98. PMID: 23634996; PMCID: PMC3767041. Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, Sonoda Y, Fujimoto T, Misawa S. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996 Dec;10(12):1911-8. PMID: 8946930. Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001 Apr 15;97(8):2434-9. doi: 10.1182/blood.v97.8.2434. PMID: 11290608. Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 2005 Aug;19(8):1345-9. doi: 10.1038/sj.leu.2403838. PMID: 15959528. Ayala R, Carreño-Tarragona G, Barragán E, Boluda B, Larráyoz MJ, Chillón MC, Carrillo-Cruz E, Bilbao C, Sánchez-García J, Bernal T, Martinez-Cuadron D, Gil C, Serrano J, Rodriguez-Medina C, Bergua J, Pérez-Simón JA, Calbacho M, Alonso-Domínguez JM, Labrador J, Tormo M, Amigo ML, Herrera-Puente P, Rapado I, Sargas C, Vazquez I, Calasanz MJ, Gomez-Casares T, García-Sanz R, Sanz MA, Martínez-López J, Montesinos P. Impact of FLT3-ITD Mutation Status and Its Ratio in a Cohort of 2901 Patients Undergoing Upfront Intensive Chemotherapy: A PETHEMA Registry Study. Cancers (Basel). 2022 Nov 24;14(23):5799. doi: 10.3390/cancers14235799. PMID: 36497281; PMCID: PMC9737662. Bazarbachi A, Bug G, Baron F, Brissot E, Ciceri F, Dalle IA, Döhner H, Esteve J, Floisand Y, Giebel S, Gilleece M, Gorin NC, Jabbour E, Aljurf M, Kantarjian H, Kharfan-Dabaja M, Labopin M, Lanza F, Malard F, Peric Z, Prebet T, Ravandi F, Ruggeri A, Sanz J, Schmid C, Shouval R, Spyridonidis A, Versluis J, Vey N, Savani BN, Nagler A, Mohty M. Clinical practice recommendation on hematopoietic stem cell transplantation for acute myeloid leukemia patients with FLT3 -internal tandem duplication: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2020 Jun;105(6):1507-1516. doi: 10.3324/haematol.2019.243410. Epub 2020 Apr 2. PMID: 32241850; PMCID: PMC7271578. Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, Späth D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H; German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008 May 1;358(18):1909-18. doi: 10.1056/NEJMoa074306. PMID: 18450602. Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. doi: 10.1056/NEJMoa1614359. Epub 2017 Jun 23. PMID: 28644114; PMCID: PMC5754190. Döhner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, Ebert BL, Fenaux P, Godley LA, Hasserjian RP, Larson RA, Levine RL, Miyazaki Y, Niederwieser D, Ossenkoppele G, Röllig C, Sierra J, Stein EM, Tallman MS, Tien HF, Wang J, Wierzbowska A, Löwenberg B. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022 Sep 22;140(12):1345-1377. doi: 10.1182/blood.2022016867. PMID: 35797463. Pollyea DA, Bixby D, Perl A, Bhatt VR, Altman JK, Appelbaum FR, de Lima M, Fathi AT, Foran JM, Gojo I, Hall AC, Jacoby M, Lancet J, Mannis G, Marcucci G, Martin MG, Mims A, Neff J, Nejati R, Olin R, Percival ME, Prebet T, Przespolewski A, Rao D, Ravandi-Kashani F, Shami PJ, Stone RM, Strickland SA, Sweet K, Vachhani P, Wieduwilt M, Gregory KM, Ogba N, Tallman MS. NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021. J Natl Compr Canc Netw. 2021 Jan 6;19(1):16-27. doi: 10.6004/jnccn.2021.0002. PMID: 33406488. Röllig C, Serve H, Hüttmann A, Noppeney R, Müller-Tidow C, Krug U, Baldus CD, Brandts CH, Kunzmann V, Einsele H, Krämer A, Schäfer-Eckart K, Neubauer A, Burchert A, Giagounidis A, Krause SW, Mackensen A, Aulitzky W, Herbst R, Hänel M, Kiani A, Frickhofen N, Kullmer J, Kaiser U, Link H, Geer T, Reichle A, Junghanß C, Repp R, Heits F, Dürk H, Hase J, Klut IM, Illmer T, Bornhäuser M, Schaich M, Parmentier S, Görner M, Thiede C, von Bonin M, Schetelig J, Kramer M, Berdel WE, Ehninger G; Study Alliance Leukaemia. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015 Dec;16(16):1691-9. doi: 10.1016/S1470-2045(15)00362-9. Epub 2015 Nov 6. PMID: 26549589. Loo S, Roberts AW, Anstee NS, Kennedy GA, He S, Schwarer AP, Enjeti AK, D'Rozario J, Marlton P, Bilmon IA, Taper J, Cull G, Tiley C, Verner E, Hahn U, Hiwase DK, Iland HJ, Murphy N, Ramanathan S, Reynolds J, Ong DM, Tiong IS, Wall M, Murray M, Rawling T, Leadbetter J, Rowley L, Latimer M, Yuen S, Ting SB, Fong CY, Morris K, Bajel A, Seymour JF, Levis MJ, Wei AH. Sorafenib plus intensive chemotherapy in newly diagnosed FLT3-ITD AML: a randomized, placebo-controlled study by the ALLG. Blood. 2023 Dec 7;142(23):1960-1971. doi: 10.1182/blood.2023020301. PMID: 37647654; PMCID: PMC10733823. Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. doi: 10.1016/S0140-6736(23)00464-6. Epub 2023 Apr 25. Erratum in: Lancet. 2023 Oct 14;402(10410):1328. doi: 10.1016/S0140-6736(23)02235-3. PMID: 37116523 Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. doi: 10.1016/S0140-6736(12)60485-1. Epub 2012 Apr 5. Erratum in: Lancet. 2018 Mar 3;391(10123):838. doi: 10.1016/S0140-6736(17)32105-0. PMID: 22482940. Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019 Jan;104(1):113-119. doi: 10.3324/haematol.2018.188888. Epub 2018 Aug 3. PMID: 30076173; PMCID: PMC6312010. Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC. CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia. J Clin Oncol. 2018 Sep 10;36(26):2684-2692. doi: 10.1200/JCO.2017.77.6112. Epub 2018 Jul 19. PMID: 30024784; PMCID: PMC6127025. Lübbert M, Wijermans PW, Kicinski M, Chantepie S, Van der Velden WJFM, Noppeney R, Griškevičius L, Neubauer A, Crysandt M, Vrhovac R, Luppi M, Fuhrmann S, Audisio E, Candoni A, Legrand O, Foà R, Gaidano G, van Lammeren-Venema D, Posthuma EFM, Hoogendoorn M, Giraut A, Stevens-Kroef M, Jansen JH, de Graaf AO, Efficace F, Ammatuna E, Vilque JP, Wäsch R, Becker H, Blijlevens N, Dührsen U, Baron F, Suciu S, Amadori S, Venditti A, Huls G; EORTC Leukemia Group, GIMEMA, and German MDS Study Group. 10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial. Lancet Haematol. 2023 Nov;10(11):e879-e889. doi: 10.1016/S2352-3026(23)00273-9. Erratum in: Lancet Haematol. 2024 Oct;11(10):e723. doi: 10.1016/S2352-3026(24)00252-7. PMID: 37914482. Efficace F, Kicinski M, Coens C, Suciu S, van der Velden WJFM, Noppeney R, Chantepie S, Griskevicius L, Neubauer A, Audisio E, Luppi M, Fuhrmann S, Foà R, Crysandt M, Gaidano G, Vrhovac R, Venditti A, Posthuma EFM, Candoni A, Baron F, Legrand O, Mengarelli A, Fazi P, Vignetti M, Giraut A, Wijermans PW, Huls G, Lübbert M. Decitabine in older patients with AML: quality of life results of the EORTC-GIMEMA-GMDS-SG randomized phase 3 trial. Blood. 2024 Aug 1;144(5):541-551. doi: 10.1182/blood.2023023625. PMID: 38717861. Sekeres MA, Montesinos P, Novak J, Wang J, Jeyakumar D, Tomlinson B, Mayer J, Jou E, Robak T, Taussig DC, Dombret H, Merchant A, Shaik N, O'Brien T, Roh W, Liu X, Ma W, DiRienzo CG, Chan G, Cortes JE. Glasdegib plus intensive or non-intensive chemotherapy for untreated acute myeloid leukemia: results from the randomized, phase 3 BRIGHT AML 1019 trial. Leukemia. 2023 Oct;37(10):2017-2026. doi: 10.1038/s41375-023-02001-z. Epub 2023 Aug 21. PMID: 37604981; PMCID: PMC10539167. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates CJ, Cheng HY, Corbett MS, Eldridge SM, Emberson JR, Hernán MA, Hopewell S, Hróbjartsson A, Junqueira DR, Jüni P, Kirkham JJ, Lasserson T, Li T, McAleenan A, Reeves BC, Shepperd S, Shrier I, Stewart LA, Tilling K, White IR, Whiting PF, Higgins JPT. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019 Aug 28;366:l4898. doi: 10.1136/bmj.l4898. PMID: 31462531. R Core Team. (2025). R: A language and environment for statistical computing. R Foundation for Statistical Computing. van Valkenhoef, Gert, and Jeroen Kuiper. 2023. gemtc: Network Meta-Analysis Using Bayesian Methods. R package version 1.0-2. https://CRAN.R-project.org/package=gemtc Plummer, Martyn. rjags: Bayesian Graphical Models Using MCMC. Version X.X, 2025. R package version 4-17, https://CRAN.R-project.org/package=rjags Molica M, Perrone S, Rossi M, Giannarelli D. The impact of different FLT3-inhibitors on overall survival of de novo acute myeloid leukemia: A network meta-analysis. Leuk Res. 2024 Sep;144:107549. doi: 10.1016/j.leukres.2024.107549. Epub 2024 Jul 17. PMID: 39067406. Bazinet A, Bataller A, Kadia T, Daver N, Short NJ, Yilmaz M, Sasaki K, DiNardo CD, Borthakur GM, Issa G, Bouligny I, Pierce S, Garcia-Manero G, Ravandi F, Kantarjian HM. A retrospective study of outcomes across time and treatment regimens in newly diagnosed, FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia. Cancer. 2025 Mar 15;131(6):e35813. doi: 10.1002/cncr.35813. PMID: 40097915. Wang ES, Goldberg AD, Tallman M, Walter RB, Karanes C, Sandhu K, Vigil CE, Collins R, Jain V, Stone RM. Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML. J Clin Oncol. 2024 May 20;42(15):1776-1787. doi: 10.1200/JCO.23.01061. Epub 2024 Feb 7. PMID: 38324741; PMCID: PMC11107896. Weinbergerová B, Čerňan M, Kabut T, Semerád L, Podstavková N, Szotkowski T, Ježíšková I, Mayer J. Gemtuzumab ozogamicin plus midostaurin in conjunction with standard intensive therapy for FLT3- mutated acute myeloid leukemia patients - Czech center experience. Haematologica. 