Efficacy of FLT3 Inhibitors in Patients with FLT3-Mutated Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Efficacy of FLT3 Inhibitors in Patients with FLT3-Mutated Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: A Systematic Review and Meta-Analysis of Randomized Controlled 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 Efficacy of FLT3 Inhibitors in Patients with FLT3-Mutated Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Henri Fero, Ester Faccin, Erilda Mera, Kristi Trako, Frenki Gjika, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5760913/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Introduction: FLT3 inhibitors have demonstrated increased efficacy in patients with FLT3-mutated acute myeloid leukemia (AML). However, their effects on patients unfit for intensive chemotherapy remain undefined. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of FLT3 inhibitors in AML patients unfit for intensive chemotherapy. Methods: A systematic search was conducted between October 2024 and December 2024 across PubMed, Embase, and Cochrane Central. Studies included patients with AML who were unfit for intensive chemotherapy, treated with FLT3 inhibitors as monotherapy or in combination with low-intensity regimens, compared to standard low-intensity chemotherapy regimens. The primary outcome was the OS, defined as the proportion of patients alive at a specified time after treatment initiation or diagnosis. Statistical analysis was performed under a random effects model using Review Manager 8.11.0. Heterogeneity was assessed using I² statistics. Results: 745 patients from six randomized controlled trials (RCTs) were included. FLT3 inhibitors were used in 421 (56.51%) AML patients unfit for intensive chemotherapy. Among the six studies, one reported quizartinib combined with low-dose cytarabine, two reported gilteritinib monotherapy, one reported gilteritinib with azacitidine, one reported quizartinib monotherapy, and one reported decitabine with midostaurin. Follow-up ranged from 6.5 to 48 months. FLT3 inhibitors significantly improved OS (HR 0.52; 95% CI 0.35–0.78, P = 0.001; I² = 51%) compared to standard chemotherapy. However, the risk of grade ≥3 adverse events (RR 1.42; 95% CI 1.03–1.96, P = 0.03; I² = 0%) and QT interval prolongation (RR 3.49; 95% CI 1.43–8.51, P = 0.006; I² = 0%) was significantly higher in the FLT3 inhibitors group. Conclusion: FLT3 inhibitors, used either as monotherapy or in combination with low-intensity chemotherapy, improve OS in FLT3-mutated AML patients unfit for intensive chemotherapy. However, the increased risk of grade ≥3 adverse events and QT interval prolongation warrants careful monitoring in clinical practice. AML FLT3 mutation chemotherapy FLT3 inhibitors Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Methods This systematic review and meta-analysis was performed and reported in accordance with the Cochrane Collaboration Handbook of Systematic Review of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement Guidelines. [1,2]. Given the nature of this study, ethical approval and informed consent from participants were not required. The prospective meta-analysis was registered on PROSPERO on December 5, 2024, under protocol #CRD42024619252. Eligibility Criteria: Inclusion in this meta-analysis was restricted to studies that met all the following eligibility criteria: (1) Randomized Controlled Trials; (2) comparing FLT3 inhibitors to standard low-intensity chemotherapy regimens, and (3) enrolling patients with AML who are unfit for intensive chemotherapy. In addition, studies were included if they reported outcomes of interest such as OS and/or AEs. We excluded studies with (1) no control group; (2) no administration of FLT3 Inhibitors; (3) no administration of low-intensity chemotherapy. Figure 1. Search Strategy: We systematically searched PubMed, Cochrane Central, and Embase from inception to November 2024 with the following search terms: “acute myeloid leukemia”, “FLT3”, “quizartinib”, “gilteritinib”, “midostaurin”, “sorafenib”, “chemotherapy”, “LoDAC”. The references from all included studies, previous systematic reviews, and meta-analyses were manually searched for any additional studies. Two authors (E.F. and D.J.) independently extracted the data following predefined search criteria and quality assessment. Endpoints: Outcomes were selected according to data availability and included the following: primary outcomes the OS; secondary outcomes the adverse events (AEs), CTCAE – Common terminology criteria for adverse events, grade ≥3 adverse events, and a QT interval prolongation. Quality assessment: We evaluated the risk of bias in randomized studies using version 2 of the Cochrane Risk of Bias assessment tool.[3] Two independent authors completed the risk of bias assessment (E.M. and F.G.). Disagreements were resolved by a third author (K.T.). Publication Bias was investigated by funnel-plot analysis of point estimates in relation to study weights. Statistical analysis: We used HR with 95% CI to compare treatment effects for time-to-event endpoints. We used RR to compare treatment effects for categor i cal endpoints. We assessed heterogeneity with I 2 statistics and Cochran Q test; p-values 25% were considered significant for heterogeneity. We used the DerSimonian and Laird random-effects model. We also performed the “remove one study” test to assess sensitivity in randomized trials. We used leave-one-out sensitivity analyses to ensure that results were not dependent on one study. We used Review Manager 8.11.0 for statistical analysis. Results The initial search yielded 4197 results. After removing duplicate records and ineligible studies, 126 studies remained and were fully reviewed based on the inclusion criteria and exclusion. Six Randomized Controlled Trials published between 2021 and 2024 were selected for data extraction, encompassing a total of 745 patients. A total of 421 (56.51%) patients received FLT3 inhibitors and 324 (43.49%) received standard low-intensity chemotherapy regimens. Study characteristics are reported in Table 1. The studies primarily focused on high-risk groups, such as relapsed/refractory FLT3-mutated AML and patients unfit for intensive chemotherapy. Median ages ranged from 49.5 to 78 years, with consistent male representation (56.8%-67%). Interventions included FLT3 inhibitors (gilteritinib, quizartinib), azacitidine, and midostaurin, often combined with low-dose or standard chemotherapy. Control arms used low-dose cytarabine, decitabine, or azacitidine alone. Pooled Results: In those receiving FLT3 inhibitors, there was an overall trend towards increasing OS (HR 0.52; 95% CI 0.35-0.78, P = 0.001; I² = 51%) in patients treated with FLT3 mutated AML unfit for intensive chemotherapy regimens. Figure 2. However, rates of Grade ≥3 Adverse Events Across Studies, defined based on the Common Terminology Criteria for Adverse Events (CTCAE), (RR 1.42; 95% CI 1.03-1.96, P= 0.03; I 2 = 0%) were increased. Figure 3. In addition QT interval prolongation (RR 3.49; 95% CI 1.43-8.51; p=0.006; I 2 =0%) were also significantly increased in the FLT3 inhibitors group. Figure 4. Due to high heterogeneity, we performed a leave-one-out sensitivity analysis by iteratively removing one study at a time to ensure the results were not dependent on a single study. Overall, performing the leave one out sensitivity analysis did not affect the endpoint of the OS. Quality Assessment: We evaluated the risk of bias in randomized studies using version 2 of the Cochrane Risk of Bias assessment tool.