2023 Oct 1;108(10):2826-2829. doi: 10.3324/haematol.2022.282263. PMID: 36815379; PMCID: PMC10542832. Borate U, Dvorak-Kornaus KM, Zhao Q, Walter RB, Cook RJ, Saultz JN, Swords RT, Grieselhuber NR, Mims A, Larkin KT, Sahasrabudhe KD, Blachly JS, Behbehani GK, Eisfeld A, Long M, Srisuwananukorn A, Koenig KL; A Phase I Study to Evaluate the Safety and Tolerability of Gemtuzumab Ozogamicin and Midostaurin When Used in Combination with Standard Cytarabine and Daunorubicin Induction for Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia. Blood 2024; 144 (Supplement 1): 4286. doi: https://doi.org/10.1182/blood-2024-210605 Röllig C, Schliemann C, Ruhnke L, Fransecky L, Heydrich BN, Hanoun M, Noppeney R, Schäfer-Eckart K, Wendelin K, Mikesch JH, Middeke JM, Reimann M, Fiebig F, Zukunft S, Wermke M, Serve H, Platzbecker U, Müller-Tidow C, Baldus CD, Bornhäuser M. Gemtuzumab ozogamicin plus midostaurin in combination with standard '7 + 3' induction therapy in newly diagnosed AML: Results from the SAL-MODULE phase I study. Br J Haematol. 2024 Jun;204(6):2254-2258. doi: 10.1111/bjh.19436. Epub 2024 Apr 9. PMID: 38593353. Andrews C, Pullarkat V, Recher C. CPX-351 in FLT3-mutated acute myeloid leukemia. Front Oncol. 2023 Nov 17;13:1271722. doi: 10.3389/fonc.2023.1271722. PMID: 38044999; PMCID: PMC10691756. Chan O, Sweet KL, Hunter J, Ball S, Mo Q, Xie Z, Yun S, Kuykendall AT, Padron E, Walker AR, Komrokji RS, Lancet JE, Sallman D; A Phase 1 Study of CPX-351 Plus Gilteritinib in Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia. Blood 2024; 144 (Supplement 1): 1520. doi: https://doi.org/10.1182/blood-2024-205977 Pullarkat VA, Levis M, McCloskey J, Mannis GN, Strickland SA, Fathi AT, Lin TL, Bhatt VR, Vanniyasingam T, Chakravarthy D, Lutska Y, Faderl S, Cheung RS, Erba HP. V-FAST: a phase 1b master trial to investigate CPX-351 combined with targeted agents in adults with newly diagnosed AML. Blood Neoplasia. 2025 Jun 3;2(4):100123. doi: 10.1016/j.bneo.2025.100123. PMID: 40932876; PMCID: PMC12418821. Yoshimoto G, Miyamoto T, Jabbarzadeh-Tabrizi S, Iino T, Rocnik JL, Kikushige Y, Mori Y, Shima T, Iwasaki H, Takenaka K, Nagafuji K, Mizuno S, Niiro H, Gilliland GD, Akashi K. FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation. Blood. 2009 Dec 3;114(24):5034-43. doi: 10.1182/blood-2008-12-196055. Epub 2009 Oct 6. PMID: 19808698; PMCID: PMC2788977. Maiti A, DiNardo CD, Daver NG, Rausch CR, Ravandi F, Kadia TM, Pemmaraju N, Borthakur G, Bose P, Issa GC, Short NJ, Yilmaz M, Montalban-Bravo G, Ferrajoli A, Jabbour EJ, Jain N, Ohanian M, Takahashi K, Thompson PA, Loghavi S, Montalbano KS, Pierce S, Wierda WG, Kantarjian HM, Konopleva MY. Triplet therapy with venetoclax, FLT3 inhibitor and decitabine for FLT3-mutated acute myeloid leukemia. Blood Cancer J. 2021 Feb 1;11(2):25. doi: 10.1038/s41408-021-00410-w. PMID: 33563904; PMCID: PMC7873265. Short NJ, Daver N, Dinardo CD, Kadia T, Nasr LF, Macaron W, Yilmaz M, Borthakur G, Montalban-Bravo G, Garcia-Manero G, Issa GC, Chien KS, Jabbour E, Nasnas C, Huang X, Qiao W, Matthews J, Stojanik CJ, Patel KP, Abramova R, Thankachan J, Konopleva M, Kantarjian H, Ravandi F. Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory FLT3-Mutated AML. J Clin Oncol. 2024 May 1;42(13):1499-1508. doi: 10.1200/JCO.23.01911. Epub 2024 Jan 26. PMID: 38277619; PMCID: PMC11095865. Additional Declarations No competing interests reported. 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1","display":"","copyAsset":false,"role":"figure","size":1361032,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA 2020 flow diagram of study selection.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8529770/v1/3518b125d1c6e83c0f7631a9.png"},{"id":100406497,"identity":"db2f26e7-4209-42a5-905b-4a88cb007d7c","added_by":"auto","created_at":"2026-01-16 13:02:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":309464,"visible":true,"origin":"","legend":"\u003cp\u003eRisk-of-bias assessment of the included RCTs. (A) Traffic-light plot of domain-level RoB 2 ratings. (B) A stacked bar chart summarising the proportion of trials rated Low risk (green), Some concerns (yellow), or High risk (red) across each domain.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8529770/v1/b91047a0863f0425b49d7e8a.png"},{"id":100405658,"identity":"1ccdc014-f112-4496-9ae1-10cc28c1c48d","added_by":"auto","created_at":"2026-01-16 12:10:40","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1543547,"visible":true,"origin":"","legend":"\u003cp\u003eEvidence network for overall survival. Nodes represent treatment regimens, scaled to the total number of FLT3\u003csup\u003emut\u003c/sup\u003e participants; edges represent direct trial comparisons, with line thickness proportional to the number of trials.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8529770/v1/48795fbbe545f50f6a1b0536.png"},{"id":100421986,"identity":"be2e1f54-3b63-4aa7-a491-551dc8815998","added_by":"auto","created_at":"2026-01-16 14:04:36","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":346278,"visible":true,"origin":"","legend":"\u003cp\u003eBayesian forest plot of HRs \u003cem\u003eversus\u003c/em\u003e standard 3+7. Posterior median HRs and 95% CrIs from the random-effects NMA are plotted for each experimental regimen against the common comparator 3+7. Treatments are ordered from most to least favourable (left to right). The dashed vertical line marks HR = 1 (no difference).\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8529770/v1/372ba64de6ded9b4502234ac.png"},{"id":100406586,"identity":"1b6db9e5-e888-4bcb-8b35-bf8fe8578542","added_by":"auto","created_at":"2026-01-16 13:03:02","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1351462,"visible":true,"origin":"","legend":"\u003cp\u003eRanking of analysed regimens by SUCRA values. (A) Stacked rankogram showing the posterior probability that each regimen occupies every rank position (Rank 1 = best, Rank 8 = worst). (B) Heat-map of SUCRA values. Numbers inside bars give SUCRA expressed as percentages.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-8529770/v1/e088238ecd5ba32e2f04cc83.png"},{"id":106808747,"identity":"b45fd7a3-4ac6-4209-a7ea-443ff7d89856","added_by":"auto","created_at":"2026-04-13 16:00:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6255657,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8529770/v1/a163153d-3e60-475d-95d9-a64a84c14add.pdf"},{"id":100406775,"identity":"98246a8e-45c4-40e1-ad3f-04c6e5dbc49d","added_by":"auto","created_at":"2026-01-16 13:03:18","extension":"tiff","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":263457,"visible":true,"origin":"","legend":"","description":"","filename":"FigureS1.tiff","url":"https://assets-eu.researchsquare.com/files/rs-8529770/v1/4b543e9dbcde999f51b2a370.tiff"},{"id":100406854,"identity":"e7a8426c-b56d-4155-a5b9-3113dc3384d9","added_by":"auto","created_at":"2026-01-16 13:03:29","extension":"tiff","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":377973,"visible":true,"origin":"","legend":"","description":"","filename":"FigureS2.tiff","url":"https://assets-eu.researchsquare.com/files/rs-8529770/v1/fa519992cff5bd7c43181f57.tiff"},{"id":100406823,"identity":"c1a63a2e-22aa-4f71-850a-6299b3f6be6a","added_by":"auto","created_at":"2026-01-16 13:03:24","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":20028,"visible":true,"origin":"","legend":"","description":"","filename":"SUPPLEMENTARYAPPENDIXCONTENTS.docx","url":"https://assets-eu.researchsquare.com/files/rs-8529770/v1/669587acc1ee36bbceab5e92.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparative Efficacy of Intensive Frontline Regimens in FLT3-Mutated AML: A Bayesian Network Meta-Analysis of Randomized Trials","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAcute myeloid leukemia (AML) is a biologically and clinically heterogeneous hematologic malignancy characterized by a spectrum of cytogenetic and molecular abnormalities. Among the most frequent genetic lesions (detected in approximately 25\u0026ndash;30% of AML), there are mutations in the FMS-like tyrosine kinase 3 (FLT3) gene, the two most frequent ones are internal tandem duplications (FLT3-ITD) in the juxtamembrane domain, and point mutations or small deletions within the tyrosine kinase domain (FLT3-TKD) [1\u0026ndash;5].\u003c/p\u003e \u003cp\u003eFLT3-ITD mutations have consistently been associated with an adverse prognosis, including higher relapse rates and reduced overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS) compared to wild-type FLT3-ITD, particularly following chemotherapy or allogeneic stem cell transplantation (alloSCT) [1\u0026ndash;2,6\u0026ndash;9]. In contrast, the prognostic impact of FLT3-TKD mutations remains less well-defined and may be influenced by co-occurring genetic abnormalities.