[3] Two independent authors completed the risk of bias assessment (E.M. and F.G.). Disagreements were resolved by a third author (K.T.). Table 2. Publication Bias was investigated by funnel-plot analysis of point estimates in relation to study weights. Figure 5. Introduction AML is a heterogeneous group of aggressive blood cancers that arise from malignant transformation and clonal expansion of hematopoietic stem cells in the bone marrow. AML is the most common form of leukemia in adults, with most cases occurring in individuals over the age of 60 years.[4]Genetic mutations (eg, NPM1, FLT3, CEBPA, TET-2, c-KIT, DNMT3A, IDH, RUNX1, AXSL1, WT1, Ras gene mutations) serve as important prognostic markers and potential therapeutic targets.[5] Internal tandem duplications (ITD) in FLT3 represent the most common genetic alteration in de novo AML.[6] Patients with newly diagnosed FLT3-mutated AML who may be considered unfit for standard intensive induction chemotherapy have a poor prognosis characterized by worse survival or treatment response compared with their counterparts without multiple comorbidities, or poor performance status or advanced age; the presence of FLT3 mutations is also associated with worse survival.[7]Patients considered fit for IIC were required to have newly diagnosed FLT3-mutated AML, not therapy-related and without coexisting illnesses.[8] Intensive induction therapy plus FLT3 inhibitors are the standard of care for fit younger adults.[9] Medical research has witnessed a significant breakthrough in producing FLT3 inhibitors in recent years, leading to their emergence in clinical trials. These inhibitors are intended for use in single-agent or combination therapy, and they are currently being evaluated for their effectiveness in the treatment of various stages of diseases.[10] FLT3 tyrosine kinase inhibitors are a diverse group of drugs that showcase variability in their effectiveness, preference, binding capacity, and site. Type I inhibitors, such as midostaurin, gilteritinib, and crenolanib, bind to the kinase-active conformation of FLT3, while type II inhibitors, including quizartinib and sorafenib, bind to the inactive structure.[11] First and second-generation FLT3 inhibitors provide treatment options in both the first-line and relapse and refractory setting.[12] Prior meta-analyses focus on patients who are fit for intensive chemotherapy. Data related to patients who are ineligible for intensive chemotherapy are lacking and treatment options for this group of patients remain ineffective. The goals of care in unfit patients with AML are to achieve remission as the most effective way to alleviate symptoms, improve QoL, and extend survival. These goals support the inclusion of articles looking at survival rates in the short term. This review aims to fill existing gaps in the literature by focusing on a high-risk group, providing valuable data on the efficacy and safety of FLT3 inhibitors in unfit AML patients. Considering both benefits and potential harms, the review aims to support clinical practice decision-making for these patients. Discussion In this systematic review and meta-analysis of 6 RCTs comprising 745 patients, we evaluated the efficacy and safety of FLT3 inhibitors compared to low-intensity chemotherapy and low-intensity regimens in AML patients unfit for intensive chemotherapy. The use of FLT3 inhibitors was associated with a notably higher risk of severe adverse events. FLT3 inhibitors modestly increased the likelihood of cardiac events, specifically QT interval prolongation. Despite these risks, treatment with FLT3 inhibitors demonstrated a significant survival benefit over low-intensity chemotherapy, effectively reducing the overall risk of death. The treatment landscape for AML patients unfit for intensive chemotherapy has evolved significantly over the past two decades. Historically, these patients were treated with low-dose cytarabine or hypomethylating agents (HMAs) like azacitidine and decitabine, which offered limited efficacy and modest improvements in survival.[13-14] Although standard induction-style chemotherapy regimens in combination with midostaurin are recommended for ND FLT3 mutated AML in patients eligible for intensive chemotherapy, there is no universal standard chemotherapy for patients with ND FLT3-mutant AML considered unfit for intensive induction chemotherapy.[15-17] The most common treatments for FLT3 mutated AML unfit patients include venetoclax plus azacitidine or low-dose cytarabine. To determine the patients eligibility for intensive chemotherapy, prognostic models incorporating cytogenetic information, age, and clinical indicators attempt to risk-stratify patients according to their likelihood of experiencing treatment-related morbidity and mortality, but no prognostic scoring system has become standard.[18-19] This leads to great variability in defining eligibility criteria for unfit patients. Mutations in the FLT3 gene are seen in approximately 30% of patients with AML.[20] Among patients with FLT3 mutations, internal tandem duplication (ITD) is more common, but point mutations in the tyrosine kinase domain are also seen.[9] ITD FLT3-mutated AML in particular has been associated with a poor prognosis.[21] Many studies have shown that FLT3-ITD is an independent prognostic marker associated with high leukemic burden and leukocytosis, poor OS, and early relapse.[22] The treatment of FLT3-mutated AML patients who are unfit for intensive chemotherapy represents a particular clinical challenge, given the lack of an approved FLT3 inhibitor for use in this setting.