\u003c/p\u003e \u003cp\u003eThe therapeutic landscape for FLT3-mutated (FLT3\u003csup\u003emut\u003c/sup\u003e) has evolved substantially with the introduction of FLT3 inhibitors (FLT3is). The pivotal phase III RATIFY trial demonstrated that the addition of midostaurin to standard induction and consolidation chemotherapy significantly improved complete remission (CR) rates, OS, and RFS with the addition of midostaurin to conventional chemotherapy in newly diagnosed, fit patients with FLT3\u003csup\u003emut\u003c/sup\u003e AML [10]. As a result, given the therapeutic relevance of FLT3 targeting, current European Leukemia Net (ELN) and the National Comprehensive Cancer Network (NCCN) guidelines recommend FLT3 mutation testing at diagnosis in all AML patients, and recommend adding midostaurin to intensive chemotherapy [11\u0026ndash;12].\u003c/p\u003e \u003cp\u003eOther FLT3is have also been evaluated in both pre-alloSCT and post-alloSCT settings. Sorafenib has been investigated in phase II trials with conflicting results when added to standard chemotherapy [13\u0026ndash;14]. More recently, the phase III QuANTUM-First trial showed that quizartinib, when combined with intensive chemotherapy, led to improved CR rates, OS, and EFS compared to chemotherapy alone in patients with FLT3-ITD AML [15].\u003c/p\u003e \u003cp\u003eIn parallel with the development of FLT3is, several other agents have been explored in the frontline treatment of newly diagnosed AML irrespective of FLT3\u003csup\u003emut\u003c/sup\u003e [16\u0026ndash;21].\u003c/p\u003e \u003cp\u003eWhile several of these studies included patients with FLT3 mutations, most were not specifically powered to assess efficacy in this subgroup. Furthermore, no head-to-head randomized trials have directly compared different FLT3is combined with chemotherapy, nor have studies systematically evaluated the addition of FLT3is to alternative intensive regimens.\u003c/p\u003e \u003cp\u003eThe present network meta-analysis aims to synthesize available evidence on the comparative efficacy of intensive strategies in newly diagnosed, fit patients with FLT3\u003csup\u003emut\u003c/sup\u003e AML. By integrating data from randomized trials, this analysis seeks to inform optimal first-line therapeutic approaches in this molecularly defined subgroup.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e \u003cb\u003eSearch strategy\u003c/b\u003e \u003c/p\u003e \u003cp\u003eA systematic literature review was conducted to identify randomized controlled trials (RCTs) evaluating first-line treatments in newly diagnosed (treatment-na\u0026iuml;ve, TN) AML patients harboring FLT3 mutations. Both published and unpublished studies, including congress abstracts, were considered eligible provided that they reported sufficient methodological and outcome data.\u003c/p\u003e \u003cp\u003e \u003cb\u003eEligibility Criteria\u003c/b\u003e \u003c/p\u003e \u003cp\u003eStudies were eligible for inclusion if they met the following criteria: (i) randomized controlled design, regardless of blinding status; (ii) enrolled adult patients with TN FLT3\u003csup\u003emut\u003c/sup\u003e AML; (iii) investigated novel or non-standard first-line regimens in the experimental arms, with standard induction therapy as comparator; and (iv) reported at least one efficacy outcome, including OS, specifically for the FLT3-mutated subgroup.\u003c/p\u003e \u003cp\u003eStudies were excluded if they were non-randomized or non-prospective, lacked relevant outcome data for the FLT3-mutated subgroup, had unclear or incomplete methodology, or evaluated treatments outside the first-line.\u003c/p\u003e \u003cp\u003e \u003cb\u003eData extraction and quality assessment\u003c/b\u003e \u003c/p\u003e \u003cp\u003e Two reviewers (A.B. and M.G.) independently screened titles and abstracts, assessed full-text articles for eligibility, and extracted data using a standardized form.\u003c/p\u003e \u003cp\u003eExtracted data included: i) study identifiers (first author, publication year); study design characteristics, patient demographics, patient FLT3 mutation status, treatment details, and reported hazard ratios (HRs) for OS in the FLT3-mutated population. Each reviewer maintained a separate database; results were compared, and discrepancies were resolved by discussion. Duplicates were removed following cross-checking.\u003c/p\u003e \u003cp\u003e \u003cb\u003eRisk of bias assessment\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe risk of bias for included studies was evaluated using the Cochrane Risk of Bias 2 (RoB 2) tool [22], which assesses bias across the five domains: randomisation process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of the reported result. Each study was independently assessed by two reviewers. Any disagreements were resolved through discussion or consultation with a third reviewer, if necessary. Studies were classified as having \u0026lsquo;Low risk\u0026rsquo;, \u0026lsquo;Some concerns\u0026rsquo;, or \u0026rsquo;High risk\u0026rsquo; of bias. Summary results were visualized using traffic‑light plots and a bar chart.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eA Bayesian random‑effects contrast‑based network meta‑analysis (NMA) was performed to compare the efficacy of different intensive first-line regimens in FLT3\u003csup\u003emut\u003c/sup\u003e AML. The outcome analysed was the HR of the OS contrast. Non-informative normal priors (mean 0, large variance) were applied to basic treatment effects, while a wide Uniform prior was used for the between-study standard deviation (τ). Robustness was assessed using a moderately informative half-Normal prior for τ.\u003c/p\u003e \u003cp\u003eFour parallel Markov chains were run (40,000 iterations; burn-in =\u0026thinsp;20,000; thinning\u0026thinsp;=\u0026thinsp;10). Convergence was confirmed visually and with Brooks-Gelman-Rubin diagnostics (all potential scale-reduction factors\u0026thinsp;\u0026le;\u0026thinsp;1.05). Model adequacy was judged by the posterior mean residual deviance and the deviance-information criterion (DIC). A forest plot was used to display pooled posterior HRs and 95% credible intervals (CrIs) for each regimen versus the reference regimen.\u003c/p\u003e \u003cp\u003eTreatment ranking was summarised with surface under the cumulative ranking curve (SUCRA) and reported alongside posterior medians and 95% CrIs for every pairwise contrast.\u003c/p\u003e \u003cp\u003eSensitivity analyses were carried out to assess robustness of the results, in particular: i) an NMA limited to trials that enrolled only FLT3-mutated patients (excluding subgroup data); ii) leave-one-treatment-out (NMAs leaving out one treatment each time) analyses to eventually identify influential studies; iii) Bayesian meta-regressions incorporating median age, an indicator for \u0026ldquo;older-patient-only\u0026rdquo; trials and an indicator of subgroups derived results, to explore potential effect modification and violations of NMA assumptions.\u003c/p\u003e \u003cp\u003eAll analyses were conducted in R 4.5.0 [23], with NMA models implemented in JAGS, via the gemtc [24] and rjags R packages [25].\u003c/p\u003e \u003cp\u003eThe present network meta-analysis was not registered in the PROSPERO international prospective register of systematic reviews.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003e \u003cb\u003eStudy selection\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe study selection process is summarized in the PRISMA flow diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFrom an initial pool of 4,317 records, identified between 2012 and 2025\u0026mdash;including full articles and conference abstracts\u0026mdash;1,881 review articles were excluded, yielding 2,436 potentially eligible studies. After title and abstract screening, 2,078 reports were excluded due to irrelevance or ineligible design, leaving 358 clinical trials for further evaluation. Among these, 244 studies were excluded owing to the absence of a suitable comparator arm. Full-text review was conducted on 114 studies, of which 106 were excluded for methodological limitations or lack of data specific to FLT3-mutated AM. Ultimately, eight trials, including 1,793 TN FLT3\u003csup\u003emut\u003c/sup\u003e AML patients, were deemed eligible for inclusion in the network meta-analysis (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMain characteristics of clinical trials included in the meta-analysis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTrial (Authors)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePublication Year\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTreatment arms\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRandomized patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFLT3-mutated\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRATIFY (\u003c/b\u003eStone et al.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMidostaurin\u0026thinsp;+\u0026thinsp;3\u0026thinsp;+\u0026thinsp;7\u003c/p\u003e \u003cp\u003e3\u0026thinsp;+\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e360\u003c/p\u003e \u003cp\u003e357\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e360\u003c/p\u003e \u003cp\u003e357\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eQuANTUM First (\u003c/b\u003eErba et al.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eQuizartinib\u0026thinsp;+\u0026thinsp;3\u0026thinsp;+\u0026thinsp;7\u003c/p\u003e \u003cp\u003e3\u0026thinsp;+\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e268\u003c/p\u003e \u003cp\u003e271\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e268\u003c/p\u003e \u003cp\u003e271\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSORAML (\u003c/b\u003eRolling et al.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSorafenib\u0026thinsp;+\u0026thinsp;3\u0026thinsp;+\u0026thinsp;7\u003c/p\u003e \u003cp\u003e3\u0026thinsp;+\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e134\u003c/p\u003e \u003cp\u003e133\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e23\u003c/p\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStudy by ALLG (\u003c/b\u003eLoo et al.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSorafenib\u0026thinsp;+\u0026thinsp;3\u0026thinsp;+\u0026thinsp;7\u003c/p\u003e \u003cp\u003e3\u0026thinsp;+\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e35\u003c/p\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e35\u003c/p\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eALFA-0701 (\u003c/b\u003eCastaigne et al.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGO\u0026thinsp;+\u0026thinsp;3\u0026thinsp;+\u0026thinsp;7\u003c/p\u003e \u003cp\u003e3\u0026thinsp;+\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e140\u003c/p\u003e \u003cp\u003e140\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e22\u003c/p\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNCT02172872 (\u003c/b\u003eL\u0026uuml;bbert et al.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10day-DEC\u003c/p\u003e \u003cp\u003e3\u0026thinsp;+\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e303\u003c/p\u003e \u003cp\u003e303\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e32\u003c/p\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBRIGHT AML 1019 (\u003c/b\u003eSekeres et al.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGlasdegib\u0026thinsp;+\u0026thinsp;3\u0026thinsp;+\u0026thinsp;7\u003c/p\u003e \u003cp\u003e3\u0026thinsp;+\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e201\u003c/p\u003e \u003cp\u003e203\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12\u003c/p\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStudy 301 (\u003c/b\u003eLancet et al.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPX-351\u003c/p\u003e \u003cp\u003e3\u0026thinsp;+\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e153\u003c/p\u003e \u003cp\u003e156\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e22\u003c/p\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cb\u003eAbbreviations: GO\u003c/b\u003e - Gentuzumab\u0026thinsp;+\u0026thinsp;Ozogmamicin; \u003cb\u003eDEC\u003c/b\u003e - Decitabin\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eRisk of bias assessment\u003c/b\u003e \u003c/p\u003e \u003cp\u003eRisk of bias was assessed for all included studies using the Cochrane RoB2 tool (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Nine randomised controlled trials encompassing eight distinct treatment regimens were included in the network meta-analysis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOverall, three trials were judged to be at low risk of bias, while five of the remaining were rated as having some concerns; no study was classified as being at high risk. The most frequent source of concern related to Domain 2 (deviations from intended interventions) is primarily due to open-label study designs. However, given that overall survival was the primary outcome, these deviations were unlikely to materially influence effect estimates.\u003c/p\u003e \u003cp\u003eAdditional concerns were identified in Domain 5 (selection of the reported result) for five trials, as HR estimates for overall survival were derived from subgroup analyses of FLT3-mutated patients that were not pre-specified in the original study protocols. This raised the potential for selective outcome reporting, although no clear evidence of systematic reporting bias was observed.\u003c/p\u003e \u003cp\u003e \u003cb\u003eNetwork Meta-analysis of Overall Survival\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe evidence network included eight strategies configured in a star-shaped topology, with standard 3\u0026thinsp;+\u0026thinsp;7 induction chemotherapy as the common comparator (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Direct comparisons were available only between each experimental regimen and 3\u0026thinsp;+\u0026thinsp;7; no closed loops were present, precluding statistical assessment of inconsistency. Between-study heterogeneity was moderate, with a posterior median between-study standard deviation (τ ) of 0.43 (95%CrI 0.02\u0026ndash;1.14, log-HR scale). Overall model fit was acceptable (DIC\u0026thinsp;=\u0026thinsp;15.0).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eComparative Efficacy Versus Standard Induction (3\u0026thinsp;+\u0026thinsp;7)\u003c/b\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e presents posterior median HRs and 95% CrIs for each experimental treatment \u003cem\u003eversus\u003c/em\u003e standard 3\u0026thinsp;+\u0026thinsp;7.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe combination of GO with 3\u0026thinsp;+\u0026thinsp;7 showed the most favourable point estimate (HR\u0026thinsp;=\u0026thinsp;0.30, 95%CrI 0.06\u0026ndash;1.46), followed by CPX-351 (0.51, 0.12\u0026ndash;2.15) and Sorafenib\u0026thinsp;+\u0026thinsp;3\u0026thinsp;+\u0026thinsp;7 (0.67, 0.24\u0026ndash;1.85). Combinations involving Midostaurin and Quizartinib yielded HRs clustered around 0.8. In contrast, Decitabine and Glasdegib\u0026thinsp;+\u0026thinsp;3\u0026thinsp;+\u0026thinsp;7 were associated with numerically higher HRs (1.40 and 1.98, respectively), suggesting a trend toward inferior outcomes relative to the control. However, all CrIs overlapped the null value (HR\u0026thinsp;=\u0026thinsp;1), reflecting substantial uncertainty, largely attributable to the reliance on subgroup-level data for five of the seven experimental regimens.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTreatment ranking\u003c/b\u003e \u003c/p\u003e \u003cp\u003eTreatment ranking based on SUCRA values is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. Despite the limited number of patients with FLT3 mutation treated with the first 2 regimens, the GO\u0026thinsp;+\u0026thinsp;3\u0026thinsp;+\u0026thinsp;7 regimen demonstrated the highest probability of being the most effective (SUCRA 86.1%), followed by CPX-351 (71.7%), Sorafenib\u0026thinsp;+\u0026thinsp;3\u0026thinsp;+\u0026thinsp;7 (60.3%), Midostaurin\u0026thinsp;+\u0026thinsp;3\u0026thinsp;+\u0026thinsp;7 (52.3%), and Quizartinib\u0026thinsp;+\u0026thinsp;3\u0026thinsp;+\u0026thinsp;7 (51.5%). Standard 3\u0026thinsp;+\u0026thinsp;7 ranked in the lower half of the distribution (SUCRA 33.0%), whereas Decitabine and Glasdegib\u0026thinsp;+\u0026thinsp;3\u0026thinsp;+\u0026thinsp;7 had the lowest probabilities of benefit (SUCRA 24.9% and 20.2%, respectively).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003ePairwise contrasts\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAll 28 indirect pairwise contrasts between treatments were directionally consistent with the SUCRA rankings, but lacked statistical significance. CrI for all comparisons crossed unity, reflecting wide uncertainty intervals (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). These findings underscore a key limitation of the network\u0026rsquo;s star-shaped configuration, wherein all regimens are compared only to the common comparator (3\u0026thinsp;+\u0026thinsp;7), with no direct head-to-head trials between experimental treatments.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePairwise relative treatment effects comparison as HR (95% CrI).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGemtuzumab\u003c/p\u003e \u003cp\u003eOzogamicin\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0.57 (0.07\u0026ndash;5.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eCPX-351\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0.44 (0.06\u0026ndash;2.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.76 (0.14\u0026ndash;4.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eSorafenib\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0.38 (0.05\u0026ndash;2.