[23]However our pooled analysis suggests a need for further evaluation of the use of FLT3 inhibitors, especially second-generation FLT3 inhibitors in patients who are considered unfit for intensive chemotherapy regimens and who carry the FLT3 gene mutation variants. A limitation of our study is the moderate heterogeneity in OS outcomes across the studies, which is attributed to differences in study populations, treatment regimens, and trial designs. While some trials, like AML LI, included older patients unfit for intensive chemotherapy, others, such as ADMIRAL and COMMODORE, focused on relapsed or refractory FLT3-mutated AML, and LACEWING included newly diagnosed patients ineligible for intensive therapy. Variations in FLT3 inhibitors, with quizartinib used in QuANTUM-R and gilteritinib in ADMIRAL and COMMODORE, along with combination regimens in LACEWING, further contributed to differences. Additionally, the diversity in control groups, follow-up durations, and geographic populations, such as the predominantly Asian cohort in COMMODORE, added to the observed variability. These differences underline the complexity of interpreting pooled OS results in this heterogeneous population. A sensitivity analysis was conducted to assess the robustness of the results. Removing one study at a time did not alter the overall conclusions, indicating the stability of the findings. However, when two specific trials were excluded, one at a time, heterogeneity decreased from moderate to low levels (I 2 =27), suggesting that these trials contributed to the observed variability. These findings support the clinical utility of FLT3 inhibitors and highlight the need for personalized approaches to mitigate adverse effects. We recommend that FLT3 inhibitors, especially second-generation FLT3 inhibitors, be considered a potential addition to treatment protocols in patients deemed unfit for intensive chemotherapy and carriers of the FLT3 mutations. Further research is warranted to clarify the impact of patient-specific factors, such as age, comorbidities, and geographic variations, on treatment outcomes. Whether FLT3 inhibitors should be considered as monotherapy or an addition to standard low-dose chemotherapy regimens, remains a potential topic for further exploration. Conclusion FLT3 inhibitors, used either as monotherapy or in combination with low-intensity chemotherapy, improve OS in FLT3-mutated AML patients unfit for intensive chemotherapy. However, the increased risk of grade ≥ 3 adverse events and QT interval prolongation warrants careful monitoring in clinical practice. Abbreviations AML: Acute Myeloid Leukemia; FLT3: Fms-like tyrosine kinase 3; OS: Overall Survival; HR: Hazard Ratio; CI: Confidence Interval; RR: Risk Ratio; I²: I-squared (measure of heterogeneity); Declarations Founding Sources: There are no sources of funding to declare. Financial Disclosures: None. Conflicts of Interest: None. References Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editors. Cochrane Handbook for Systematic Reviews of Interventions. Version 6.3 [updated February 2022]. Cochrane; 2022 [cited 2024 Dec 24]. Available from: https://training.cochrane.org/handbook. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomized trials. BMJ. 2019;366:l4898. doi: 10.1136/bmj.l4898. Wachter F, Pikman Y. Pathophysiology of acute myeloid leukemia. Acta Haematol. 2024;147(2):229-246. Padmakumar D, Chandraprabha VR, Gopinath P, et al. A concise review on the molecular genetics of acute myeloid leukemia. Leuk Res. 2021;111:106727. doi: 10.1016/j.leukres.2021.106727. Kong T, Laranjeira ABA, Letson CT, Yu L, He F, Jayanthan A, et al. RSK1 dependency in FLT3-ITD acute myeloid leukemia. Blood Cancer J. 2024;14(1):207. doi: 10.1038/s41408-024-01187-4. PMID: 39592591; PMCID: PMC11599852. Wang ES, Montesinos P, Minden MD, Lee JH, Heuser M, Naoe T, et al. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood. 2022;140(17):1845-1857. doi: 10.1182/blood.2021014586. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464. doi: 10.1056/NEJMoa1614359. Short NJ, Kantarjian H, Ravandi F, Daver N. Emerging treatment paradigms with FLT3 inhibitors in acute myeloid leukemia. Ther Adv Hematol. 2019;10:2040620719827310. doi: 10.1177/2040620719827310. de Leeuw DC, Ossenkoppele GJ, Janssen JJWM. Older patients with acute myeloid leukemia deserve individualized treatment. Curr Oncol Rep. 2022;24:1387-1400. doi: 10.1007/s11912-022-01299-9. Ahn JS, Kim HJ. FLT3 mutations in acute myeloid leukemia: A review focusing on clinically applicable drugs. Blood Res. 2022;57:32-36. doi: 10.5045/br.2022.2022017. Zhao JC, Agarwal S, Ahmad H, Amin K, Bewersdorf JP, Zeidan AM. A review of FLT3 inhibitors in acute myeloid leukemia. Blood Rev. 2022;52:100905. doi: 10.1016/j.blre.2021.100905. Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223-232. doi: 10.1016/S1470-2045(09)70003-8. Burnett AK, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK, et al. A comparison of low dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007;109(6):1114-1124. doi: 10.1002/cncr.22496. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447. doi: 10.1182/blood-2016-08-733196. Heuser M, Ofran Y, Boissel N, Daver N, Dennis M, DiNardo CD, et al; ESMO Guidelines Committee. Acute myeloid leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up [published correction appears in Ann Oncol. 2021;32(6):821]. Ann Oncol. 2020;31(6):697-712. doi: 10.1016/j.annonc.2020.03.018. Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464. doi: 10.1056/NEJMoa1614359. Pettit K, Odenike O. Defining and treating older adults with acute myeloid leukemia who are ineligible for intensive therapies. Front Oncol. 2015;5:280. doi: 10.3389/fonc.2015.00280. Kantarjian H, O’Brien S, Cortes J, Giles F, Faderl S, Issa JP, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer. 2006;106(5):1090-1098. doi: 10.1002/cncr.21744. Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019;33(2):299-312. doi: 10.1038/s41375-018-0357-9. Kayser S, Schlenk RF, Londono MC, Breitenbuecher F, Retzlaff S, Kuhn MW, et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009;114(12):2386-2392. doi: 10.1182/blood-2009-01-199208. Zhao JC, Agarwal S, Ahmad H, Amin K, Bewersdorf JP, Zeidan AM. A review of FLT3 inhibitors in acute myeloid leukemia. Blood Rev. 2022;52:100905. doi: 10.1016/j.blre.2021.100905. Short NJ, Nguyen D, Ravandi F. Treatment of older adults with FLT3-mutated AML: Emerging paradigms and the role of frontline FLT3 inhibitors. Blood Cancer J. 2023;13:142. doi: 10.1038/s41408-023-00911-w. References for analyzed Randomized Controlled Trials: Wang J, Jiang B, Li J, Liu L, Du X, Jiang H, et al. Gilteritinib versus salvage chemotherapy for relapsed/refractory FLT3-mutated acute myeloid leukemia: A phase 3, randomized, multicenter, open-label trial in Asia. Blood. 2021;138(Suppl 1):695. doi:10.1182/blood-2021-145436. Wang ES, Montesinos P, Minden MD, Lee JH, Heuser M, Naoe T, et al. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood. 2022;140(17):1845–57. doi:10.1182/blood.2021014586. Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381(18):1728–40. doi:10.1056/NEJMoa1902688. Huls G, Chitu DA, Tick L, Boersma R, Breems D, Herbers A, et al. Midostaurin added to 10-day decitabine for patients unfit for intensive chemotherapy with AML and higher-risk MDS, irrespective of FLT3 mutational status, does not improve outcome. Ann Hematol. 2024. doi:10.1007/s00277-024-06033-y. Dennis M, Thomas I, Ariti C, Upton L, Burnett A, Radia R, et al. A randomised evaluation of low-dose Ara-C plus AC220 (quizartinib) versus low-dose Ara-C in older patients with acute myeloid leukaemia: Results from the LI-1 trial. HemaSphere. Abstract Book: 25th Congress of the European Hematology Association Virtual Edition; 2020. Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicenter, randomized, controlled, open-label, phase 3 trial. Lancet Oncol. 2019;20(7):984–97. doi:10.1016/S1470-2045(19)30150-0. Tables Table 1: Baseline characteristics of included studies. Study Follow-up, months Study population (n) Intervention Control Age (years)¹ Men (%) Mutation status ICC treatment AML LI, 2021 13.1 99/103 QUIZ + LD Ara-C LD Ara-C 77 64/63 N/A Unfit for IIC COMMODORE, 2024 10.3 23/22 GILT LD DEC 49.5/51.5 60.9/59.1 R/R FLT3-mutated AML LD CT ADMIRAL, 2022 24/48 98/49 GILT SC N/A N/A R/R FLT3-mutated AML LD CT LACEWING, 2022 9.76/17.97 74/49 GILT+ AZA AZA 78/ 76 56.8/57.1 FLT3-mutated AML Unfit for IIC QuANTUM-R, 2021 23.5 57/29 QUIZ LD DEC N/A N/A R/R FLT3-mutated AML LD CT HOVON-15, 2024 6.5/37² 70/72 DEC+MIDO DEC 74/ 75 67/59 N/A Unfit for IIC 1: Median; 2: 6.5 months for all patients and 37 months for alive patients; AML: acute myeloid leukemia; Ara-C: citarabina; AZA: azacitidine; CT: chemotherapy; DEC: decitabine; GILT: gilteritinib; IIC: intensive induction chemotherapy; LD: low dose; MIDO: midostaurin; N/A: not available; QUIZ: quizartinib; R/R: relapsed or refractory; SC: standard care. Table 2. Risk of Bias Assessment. Study ID Randomization Intended Intervention Missing Outcomes Measurement of the Outcomes Reported results Other Overall ADMIRAL Low Some concerns Low Low Low Low Some Concerns COMMODORE Low Some concerns Low Low Low Some concerns Some Concerns HOVON-155 Low Some concerns Low Low Low Some concerns Some Concerns LACEWING Low Some concerns Low Low Low Low Some Concerns QuANTUM-R Low Some concerns Low Low Low Some Concerns Some Concerns AML-LI Low Some concerns Low Low Low Some concerns Some Concerns Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 19 Feb, 2025 Reviews received at journal 17 Feb, 2025 Reviews received at journal 13 Feb, 2025 Reviewers agreed at journal 02 Feb, 2025 Reviewers agreed at journal 16 Jan, 2025 Reviewers invited by journal 15 Jan, 2025 Editor assigned by journal 09 Jan, 2025 Submission checks completed at journal 09 Jan, 2025 First submitted to journal 03 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5760913","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":399962548,"identity":"8fcfc84a-9373-4248-aa13-21e6cbbb6d0d","order_by":0,"name":"Henri Fero","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYBACAxCRYAMieRg+fABSbOxEaUkDa2GcOQOkhZkYLQxQLbN5QDQhLebsvcc+PEiwyedn4D3YbPNrmzwfMwPjh485uLVY9pxLnpGQkGY5s4EvsTm377ZhGzMDs+TMbXgcdiPHmCHxx2EDgwM85o9ze24zArWwMfPi03L/jTFDQsJ/kBbDZsue2/aEtdzgAWk5ANHC8ON2ImEtZ3JAWpINJJt5DBt7G24ntzEzNuP3y/Ezxow/EuwM+Nl7DBt+/LltO7+9+eCHj3i0IAAoOhjbQCzGBmLUw8AfUhSPglEwCkbBSAEAUsBNCaUtsZUAAAAASUVORK5CYII=","orcid":"","institution":"Western University","correspondingAuthor":true,"prefix":"","firstName":"Henri","middleName":"","lastName":"Fero","suffix":""},{"id":399962549,"identity":"cb0c9eff-9528-44ac-9fff-8b1b518a06a0","order_by":1,"name":"Ester Faccin","email":"","orcid":"","institution":"Federal University of Pelotas","correspondingAuthor":false,"prefix":"","firstName":"Ester","middleName":"","lastName":"Faccin","suffix":""},{"id":399962550,"identity":"ea325b1a-5adf-4c36-afb6-bdde9a062cdb","order_by":2,"name":"Erilda Mera","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Erilda","middleName":"","lastName":"Mera","suffix":""},{"id":399962551,"identity":"63f02f1e-78d8-4ce7-9cd8-97042610813d","order_by":3,"name":"Kristi Trako","email":"","orcid":"","institution":"University of Medicine Tirana","correspondingAuthor":false,"prefix":"","firstName":"Kristi","middleName":"","lastName":"Trako","suffix":""},{"id":399962552,"identity":"8715f601-5782-4b3a-8e80-fa02beaded97","order_by":4,"name":"Frenki Gjika","email":"","orcid":"","institution":"University of Buckingham","correspondingAuthor":false,"prefix":"","firstName":"Frenki","middleName":"","lastName":"Gjika","suffix":""},{"id":399962553,"identity":"ba5f069e-2f2d-4920-b26d-5dfd39c47046","order_by":5,"name":"Dhruvi Joshi","email":"","orcid":"","institution":"Gujarat University","correspondingAuthor":false,"prefix":"","firstName":"Dhruvi","middleName":"","lastName":"Joshi","suffix":""},{"id":399962554,"identity":"338ea4d4-3bc1-444c-80ae-d13d17c2df40","order_by":6,"name":"Fahad Alabbas","email":"","orcid":"","institution":"Riyadh Armed Forces Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fahad","middleName":"","lastName":"Alabbas","suffix":""}],"badges":[],"createdAt":"2025-01-04 02:08:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5760913/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5760913/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":73781601,"identity":"0d9221fa-2793-4198-a3d2-691d48f37487","added_by":"auto","created_at":"2025-01-14 15:24:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":46976,"visible":true,"origin":"","legend":"\u003cp\u003eA PRISMA flow diagram depicting the identification, screening, eligibility, and inclusion process of studies in the systematic review and meta-analysis. The figure highlights the number of records identified, screened, and reasons for exclusion, culminating in six included studies.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5760913/v1/40a56d262f42345492a0518d.png"},{"id":73781600,"identity":"f7598512-07b6-4797-b4dd-37ce6a94ec79","added_by":"auto","created_at":"2025-01-14 15:24:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":33831,"visible":true,"origin":"","legend":"\u003cp\u003eA forest plot summarizing the overall survival (OS) results from included studies. Hazard ratios (HRs) with 95% confidence intervals (CIs) are presented for each study and pooled analysis. The diamond represents the overall effect size favoring FLT3 inhibitors.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5760913/v1/1f6d018246ddfd764a795962.png"},{"id":73781603,"identity":"15c426d8-f14b-47f1-a468-4da2455fb854","added_by":"auto","created_at":"2025-01-14 15:24:20","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":31485,"visible":true,"origin":"","legend":"\u003cp\u003eA forest plot showing the risk ratios (RRs) for grade ≥3 adverse events comparing FLT3 inhibitors to low-intensity chemotherapy regimens. Individual study results and the overall effect size are displayed.