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.67 (0.09\u0026ndash;4.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.87 (0.16\u0026ndash;4.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eMidostaurin\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0.38 (0.05\u0026ndash;2.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.66 (0.09\u0026ndash;4.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.87 (0.17\u0026ndash;4.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.99 (0.16\u0026ndash;6.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eQuizartinib\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0.30 (0.06\u0026ndash;1.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.52 (0.12\u0026ndash;2.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.68 (0.24\u0026ndash;1.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.78 (0.21\u0026ndash;2.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.78 (0.21\u0026ndash;2.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e3\u0026thinsp;+\u0026thinsp;7\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0.21 (0.02\u0026ndash;2.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.37 (0.04\u0026ndash;3.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.48 (0.08\u0026ndash;3.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.56 (0.08\u0026ndash;4.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.56 (0.08\u0026ndash;4.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.72 (0.16\u0026ndash;3.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003eDecitabin\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0.15 (0.01\u0026ndash;1.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.26 (0.02\u0026ndash;3.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.34 (0.04\u0026ndash;3.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.40 (0.04\u0026ndash;4.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.40 (0.04\u0026ndash;4.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.52 (0.07\u0026ndash;3.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.71 (0.05\u0026ndash;9.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003eGlasdegib\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eSensitivity analyses\u003c/b\u003e \u003c/p\u003e \u003cp\u003eMultiple sensitivity analyses were undertaken to assess the robustness of the results and to identify potential violations of model assumptions.\u003c/p\u003e \u003cp\u003eFirst, restricting the analysis to trials exclusively enrolling FLT3\u003csup\u003emut\u003c/sup\u003e patients [12,14\u0026ndash;15] yielded consistent SUCRA rankings (Supplementary Tables\u0026nbsp;1, 2), with 3\u0026thinsp;+\u0026thinsp;7 consistently ranked lowest. Effect sizes from the original trials showing statistically significant OS benefit (e.g., RATIFY and QuANTUM-First) were attenuated in the network model. While point estimates remained similar (HR\u0026thinsp;=\u0026thinsp;0.78), the 95% CrIs widened and crossed unity in both cases: Midostaurin (HR\u0026thinsp;=\u0026thinsp;0.78; 95% CrI, 0.52\u0026ndash;3.00) and Quizartinib (HR\u0026thinsp;=\u0026thinsp;0.78; 95% CrI, 0.52\u0026ndash;1.17).\u003c/p\u003e \u003cp\u003eLeave-one-treatment-out analyses demonstrated minimal impact on SUCRA rankings and pairwise HRs (Supplementary Figs.\u0026nbsp;1 and 2). Removal of any single treatment did not alter the top three ranked therapies, and the absolute percentage change in HRs did not exceed\u0026thinsp;~\u0026thinsp;3%.\u003c/p\u003e \u003cp\u003eIn addition, we performed a dedicated sensitivity analysis excluding decitabine from the network.\u003c/p\u003e \u003cp\u003eAfter removal of decitabine, the relative positioning of the main regimens of interest remained substantially unchanged. The corresponding SUCRA profiles showed only minor redistribution across adjacent ranks, without inversion of the relative ordering of top-ranked treatments (Supplementary Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003eConsistently, the pairwise HR estimates involving 3\u0026thinsp;+\u0026thinsp;7\u0026thinsp;+\u0026thinsp;GO and CPX-351 remained stable, with differences well within the range observed in the leave-one-treatment-out analyses (absolute changes\u0026thinsp;\u0026lt;\u0026thinsp;3%).\u003c/p\u003e \u003cp\u003e \u003cb\u003eMeta-regression Analyses\u003c/b\u003e \u003c/p\u003e \u003cp\u003eExploratory meta-regression analyses were conducted to explore the potential influence of study-level covariates (Supplementary Table\u0026nbsp;4). Incorporating median age as a continuous covariate did not meaningfully modify the treatment effect estimated (HR ratio\u0026thinsp;=\u0026thinsp;0.99 per 10-year increase; 95% CrI 0.02\u0026ndash;21.18). Model fit improved only marginally (DIC\u0026thinsp;=\u0026thinsp;13.4 \u003cem\u003eversus\u003c/em\u003e 15.0), and τ remained stable. Similarly, the introduction of a binary covariate for trials restricted to older populations yielded null findings.\u003c/p\u003e \u003cp\u003eA third model assessing whether dedicated FLT3\u003csup\u003emut\u003c/sup\u003e trials differed from subgroup-based analyses also showed no significant effect modification (HR ratio\u0026thinsp;=\u0026thinsp;0.89; 95% CrI, 0.19\u0026ndash;6.12), although this model introduced slightly greater residual heterogeneity (τ\u0026thinsp;=\u0026thinsp;0.55) and a modest increase in DIC (15.6). These findings suggest that variation in patient age and trial design does not significantly confound treatment effect estimates within the network.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003e For nearly four decades, the combination of cytarabine and an anthracycline (commonly referred to as the 3\u0026thinsp;+\u0026thinsp;7 regimen) has represented the standard of care for patients with AML eligible for intensive chemotherapy. However, growing insights into the genetic and molecular heterogeneity of AML have facilitated a shift toward more personalized treatment approaches. This shift is reflected in recent classifications, such as the International Consensus Classification (ICC), which underscore the complexity of AML subtyping and highlight the challenges of individualized treatment selection [1].\u003c/p\u003e \u003cp\u003eIn the subset of AML patients harboring FLT3\u003csup\u003emut\u003c/sup\u003e\u0026mdash;a group comprising approximately 25\u0026ndash;30% of adult AML\u0026mdash;therapeutic advances have been largely driven by the development of FLT3is. These agents have shown efficacy both as monotherapies and in combination with intensive regimens. Despite this progress, outcomes remain suboptimal, with median RFS around 30 months, and CR rates approximately 70% in clinical trials, suggesting that FLT3i-based triplet regimens may still be improved [10,15].\u003c/p\u003e \u003cp\u003eIn the present NMA, when restricted to trials enrolling exclusively FLT3\u003csup\u003emut\u003c/sup\u003e patients treated with 3\u0026thinsp;+\u0026thinsp;7 plus a FLT3i, no substantial differences in efficacy emerged among the experimental regimens. SUCRA values were comparable, and standard 3\u0026thinsp;+\u0026thinsp;7 consistently ranked lowest, suggesting a reduced probability of being the most effective regimen. Notably, effect sizes from pivotal trials, such as RATIFY (midostaurin) and QuANTUM-First (quizartinib), which had reported statistically significant improvements in OS, were attenuated in the NMA [10,14\u0026ndash;15].\u003c/p\u003e \u003cp\u003eThis attenuation reflects the application of a random-effects prior, which accounts for between-study heterogeneity and incorporates hierarchical shrinkage, thereby widening credible intervals when few studies inform a comparison. These findings are consistent with a prior meta-analysis by Molica et al., which similarly found no significant OS differences among FLT3is [26]. A retrospective analysis also suggested improved RFS and OS with FLT3is, particularly in lower-intensity treatment settings [27].\u003c/p\u003e \u003cp\u003eEmerging FLT3is, such as crenolanib, may offer further therapeutic gains [28].\u003c/p\u003e \u003cp\u003eDespite important limitations in our star-shaped network\u0026mdash;specifically the lack of direct head-to-head comparisons between experimental regimens\u0026mdash;and the small sample sizes of included trials, the combinations of 3\u0026thinsp;+\u0026thinsp;7\u0026thinsp;+\u0026thinsp;GO and CPX-351 ranked highest.\u003c/p\u003e \u003cp\u003eMost FLT3\u003csup\u003emut\u003c/sup\u003e cases fall into the intermediate-risk category, potentially benefiting from GO [16,17], while others with secondary AML may be candidates for CPX-351.\u003c/p\u003e \u003cp\u003eImportantly, no randomized trial has specifically evaluated these regimens in FLT3\u003csup\u003emut\u003c/sup\u003e AML despite a plausible biological and clinical rationale.