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-5760913/v1/3d9bc36ed394bc43c11e549f.png"},{"id":73781602,"identity":"3761bd19-c93c-4904-9af4-c4c9186b49b8","added_by":"auto","created_at":"2025-01-14 15:24:20","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":31276,"visible":true,"origin":"","legend":"\u003cp\u003eA forest plot of the risk ratios (RRs) for QT interval prolongation comparing FLT3 inhibitors to low-intensity chemotherapy regimens. The pooled analysis demonstrates a significant increase in risk with FLT3 inhibitors.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-5760913/v1/f4f77583a7b09509bb2b88c0.png"},{"id":73781605,"identity":"5416014e-82de-4452-bf3c-a4e266d2f125","added_by":"auto","created_at":"2025-01-14 15:24:20","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":19518,"visible":true,"origin":"","legend":"\u003cp\u003eA funnel plot assessing publication bias in the meta-analysis. The symmetrical distribution of studies around the pooled effect size indicates a low likelihood of publication bias.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-5760913/v1/ce232bc73f19fdb05d35f3d4.png"},{"id":73783129,"identity":"80281935-bc82-4b6e-9a4c-a97945004a85","added_by":"auto","created_at":"2025-01-14 15:40:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":694225,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5760913/v1/bac970ee-f5c1-4157-ab42-284d6e0b3df5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eEfficacy of FLT3 Inhibitors in Patients with FLT3-Mutated Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials\u003c/p\u003e","fulltext":[{"header":"Methods","content":"\u003cp\u003eThis systematic review and meta-analysis was performed and reported in accordance with the Cochrane Collaboration Handbook of Systematic Review of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement Guidelines. [1,2]. Given the nature of this study, ethical approval and informed consent from participants were not required. The prospective meta-analysis was registered on PROSPERO on December 5, 2024, under protocol #CRD42024619252.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility Criteria:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInclusion in this meta-analysis was restricted to studies that met all the following eligibility criteria: (1) Randomized Controlled Trials; (2) comparing FLT3 inhibitors to standard low-intensity chemotherapy regimens, and (3) enrolling patients with AML who are unfit for intensive chemotherapy. In addition, studies were included if they reported outcomes of interest such as OS and/or AEs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe excluded studies with (1) no control group; (2) no administration of FLT3 Inhibitors; (3) no administration of low-intensity chemotherapy. Figure 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSearch Strategy:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe systematically searched PubMed, Cochrane Central, and Embase from inception to November 2024 with the following search terms: \u0026ldquo;acute myeloid leukemia\u0026rdquo;, \u0026ldquo;FLT3\u0026rdquo;, \u0026ldquo;quizartinib\u0026rdquo;, \u0026ldquo;gilteritinib\u0026rdquo;, \u0026ldquo;midostaurin\u0026rdquo;, \u0026ldquo;sorafenib\u0026rdquo;, \u0026ldquo;chemotherapy\u0026rdquo;, \u0026ldquo;LoDAC\u0026rdquo;.\u003c/p\u003e\n\u003cp\u003eThe references from all included studies, previous systematic reviews, and meta-analyses were manually searched for any additional studies. Two authors (E.F. and D.J.) independently extracted the data following predefined search criteria and quality assessment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEndpoints:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOutcomes were selected according to data availability and included the following: primary outcomes the OS; secondary outcomes the adverse events (AEs), CTCAE \u0026ndash; Common terminology criteria for adverse events, grade \u0026ge;3 adverse events, and a QT interval prolongation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuality assessment:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe evaluated the risk of bias in randomized studies using version 2 of the Cochrane Risk of Bias assessment tool.[3] Two independent authors completed the risk of bias assessment (E.M. and F.G.). Disagreements were resolved by a third author (K.T.).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePublication Bias was investigated by funnel-plot analysis of point estimates in relation to study weights.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe used HR with 95% CI to compare treatment effects for time-to-event endpoints. We used RR to compare treatment effects for categor\u003csup\u003ei\u003c/sup\u003ecal endpoints. We assessed heterogeneity with I\u003csup\u003e2\u003c/sup\u003e statistics and Cochran Q test; p-values \u0026lt; 0.10 and I\u003csup\u003e2\u003c/sup\u003e\u0026gt;25% were considered significant for heterogeneity. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe used the DerSimonian and Laird random-effects model. We also performed the \u0026ldquo;remove one study\u0026rdquo; test to assess sensitivity in randomized trials. We used leave-one-out sensitivity analyses to ensure that results were not dependent on one study. We used Review Manager 8.11.0 for statistical analysis.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe initial search yielded 4197 results. After removing duplicate records and ineligible studies, 126 studies remained and were fully reviewed based on the inclusion criteria and exclusion. Six Randomized Controlled Trials published between 2021 and 2024 were selected for data extraction, encompassing a total of 745 patients.\u003c/p\u003e\n\u003cp\u003eA total of 421 (56.51%) patients received FLT3 inhibitors and 324 (43.49%) received standard low-intensity chemotherapy regimens. Study characteristics are reported in Table 1. The studies primarily focused on high-risk groups, such as relapsed/refractory FLT3-mutated AML and patients unfit for intensive chemotherapy. Median ages ranged from 49.5 to 78 years, with consistent male representation (56.8%-67%). Interventions included FLT3 inhibitors (gilteritinib, quizartinib), azacitidine, and midostaurin, often combined with low-dose or standard chemotherapy. Control arms used low-dose cytarabine, decitabine, or azacitidine alone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePooled Results:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn those receiving FLT3 inhibitors, there was an overall trend towards increasing OS (HR 0.52; 95% CI 0.35-0.78, P = 0.001; I\u0026sup2; = 51%) in patients treated with FLT3 mutated AML unfit for intensive chemotherapy regimens. Figure 2. However, rates of Grade \u0026ge;3 Adverse Events Across Studies, defined based on the Common Terminology Criteria for Adverse Events (CTCAE), (RR 1.42; 95% CI 1.03-1.96, P= 0.03; I\u003csup\u003e2\u003c/sup\u003e = 0%) were increased. Figure 3. In addition QT interval prolongation (RR 3.49; 95% CI 1.43-8.51; p=0.006; I\u003csup\u003e2\u003c/sup\u003e=0%) were also significantly increased in the FLT3 inhibitors group.