\u003c/p\u003e \u003cp\u003eInterestingly, the only 49 FLT3\u003csup\u003emut\u003c/sup\u003e patients enrolled in the ALFA-0701 trial showed no substantial differences in performance status or cytogenetic risk compared to the patients enrolled in the other trials considered for the present meta-analysis. Moreover, patients would not had recived a better supportive treatments considering that ALFA-0701 was among the oldest trials analyzed [16, 17]. Furthermore, a small retrospective study involving 11 FLT3\u003csup\u003emut\u003c/sup\u003e patients reported a CR rate of 91% with the combination of GO, midostaurin, and intensive chemotherapy [29]. In line with these results, the SAL-MODULE phase I study investigated a four-drug regimen (3\u0026thinsp;+\u0026thinsp;7\u0026thinsp;+\u0026thinsp;GO\u0026thinsp;+\u0026thinsp;midostaurin) in 12 patients (10 with FLT3 mutations), achieving a CR rate of 75% and an overall response rate (ORR) of 92% [30]. Conversely, another phase I study enrolling a similar patient population reported a composite CR rate of 76% and OS rates of 79%, 65%, and 39% at 6 months, 1 year, and 2 years, respectively, with frequent grade\u0026thinsp;\u0026ge;\u0026thinsp;3 cytopenias [31].\u003c/p\u003e \u003cp\u003eThe phase III study 301, which included 43 FLT3\u003csup\u003emut\u003c/sup\u003e patients, also demonstrated promising outcomes with CPX-351, despite a population characterized by older age, secondary disease, and adverse cytogenetics. Post hoc analyses revealed increased sensitivity of FLT3-ITD blasts to CPX-351, including enhanced drug uptake and cytotoxicity compared to FLT3-wild-type blasts [32].\u003c/p\u003e \u003cp\u003eAlthough robust data are lacking on combining CPX-351 with FLT3is, preliminary results are encouraging. A phase I study of CPX-351\u0026thinsp;+\u0026thinsp;gilteritinib in relapsed/refractory AML reported a composite CR/CRi rate of 46.2% and median OS of 11.9 months, with manageable toxicity [33]. The phase Ib V-FAST trial explored CPX-351\u0026thinsp;+\u0026thinsp;midostaurin in newly diagnosed FLT3\u003csup\u003emut\u003c/sup\u003e AML, showing CR rates of 82% (FLT3-ITD) and 83% (FLT3-TKD) [34]. Several ongoing trials are evaluating combinations of CPX-351, GO, and FLT3is. One such phase III trial (NCT04293562) is randomizing newly diagnosed AML patients to receive chemotherapy with or without GO, with the addition of gilteritinib for FLT3-mutated patients.\u003c/p\u003e \u003cp\u003eBeyond the small sample size of FLT3\u003csup\u003emut\u003c/sup\u003e patients enrolled in most of the analysed trials, another important limitation of the present study are lack of prospective stratification by FLT3 status and the lack of data on alloSCT. Among the analyzed trials, the exact percentage of patients that received alloSCT and their outcomes are available only for patients enrolled in the ALFA 0701 and QUANTUM-first; for the other studies, data are incomplete. Moreover, comparing the percentage of transplanted patients in ALFA 0701 and QUANTUM-first, it is notable that only 1/3 of patients in ALFA0701 underwent alloSCT compared to 50% of QUANTUM-first, reflecting the different approaches to alloSCT in AML patients in a 10year period [15\u0026ndash;17]. Moreover, data on therapeutic options for post-transplant relapses are limited, as data comparing consolidation strategies (alloSCT or FLT3is).\u003c/p\u003e \u003cp\u003eAnother important limitation to take into consideration is that our NMA focuses on OS that is influenced not only by the efficacy and safety of chemotherapy but also by the optimization of supportive care and possible post relapse salvage strategies, whose data are not comparable in the selected studies.\u003c/p\u003e \u003cp\u003eFLT3is are also being explored in less intensive regimens. Preclinical synergy between FLT3is and BCL-2 inhibitors has led to studies combining venetoclax with FLT3is, yielding promising early results and potentially more durable responses [41\u0026ndash;43]. Although decitabine did not improve outcomes \u003cem\u003eversus\u003c/em\u003e standard induction in FLT3\u003csup\u003emut\u003c/sup\u003e AML [19], further research is needed to evaluate whether FLT3i combinations with hypomethylating agents may enhance therapeutic response.\u003c/p\u003e \u003cp\u003eIn conclusion, FLT3\u003csup\u003emut\u003c/sup\u003e AML represents a biologically distinct and therapeutically challenging subset of the disease. This network meta-analysis suggests that 3\u0026thinsp;+\u0026thinsp;7\u0026thinsp;+\u0026thinsp;GO and CPX-351 may be effective in the treatment of FLT3\u003csup\u003emut\u003c/sup\u003e patients; however, definitive conclusions are limited by small sample sizes and a lack of direct comparative trials. Future studies should focus on integrating FLT3is with additional targeted agents and optimizing treatment intensity based on individual molecular and clinical profiles. The continued development of rational combinations tailored to FLT3\u003csup\u003emut\u003c/sup\u003eAML has the potential to significantly improve long-term outcomes in this high-risk population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003eAll authors contributed to the manuscript and were involved in revisions and proofreading. All authors approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u0026nbsp;\u003c/strong\u003eThe authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u0026nbsp;\u003c/strong\u003eData sharing does not apply to this article, as no new data were generated or analyzed in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman Ethics and Consent to Participate declarations:\u0026nbsp;\u003c/strong\u003enot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Declaration:\u0026nbsp;\u003c/strong\u003eno funding.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eArber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, Wang SA, Bagg A, Barbui T, Branford S, Bueso-Ramos CE, Cortes JE, Dal Cin P, DiNardo CD, Dombret H, Duncavage EJ, Ebert BL, Estey EH, Facchetti F, Foucar K, Gangat N, Gianelli U, Godley LA, G\u0026ouml;kbuget N, Gotlib J, Hellstr\u0026ouml;m-Lindberg E, Hobbs GS, Hoffman R, Jabbour EJ, Kiladjian JJ, Larson RA, Le Beau MM, Loh ML, L\u0026ouml;wenberg B, Macintyre E, Malcovati L, Mullighan CG, Niemeyer C, Odenike OM, Ogawa S, Orfao A, Papaemmanuil E, Passamonti F, Porkka K, Pui CH, Radich JP, Reiter A, Rozman M, Rudelius M, Savona MR, Schiffer CA, Schmitt-Graeff A, Shimamura A, Sierra J, Stock WA, Stone RM, Tallman MS, Thiele J, Tien HF, Tzankov A, Vannucchi AM, Vyas P, Wei AH, Weinberg OK, Wierzbowska A, Cazzola M, D\u0026ouml;hner H, Tefferi A. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022 Sep 15;140(11):1200-1228. doi: 10.1182/blood.2022015850. PMID: 35767897; PMCID: PMC9479031.\u003c/li\u003e\n\u003cli\u003eKhoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, Bejar R, Berti E, Busque L, Chan JKC, Chen W, Chen X, Chng WJ, Choi JK, Colmenero I, Coupland SE, Cross NCP, De Jong D, Elghetany MT, Takahashi E, Emile JF, Ferry J, Fogelstrand L, Fontenay M, Germing U, Gujral S, Haferlach T, Harrison C, Hodge JC, Hu S, Jansen JH, Kanagal-Shamanna R, Kantarjian HM, Kratz CP, Li XQ, Lim MS, Loeb K, Loghavi S, Marcogliese A, Meshinchi S, Michaels P, Naresh KN, Natkunam Y, Nejati R, Ott G, Padron E, Patel KP, Patkar N, Picarsic J, Platzbecker U, Roberts I, Schuh A, Sewell W, Siebert R, Tembhare P, Tyner J, Verstovsek S, Wang W, Wood B, Xiao W, Yeung C, Hochhaus A. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022 Jul;36(7):1703-1719. doi: 10.1038/s41375-022-01613-1. Epub 2022 Jun 22. PMID: 35732831; PMCID: PMC9252913.\u003c/li\u003e\n\u003cli\u003eCancer Genome Atlas Research Network; Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, Hoadley K, Triche TJ Jr, Laird PW, Baty JD, Fulton LL, Fulton R, Heath SE, Kalicki-Veizer J, Kandoth C, Klco JM, Koboldt DC, Kanchi KL, Kulkarni S, Lamprecht TL, Larson DE, Lin L, Lu C, McLellan MD, McMichael JF, Payton J, Schmidt H, Spencer DH, Tomasson MH, Wallis JW, Wartman LD, Watson MA, Welch J, Wendl MC, Ally A, Balasundaram M, Birol I, Butterfield Y, Chiu R, Chu A, Chuah E, Chun HJ, Corbett R, Dhalla N, Guin R, He A, Hirst C, Hirst M, Holt RA, Jones S, Karsan A, Lee D, Li HI, Marra MA, Mayo M, Moore RA, Mungall K, Parker J, Pleasance E, Plettner P, Schein J, Stoll D, Swanson L, Tam A, Thiessen N, Varhol R, Wye N, Zhao Y, Gabriel S, Getz G, Sougnez C, Zou L, Leiserson MD, Vandin F, Wu HT, Applebaum F, Baylin SB, Akbani R, Broom BM, Chen K, Motter TC, Nguyen K, Weinstein JN, Zhang N, Ferguson ML, Adams C, Black A, Bowen J, Gastier-Foster J, Grossman T, Lichtenberg T, Wise L, Davidsen T, Demchok JA, Shaw KR, Sheth M, Sofia HJ, Yang L, Downing JR, Eley G. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013 May 30;368(22):2059-74. doi: 10.1056/NEJMoa1301689. Epub 2013 May 1. Erratum in: N Engl J Med. 2013 Jul 4;369(1):98. PMID: 23634996; PMCID: PMC3767041.