\u0026nbsp;Figure 4.\u003c/p\u003e\n\u003cp\u003eDue to high heterogeneity, we performed a leave-one-out sensitivity analysis by iteratively removing one study at a time to ensure the results were not dependent on a single study. Overall, performing the leave one out sensitivity analysis did not affect the endpoint of the OS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuality Assessment:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe evaluated the risk of bias in randomized studies using version 2 of the Cochrane Risk of Bias assessment tool.[3] Two independent authors completed the risk of bias assessment (E.M. and F.G.). Disagreements were resolved by a third author (K.T.). Table 2.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePublication Bias was investigated by funnel-plot analysis of point estimates in relation to study weights. Figure 5.\u0026nbsp;\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eAML is a heterogeneous group of aggressive blood cancers that arise from malignant transformation and clonal expansion of hematopoietic stem cells in the bone marrow. AML is the most common form of leukemia in adults, with most cases occurring in individuals over the age of 60 years.[4]Genetic mutations (eg, NPM1, FLT3, CEBPA, TET-2, c-KIT, DNMT3A, IDH, RUNX1, AXSL1, WT1, Ras gene mutations) serve as important prognostic markers and potential therapeutic targets.[5] Internal tandem duplications (ITD) in FLT3 represent the most common genetic alteration in de novo AML.[6] Patients with newly diagnosed FLT3-mutated AML who may be considered unfit for standard intensive induction chemotherapy have a poor prognosis characterized by worse survival or treatment response compared with their counterparts without multiple comorbidities, or poor performance status or advanced age; the presence of FLT3 mutations is also associated with worse survival.[7]Patients considered fit for IIC were required to have newly diagnosed FLT3-mutated AML, not therapy-related and without coexisting illnesses.[8] Intensive induction therapy plus FLT3 inhibitors are the standard of care for fit younger adults.[9]\u003c/p\u003e\n\u003cp\u003eMedical research has witnessed a significant breakthrough in producing FLT3 inhibitors in recent years, leading to their emergence in clinical trials. These inhibitors are intended for use in single-agent or combination therapy, and they are currently being evaluated for their effectiveness in the treatment of various stages of diseases.[10] FLT3 tyrosine kinase inhibitors are a diverse group of drugs that showcase variability in their effectiveness, preference, binding capacity, and site. Type I inhibitors, such as midostaurin, gilteritinib, and crenolanib, bind to the kinase-active conformation of FLT3, while type II inhibitors, including quizartinib and sorafenib, bind to the inactive structure.[11] First and second-generation FLT3 inhibitors provide treatment options in both the first-line and relapse and refractory setting.[12]\u003c/p\u003e\n\u003cp\u003ePrior meta-analyses focus on patients who are fit for intensive chemotherapy. Data related to patients who are ineligible for intensive chemotherapy are lacking and treatment options for this group of patients remain ineffective. The goals of care in unfit patients with AML are to achieve remission as the most effective way to alleviate symptoms, improve QoL, and extend survival. These goals support the inclusion of articles looking at survival rates in the short term. This review aims to fill existing gaps in the literature by focusing on a high-risk group, providing valuable data on the efficacy and safety of FLT3 inhibitors in unfit AML patients. Considering both benefits and potential harms, the review aims to support clinical practice decision-making for these patients.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this systematic review and meta-analysis of 6 RCTs comprising 745 patients, we evaluated the efficacy and safety of FLT3 inhibitors compared to low-intensity chemotherapy and low-intensity regimens in AML patients unfit for intensive chemotherapy. The use of FLT3 inhibitors was associated with a notably higher risk of severe adverse events. FLT3 inhibitors modestly increased the likelihood of cardiac events, specifically QT interval prolongation. Despite these risks, treatment with FLT3 inhibitors demonstrated a significant survival benefit over low-intensity chemotherapy, effectively reducing the overall risk of death.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe treatment landscape for AML patients unfit for intensive chemotherapy has evolved significantly over the past two decades. Historically, these patients were treated with low-dose cytarabine or hypomethylating agents (HMAs) like azacitidine and decitabine, which offered limited efficacy and modest improvements in survival.[13-14]\u003c/p\u003e\n\u003cp\u003eAlthough standard induction-style chemotherapy regimens in combination with midostaurin are recommended for ND FLT3 mutated AML in patients eligible for intensive chemotherapy, there is no universal standard chemotherapy for patients with ND FLT3-mutant AML considered unfit for intensive induction chemotherapy.[15-17] The most common treatments for FLT3 mutated AML unfit patients include venetoclax plus azacitidine or low-dose cytarabine. To determine the patients eligibility for intensive chemotherapy, prognostic models incorporating cytogenetic information, age, and clinical indicators attempt to risk-stratify patients according to their likelihood of experiencing treatment-related morbidity and mortality, but no prognostic scoring system has become standard.[18-19] This leads to great variability in defining eligibility criteria for unfit patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMutations in the FLT3 gene are seen in approximately 30% of patients with AML.[20] Among patients with FLT3 mutations, internal tandem duplication (ITD) is more common, but point mutations in the tyrosine kinase domain are also seen.[9] ITD FLT3-mutated AML in particular has been associated with a poor prognosis.[21] Many studies have shown that FLT3-ITD is an independent prognostic marker associated with high leukemic burden and leukocytosis, poor OS, and early relapse.