\u003c/li\u003e\n\u003cli\u003eNakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, Sonoda Y, Fujimoto T, Misawa S. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996 Dec;10(12):1911-8. PMID: 8946930.\u003c/li\u003e\n\u003cli\u003eYamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001 Apr 15;97(8):2434-9. doi: 10.1182/blood.v97.8.2434. PMID: 11290608.\u003c/li\u003e\n\u003cli\u003eYanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 2005 Aug;19(8):1345-9. doi: 10.1038/sj.leu.2403838. PMID: 15959528.\u003c/li\u003e\n\u003cli\u003eAyala R, Carre\u0026ntilde;o-Tarragona G, Barrag\u0026aacute;n E, Boluda B, Larr\u0026aacute;yoz MJ, Chill\u0026oacute;n MC, Carrillo-Cruz E, Bilbao C, S\u0026aacute;nchez-Garc\u0026iacute;a J, Bernal T, Martinez-Cuadron D, Gil C, Serrano J, Rodriguez-Medina C, Bergua J, P\u0026eacute;rez-Sim\u0026oacute;n JA, Calbacho M, Alonso-Dom\u0026iacute;nguez JM, Labrador J, Tormo M, Amigo ML, Herrera-Puente P, Rapado I, Sargas C, Vazquez I, Calasanz MJ, Gomez-Casares T, Garc\u0026iacute;a-Sanz R, Sanz MA, Mart\u0026iacute;nez-L\u0026oacute;pez J, Montesinos P. Impact of FLT3-ITD Mutation Status and Its Ratio in a Cohort of 2901 Patients Undergoing Upfront Intensive Chemotherapy: A PETHEMA Registry Study. Cancers (Basel). 2022 Nov 24;14(23):5799. doi: 10.3390/cancers14235799. PMID: 36497281; PMCID: PMC9737662.\u003c/li\u003e\n\u003cli\u003eBazarbachi A, Bug G, Baron F, Brissot E, Ciceri F, Dalle IA, D\u0026ouml;hner H, Esteve J, Floisand Y, Giebel S, Gilleece M, Gorin NC, Jabbour E, Aljurf M, Kantarjian H, Kharfan-Dabaja M, Labopin M, Lanza F, Malard F, Peric Z, Prebet T, Ravandi F, Ruggeri A, Sanz J, Schmid C, Shouval R, Spyridonidis A, Versluis J, Vey N, Savani BN, Nagler A, Mohty M. Clinical practice recommendation on hematopoietic stem cell transplantation for acute myeloid leukemia patients with \u003cem\u003eFLT3\u003c/em\u003e-internal tandem duplication: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2020 Jun;105(6):1507-1516. doi: 10.3324/haematol.2019.243410. Epub 2020 Apr 2. PMID: 32241850; PMCID: PMC7271578.\u003c/li\u003e\n\u003cli\u003eSchlenk RF, D\u0026ouml;hner K, Krauter J, Fr\u0026ouml;hling S, Corbacioglu A, Bullinger L, Habdank M, Sp\u0026auml;th D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, D\u0026ouml;hner H; German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008 May 1;358(18):1909-18. doi: 10.1056/NEJMoa074306. PMID: 18450602.\u003c/li\u003e\n\u003cli\u003eStone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, D\u0026ouml;hner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, D\u0026ouml;hner H. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. doi: 10.1056/NEJMoa1614359. Epub 2017 Jun 23. PMID: 28644114; PMCID: PMC5754190.\u003c/li\u003e\n\u003cli\u003eD\u0026ouml;hner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, Ebert BL, Fenaux P, Godley LA, Hasserjian RP, Larson RA, Levine RL, Miyazaki Y, Niederwieser D, Ossenkoppele G, R\u0026ouml;llig C, Sierra J, Stein EM, Tallman MS, Tien HF, Wang J, Wierzbowska A, L\u0026ouml;wenberg B. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022 Sep 22;140(12):1345-1377. doi: 10.1182/blood.2022016867. PMID: 35797463.\u003c/li\u003e\n\u003cli\u003ePollyea DA, Bixby D, Perl A, Bhatt VR, Altman JK, Appelbaum FR, de Lima M, Fathi AT, Foran JM, Gojo I, Hall AC, Jacoby M, Lancet J, Mannis G, Marcucci G, Martin MG, Mims A, Neff J, Nejati R, Olin R, Percival ME, Prebet T, Przespolewski A, Rao D, Ravandi-Kashani F, Shami PJ, Stone RM, Strickland SA, Sweet K, Vachhani P, Wieduwilt M, Gregory KM, Ogba N, Tallman MS. NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021. J Natl Compr Canc Netw. 2021 Jan 6;19(1):16-27. doi: 10.6004/jnccn.2021.0002. PMID: 33406488.\u003c/li\u003e\n\u003cli\u003eR\u0026ouml;llig C, Serve H, H\u0026uuml;ttmann A, Noppeney R, M\u0026uuml;ller-Tidow C, Krug U, Baldus CD, Brandts CH, Kunzmann V, Einsele H, Kr\u0026auml;mer A, Sch\u0026auml;fer-Eckart K, Neubauer A, Burchert A, Giagounidis A, Krause SW, Mackensen A, Aulitzky W, Herbst R, H\u0026auml;nel M, Kiani A, Frickhofen N, Kullmer J, Kaiser U, Link H, Geer T, Reichle A, Junghan\u0026szlig; C, Repp R, Heits F, D\u0026uuml;rk H, Hase J, Klut IM, Illmer T, Bornh\u0026auml;user M, Schaich M, Parmentier S, G\u0026ouml;rner M, Thiede C, von Bonin M, Schetelig J, Kramer M, Berdel WE, Ehninger G; Study Alliance Leukaemia. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015 Dec;16(16):1691-9. doi: 10.1016/S1470-2045(15)00362-9. Epub 2015 Nov 6. PMID: 26549589.\u003c/li\u003e\n\u003cli\u003eLoo S, Roberts AW, Anstee NS, Kennedy GA, He S, Schwarer AP, Enjeti AK, D\u0026apos;Rozario J, Marlton P, Bilmon IA, Taper J, Cull G, Tiley C, Verner E, Hahn U, Hiwase DK, Iland HJ, Murphy N, Ramanathan S, Reynolds J, Ong DM, Tiong IS, Wall M, Murray M, Rawling T, Leadbetter J, Rowley L, Latimer M, Yuen S, Ting SB, Fong CY, Morris K, Bajel A, Seymour JF, Levis MJ, Wei AH. Sorafenib plus intensive chemotherapy in newly diagnosed FLT3-ITD AML: a randomized, placebo-controlled study by the ALLG. Blood. 2023 Dec 7;142(23):1960-1971. doi: 10.1182/blood.2023020301. PMID: 37647654; PMCID: PMC10733823.\u003c/li\u003e\n\u003cli\u003eErba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Ž\u0026aacute;k P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. doi: 10.1016/S0140-6736(23)00464-6. Epub 2023 Apr 25. Erratum in: Lancet. 2023 Oct 14;402(10410):1328. doi: 10.1016/S0140-6736(23)02235-3. PMID: 37116523\u003c/li\u003e\n\u003cli\u003eCastaigne S, Pautas C, Terr\u0026eacute; C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508-16. doi: 10.1016/S0140-6736(12)60485-1. Epub 2012 Apr 5. Erratum in: Lancet. 2018 Mar 3;391(10123):838. doi: 10.1016/S0140-6736(17)32105-0. PMID: 22482940.\u003c/li\u003e\n\u003cli\u003eLambert J, Pautas C, Terr\u0026eacute; C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019 Jan;104(1):113-119. doi: 10.3324/haematol.2018.188888. Epub 2018 Aug 3. PMID: 30076173; PMCID: PMC6312010.\u003c/li\u003e\n\u003cli\u003eLancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC. CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia. J Clin Oncol. 2018 Sep 10;36(26):2684-2692. doi: 10.1200/JCO.2017.77.6112. Epub 2018 Jul 19. PMID: 30024784; PMCID: PMC6127025.\u003c/li\u003e\n\u003cli\u003eL\u0026uuml;bbert M, Wijermans PW, Kicinski M, Chantepie S, Van der Velden WJFM, Noppeney R, Gri\u0026scaron;kevičius L, Neubauer A, Crysandt M, Vrhovac R, Luppi M, Fuhrmann S, Audisio E, Candoni A, Legrand O, Fo\u0026agrave; R, Gaidano G, van Lammeren-Venema D, Posthuma EFM, Hoogendoorn M, Giraut A, Stevens-Kroef M, Jansen JH, de Graaf AO, Efficace F, Ammatuna E, Vilque JP, W\u0026auml;sch R, Becker H, Blijlevens N, D\u0026uuml;hrsen U, Baron F, Suciu S, Amadori S, Venditti A, Huls G; EORTC Leukemia Group, GIMEMA, and German MDS Study Group. 10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial. Lancet Haematol. 2023 Nov;10(11):e879-e889. doi: 10.1016/S2352-3026(23)00273-9. Erratum in: Lancet Haematol. 2024 Oct;11(10):e723. doi: 10.1016/S2352-3026(24)00252-7. PMID: 37914482.\u003c/li\u003e\n\u003cli\u003eEfficace F, Kicinski M, Coens C, Suciu S, van der Velden WJFM, Noppeney R, Chantepie S, Griskevicius L, Neubauer A, Audisio E, Luppi M, Fuhrmann S, Fo\u0026agrave; R, Crysandt M, Gaidano G, Vrhovac R, Venditti A, Posthuma EFM, Candoni A, Baron F, Legrand O, Mengarelli A, Fazi P, Vignetti M, Giraut A, Wijermans PW, Huls G, L\u0026uuml;bbert M. Decitabine in older patients with AML: quality of life results of the EORTC-GIMEMA-GMDS-SG randomized phase 3 trial. Blood. 2024 Aug 1;144(5):541-551. doi: 10.1182/blood.2023023625. PMID: 38717861.\u003c/li\u003e\n\u003cli\u003eSekeres MA, Montesinos P, Novak J, Wang J, Jeyakumar D, Tomlinson B, Mayer J, Jou E, Robak T, Taussig DC, Dombret H, Merchant A, Shaik N, O\u0026apos;Brien T, Roh W, Liu X, Ma W, DiRienzo CG, Chan G, Cortes JE. Glasdegib plus intensive or non-intensive chemotherapy for untreated acute myeloid leukemia: results from the randomized, phase 3 BRIGHT AML 1019 trial. Leukemia. 2023 Oct;37(10):2017-2026. doi: 10.1038/s41375-023-02001-z. Epub 2023 Aug 21. PMID: 37604981; PMCID: PMC10539167.\u003c/li\u003e\n\u003cli\u003eSterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates CJ, Cheng HY, Corbett MS, Eldridge SM, Emberson JR, Hern\u0026aacute;n MA, Hopewell S, Hr\u0026oacute;bjartsson A, Junqueira DR, J\u0026uuml;ni P, Kirkham JJ, Lasserson T, Li T, McAleenan A, Reeves BC, Shepperd S, Shrier I, Stewart LA, Tilling K, White IR, Whiting PF, Higgins JPT. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019 Aug 28;366:l4898. doi: 10.1136/bmj.l4898. PMID: 31462531.\u003c/li\u003e\n\u003cli\u003eR Core Team. (2025). R: A language and environment for statistical computing. R Foundation for Statistical Computing.