[22]\u003c/p\u003e\n\u003cp\u003eThe treatment of FLT3-mutated AML patients who are unfit for intensive chemotherapy represents a particular clinical challenge, given the lack of an approved FLT3 inhibitor for use in this setting.[23]However our pooled analysis suggests a need for further evaluation of the use of FLT3 inhibitors, especially second-generation FLT3 inhibitors in patients who are considered unfit for intensive chemotherapy regimens and who carry the FLT3 gene mutation variants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA limitation of our study is the moderate heterogeneity in OS outcomes across the studies, which is attributed to differences in study populations, treatment regimens, and trial designs. While some trials, like AML LI, included older patients unfit for intensive chemotherapy, others, such as ADMIRAL and COMMODORE, focused on relapsed or refractory FLT3-mutated AML, and LACEWING included newly diagnosed patients ineligible for intensive therapy. Variations in FLT3 inhibitors, with quizartinib used in QuANTUM-R and gilteritinib in ADMIRAL and COMMODORE, along with combination regimens in LACEWING, further contributed to differences. Additionally, the diversity in control groups, follow-up durations, and geographic populations, such as the predominantly Asian cohort in COMMODORE, added to the observed variability. These differences underline the complexity of interpreting pooled OS results in this heterogeneous population.\u003c/p\u003e\n\u003cp\u003eA sensitivity analysis was conducted to assess the robustness of the results. Removing one study at a time did not alter the overall conclusions, indicating the stability of the findings. However, when two specific trials were excluded, one at a time, heterogeneity decreased from moderate to low levels (I\u003csup\u003e2\u003c/sup\u003e=27), suggesting that these trials contributed to the observed variability. These findings support the clinical utility of FLT3 inhibitors and highlight the need for personalized approaches to mitigate adverse effects.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe recommend that FLT3 inhibitors, especially second-generation FLT3 inhibitors, be considered a potential addition to treatment protocols in patients deemed unfit for intensive chemotherapy and carriers of the FLT3 mutations. Further research is warranted to clarify the impact of patient-specific factors, such as age, comorbidities, and geographic variations, on treatment outcomes. Whether FLT3 inhibitors should be considered as monotherapy or an addition to standard low-dose chemotherapy regimens, remains a potential topic for further exploration.\u0026nbsp;\u003cbr\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eFLT3 inhibitors, used either as monotherapy or in combination with low-intensity chemotherapy, improve OS in FLT3-mutated AML patients unfit for intensive chemotherapy. However, the increased risk of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events and QT interval prolongation warrants careful monitoring in clinical practice.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAML: Acute Myeloid Leukemia; FLT3: Fms-like tyrosine kinase 3; OS: Overall Survival; HR: Hazard Ratio; CI: Confidence Interval; RR: Risk Ratio; I²: I-squared (measure of heterogeneity);\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFounding Sources:\u0026nbsp;\u003c/strong\u003eThere are no sources of funding to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial Disclosures:\u0026nbsp;\u003c/strong\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e None.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eHiggins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editors. Cochrane Handbook for Systematic Reviews of Interventions. Version 6.3 [updated February 2022]. Cochrane; 2022 [cited 2024 Dec 24]. Available from: https://training.cochrane.org/handbook.\u003c/li\u003e\n \u003cli\u003eMoher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097.\u003c/li\u003e\n \u003cli\u003eSterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomized trials. BMJ. 2019;366:l4898. doi: 10.1136/bmj.l4898.\u003c/li\u003e\n \u003cli\u003eWachter F, Pikman Y. Pathophysiology of acute myeloid leukemia. Acta Haematol. 2024;147(2):229-246.\u003c/li\u003e\n \u003cli\u003ePadmakumar D, Chandraprabha VR, Gopinath P, et al. A concise review on the molecular genetics of acute myeloid leukemia. Leuk Res. 2021;111:106727. doi: 10.1016/j.leukres.2021.106727.\u003c/li\u003e\n \u003cli\u003eKong T, Laranjeira ABA, Letson CT, Yu L, He F, Jayanthan A, et al. RSK1 dependency in FLT3-ITD acute myeloid leukemia. Blood Cancer J. 2024;14(1):207. doi: 10.1038/s41408-024-01187-4. PMID: 39592591; PMCID: PMC11599852.\u003c/li\u003e\n \u003cli\u003eWang ES, Montesinos P, Minden MD, Lee JH, Heuser M, Naoe T, et al. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood. 2022;140(17):1845-1857. doi: 10.1182/blood.2021014586.\u003c/li\u003e\n \u003cli\u003eStone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464. doi: 10.1056/NEJMoa1614359.\u003c/li\u003e\n \u003cli\u003eShort NJ, Kantarjian H, Ravandi F, Daver N. Emerging treatment paradigms with FLT3 inhibitors in acute myeloid leukemia. Ther Adv Hematol. 2019;10:2040620719827310. doi: 10.1177/2040620719827310.\u003c/li\u003e\n \u003cli\u003ede Leeuw DC, Ossenkoppele GJ, Janssen JJWM. Older patients with acute myeloid leukemia deserve individualized treatment. Curr Oncol Rep. 2022;24:1387-1400. doi: 10.1007/s11912-022-01299-9.\u003c/li\u003e\n \u003cli\u003eAhn JS, Kim HJ. FLT3 mutations in acute myeloid leukemia: A review focusing on clinically applicable drugs. Blood Res. 2022;57:32-36. doi: 10.5045/br.2022.2022017.\u003c/li\u003e\n \u003cli\u003eZhao JC, Agarwal S, Ahmad H, Amin K, Bewersdorf JP, Zeidan AM. A review of FLT3 inhibitors in acute myeloid leukemia. Blood Rev. 2022;52:100905. doi: 10.1016/j.blre.2021.100905.\u003c/li\u003e\n \u003cli\u003eFenaux P, Mufti GJ, Hellstr\u0026ouml;m-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223-232. doi: 10.1016/S1470-2045(09)70003-8.\u003c/li\u003e\n \u003cli\u003eBurnett AK, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK, et al. A comparison of low dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007;109(6):1114-1124. doi: 10.1002/cncr.22496.\u003c/li\u003e\n \u003cli\u003eD\u0026ouml;hner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, B\u0026uuml;chner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447. doi: 10.1182/blood-2016-08-733196.\u003c/li\u003e\n \u003cli\u003eHeuser M, Ofran Y, Boissel N, Daver N, Dennis M, DiNardo CD, et al; ESMO Guidelines Committee. Acute myeloid leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up [published correction appears in Ann Oncol. 2021;32(6):821]. Ann Oncol. 2020;31(6):697-712. doi: 10.1016/j.annonc.2020.03.018.