\u003c/li\u003e\n\u003cli\u003evan Valkenhoef, Gert, and Jeroen Kuiper. 2023. gemtc: Network Meta-Analysis Using Bayesian Methods. R package version 1.0-2. https://CRAN.R-project.org/package=gemtc\u003c/li\u003e\n\u003cli\u003ePlummer, Martyn. rjags: Bayesian Graphical Models Using MCMC. Version X.X, 2025. R package version 4-17, https://CRAN.R-project.org/package=rjags\u003c/li\u003e\n\u003cli\u003eMolica M, Perrone S, Rossi M, Giannarelli D. The impact of different FLT3-inhibitors on overall survival of de novo acute myeloid leukemia: A network meta-analysis. Leuk Res. 2024 Sep;144:107549. doi: 10.1016/j.leukres.2024.107549. Epub 2024 Jul 17. PMID: 39067406.\u003c/li\u003e\n\u003cli\u003eBazinet A, Bataller A, Kadia T, Daver N, Short NJ, Yilmaz M, Sasaki K, DiNardo CD, Borthakur GM, Issa G, Bouligny I, Pierce S, Garcia-Manero G, Ravandi F, Kantarjian HM. A retrospective study of outcomes across time and treatment regimens in newly diagnosed, FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia. Cancer. 2025 Mar 15;131(6):e35813. doi: 10.1002/cncr.35813. PMID: 40097915.\u003c/li\u003e\n\u003cli\u003eWang ES, Goldberg AD, Tallman M, Walter RB, Karanes C, Sandhu K, Vigil CE, Collins R, Jain V, Stone RM. Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML. J Clin Oncol. 2024 May 20;42(15):1776-1787. doi: 10.1200/JCO.23.01061. Epub 2024 Feb 7. PMID: 38324741; PMCID: PMC11107896.\u003c/li\u003e\n\u003cli\u003eWeinbergerov\u0026aacute; B, Čerňan M, Kabut T, Semer\u0026aacute;d L, Podstavkov\u0026aacute; N, Szotkowski T, Jež\u0026iacute;\u0026scaron;kov\u0026aacute; I, Mayer J. Gemtuzumab ozogamicin plus midostaurin in conjunction with standard intensive therapy for FLT3- mutated acute myeloid leukemia patients - Czech center experience. Haematologica. 2023 Oct 1;108(10):2826-2829. doi: 10.3324/haematol.2022.282263. PMID: 36815379; PMCID: PMC10542832.\u003c/li\u003e\n\u003cli\u003eBorate U, Dvorak-Kornaus KM, Zhao Q, Walter RB, Cook RJ, Saultz JN, Swords RT, Grieselhuber NR, Mims A, Larkin KT, Sahasrabudhe KD, Blachly JS, Behbehani GK, Eisfeld A, Long M, Srisuwananukorn A, Koenig KL; A Phase I Study to Evaluate the Safety and Tolerability of Gemtuzumab Ozogamicin and Midostaurin When Used in Combination with Standard Cytarabine and Daunorubicin Induction for Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia. Blood 2024; 144 (Supplement 1): 4286. doi: https://doi.org/10.1182/blood-2024-210605\u003c/li\u003e\n\u003cli\u003eR\u0026ouml;llig C, Schliemann C, Ruhnke L, Fransecky L, Heydrich BN, Hanoun M, Noppeney R, Sch\u0026auml;fer-Eckart K, Wendelin K, Mikesch JH, Middeke JM, Reimann M, Fiebig F, Zukunft S, Wermke M, Serve H, Platzbecker U, M\u0026uuml;ller-Tidow C, Baldus CD, Bornh\u0026auml;user M. Gemtuzumab ozogamicin plus midostaurin in combination with standard \u0026apos;7\u0026thinsp;+\u0026thinsp;3\u0026apos; induction therapy in newly diagnosed AML: Results from the SAL-MODULE phase I study. Br J Haematol. 2024 Jun;204(6):2254-2258. doi: 10.1111/bjh.19436. Epub 2024 Apr 9. PMID: 38593353.\u003c/li\u003e\n\u003cli\u003eAndrews C, Pullarkat V, Recher C. CPX-351 in FLT3-mutated acute myeloid leukemia. Front Oncol. 2023 Nov 17;13:1271722. doi: 10.3389/fonc.2023.1271722. PMID: 38044999; PMCID: PMC10691756.\u003c/li\u003e\n\u003cli\u003eChan O, Sweet KL, Hunter J, Ball S, Mo Q, Xie Z, Yun S, Kuykendall AT, Padron E, Walker AR, Komrokji RS, Lancet JE, Sallman D; A Phase 1 Study of CPX-351 Plus Gilteritinib in Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia. Blood 2024; 144 (Supplement 1): 1520. doi: https://doi.org/10.1182/blood-2024-205977\u003c/li\u003e\n\u003cli\u003ePullarkat VA, Levis M, McCloskey J, Mannis GN, Strickland SA, Fathi AT, Lin TL, Bhatt VR, Vanniyasingam T, Chakravarthy D, Lutska Y, Faderl S, Cheung RS, Erba HP. V-FAST: a phase 1b master trial to investigate CPX-351 combined with targeted agents in adults with newly diagnosed AML. Blood Neoplasia. 2025 Jun 3;2(4):100123. doi: 10.1016/j.bneo.2025.100123. PMID: 40932876; PMCID: PMC12418821. \u003c/li\u003e\n\u003cli\u003eYoshimoto G, Miyamoto T, Jabbarzadeh-Tabrizi S, Iino T, Rocnik JL, Kikushige Y, Mori Y, Shima T, Iwasaki H, Takenaka K, Nagafuji K, Mizuno S, Niiro H, Gilliland GD, Akashi K. FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation. Blood. 2009 Dec 3;114(24):5034-43. doi: 10.1182/blood-2008-12-196055. Epub 2009 Oct 6. PMID: 19808698; PMCID: PMC2788977.\u003c/li\u003e\n\u003cli\u003eMaiti A, DiNardo CD, Daver NG, Rausch CR, Ravandi F, Kadia TM, Pemmaraju N, Borthakur G, Bose P, Issa GC, Short NJ, Yilmaz M, Montalban-Bravo G, Ferrajoli A, Jabbour EJ, Jain N, Ohanian M, Takahashi K, Thompson PA, Loghavi S, Montalbano KS, Pierce S, Wierda WG, Kantarjian HM, Konopleva MY. Triplet therapy with venetoclax, FLT3 inhibitor and decitabine for FLT3-mutated acute myeloid leukemia. Blood Cancer J. 2021 Feb 1;11(2):25. doi: 10.1038/s41408-021-00410-w. PMID: 33563904; PMCID: PMC7873265.\u003c/li\u003e\n\u003cli\u003eShort NJ, Daver N, Dinardo CD, Kadia T, Nasr LF, Macaron W, Yilmaz M, Borthakur G, Montalban-Bravo G, Garcia-Manero G, Issa GC, Chien KS, Jabbour E, Nasnas C, Huang X, Qiao W, Matthews J, Stojanik CJ, Patel KP, Abramova R, Thankachan J, Konopleva M, Kantarjian H, Ravandi F. Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory FLT3-Mutated AML. J Clin Oncol. 2024 May 1;42(13):1499-1508. doi: 10.1200/JCO.23.01911. Epub 2024 Jan 26. PMID: 38277619; PMCID: PMC11095865.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"FLT3mutated (FLT3mut) AML, treatment naïve AML, OS in AML, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-8529770/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8529770/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eFLT3-mutated acute myeloid leukemia (FLT3mut AML) is associated with poor outcomes. Although FLT3 inhibitors (FLT3is) combined with chemotherapy improve responses, long-term survival remains limited, and the optimal first-line strategy is unclear.\u003c/p\u003e \u003cp\u003eWe conducted a Bayesian network meta-analysis of eight randomized trials, including 1,793 patients, to compare intensive regimens for overall survival (OS). Treatments studied were 3\u0026thinsp;+\u0026thinsp;7 with midostaurin, quizartinib, sorafenib, gemtuzumab ozogamicin (GO), glasdegib, CPX-351, and decitabine.\u003c/p\u003e \u003cp\u003eFLT3i-based regimens improved outcomes but showed attenuated effects in this analysis, consistent with prior data. The small population with FLT3 mutation treated with GO\u0026thinsp;+\u0026thinsp;3\u0026thinsp;+\u0026thinsp;7 and CPX-351 provided good outcomes (SUCRA 86.1% and 71.7%), while glasdegib\u0026thinsp;+\u0026thinsp;3\u0026thinsp;+\u0026thinsp;7 and decitabine resulted in less effective strategies. Notably, 3\u0026thinsp;+\u0026thinsp;7\u0026thinsp;+\u0026thinsp;GO showed superior benefit despite limited FLT3mut subgroup evidence.\u003c/p\u003e \u003cp\u003eOngoing studies are exploring CPX-351, GO, and FLT3i combinations, as well as novel strategies. Prospective, mutation-specific trials are needed to define optimal therapy.\u003c/p\u003e","manuscriptTitle":"Comparative Efficacy of Intensive Frontline Regimens in FLT3-Mutated AML: A Bayesian Network Meta-Analysis of Randomized Trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-16 10:43:19","doi":"10.21203/rs.3.rs-8529770/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-05T00:29:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-05T00:07:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"328788460611931212644884576187602284456","date":"2026-01-15T16:11:50+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-14T12:45:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"159321724596356517969799974322802637013","date":"2026-01-13T14:12:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-12T19:22:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-12T09:22:34+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-12T09:19:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2026-01-06T09:43:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"fbb47880-3827-4872-a01d-0b037c40b17a","owner":[],"postedDate":"January 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-13T15:59:41+00:00","versionOfRecord":{"articleIdentity":"rs-8529770","link":"https://doi.org/10.1007/s00277-026-06948-8","journal":{"identity":"annals-of-hematology","isVorOnly":false,"title":"Annals of Hematology"},"publishedOn":"2026-04-06 15:56:59","publishedOnDateReadable":"April 6th, 2026"},"versionCreatedAt":"2026-01-16 10:43:19","video":"","vorDoi":"10.1007/s00277-026-06948-8","vorDoiUrl":"https://doi.org/10.1007/s00277-026-06948-8","workflowStages":[]},"version":"v1","identity":"rs-8529770","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8529770","identity":"rs-8529770","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}