\u003c/li\u003e\n \u003cli\u003eStone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464. doi: 10.1056/NEJMoa1614359.\u003c/li\u003e\n \u003cli\u003ePettit K, Odenike O. Defining and treating older adults with acute myeloid leukemia who are ineligible for intensive therapies. Front Oncol. 2015;5:280. doi: 10.3389/fonc.2015.00280.\u003c/li\u003e\n \u003cli\u003eKantarjian H, O\u0026rsquo;Brien S, Cortes J, Giles F, Faderl S, Issa JP, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer. 2006;106(5):1090-1098. doi: 10.1002/cncr.21744.\u003c/li\u003e\n \u003cli\u003eDaver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019;33(2):299-312. doi: 10.1038/s41375-018-0357-9.\u003c/li\u003e\n \u003cli\u003eKayser S, Schlenk RF, Londono MC, Breitenbuecher F, Retzlaff S, Kuhn MW, et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009;114(12):2386-2392. doi: 10.1182/blood-2009-01-199208.\u003c/li\u003e\n \u003cli\u003eZhao JC, Agarwal S, Ahmad H, Amin K, Bewersdorf JP, Zeidan AM. A review of FLT3 inhibitors in acute myeloid leukemia. Blood Rev. 2022;52:100905. doi: 10.1016/j.blre.2021.100905.\u003c/li\u003e\n \u003cli\u003eShort NJ, Nguyen D, Ravandi F. Treatment of older adults with FLT3-mutated AML: Emerging paradigms and the role of frontline FLT3 inhibitors. Blood Cancer J. 2023;13:142. doi: 10.1038/s41408-023-00911-w.\u003cstrong\u003e\u003cbr\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eReferences for analyzed Randomized Controlled Trials:\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eWang J, Jiang B, Li J, Liu L, Du X, Jiang H, et al. Gilteritinib versus salvage chemotherapy for relapsed/refractory FLT3-mutated acute myeloid leukemia: A phase 3, randomized, multicenter, open-label trial in Asia. Blood. 2021;138(Suppl 1):695. doi:10.1182/blood-2021-145436.\u003c/li\u003e\n \u003cli\u003eWang ES, Montesinos P, Minden MD, Lee JH, Heuser M, Naoe T, et al. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood. 2022;140(17):1845\u0026ndash;57. doi:10.1182/blood.2021014586.\u003c/li\u003e\n \u003cli\u003ePerl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381(18):1728\u0026ndash;40. doi:10.1056/NEJMoa1902688.\u003c/li\u003e\n \u003cli\u003eHuls G, Chitu DA, Tick L, Boersma R, Breems D, Herbers A, et al. Midostaurin added to 10-day decitabine for patients unfit for intensive chemotherapy with AML and higher-risk MDS, irrespective of FLT3 mutational status, does not improve outcome. Ann Hematol. 2024. doi:10.1007/s00277-024-06033-y.\u003c/li\u003e\n \u003cli\u003eDennis M, Thomas I, Ariti C, Upton L, Burnett A, Radia R, et al. A randomised evaluation of low-dose Ara-C plus AC220 (quizartinib) versus low-dose Ara-C in older patients with acute myeloid leukaemia: Results from the LI-1 trial. HemaSphere. Abstract Book: 25th Congress of the European Hematology Association Virtual Edition; 2020.\u003c/li\u003e\n \u003cli\u003eCortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicenter, randomized, controlled, open-label, phase 3 trial. Lancet Oncol. 2019;20(7):984\u0026ndash;97. doi:10.1016/S1470-2045(19)30150-0.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1: Baseline characteristics of included studies.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003eStudy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003eFollow-up, months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003eStudy population (n)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003eIntervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eAge (years)\u0026sup1;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003eMen (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eMutation status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eICC treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003eAML LI, 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e13.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e99/103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003eQUIZ + LD Ara-C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eLD Ara-C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e64/63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eUnfit for IIC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003eCOMMODORE, 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e10.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e23/22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003eGILT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eLD DEC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e49.5/51.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e60.9/59.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eR/R FLT3-mutated AML\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eLD CT\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003eADMIRAL, 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e24/48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e98/49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003eGILT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eR/R FLT3-mutated AML\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eLD CT\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003eLACEWING, 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e9.76/17.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e74/49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003eGILT+ AZA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eAZA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e78/ 76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e56.8/57.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eFLT3-mutated AML\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eUnfit for IIC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003eQuANTUM-R, 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e23.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e57/29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003eQUIZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eLD DEC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eR/R FLT3-mutated AML\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eLD CT\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 166px;\"\u003e\n \u003cp\u003eHOVON-15, 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e6.5/37\u0026sup2;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e70/72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003eDEC+MIDO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eDEC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e74/ 75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e67/59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eUnfit for IIC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e1: Median; 2: 6.5 months for all patients and 37 months for alive patients; AML: acute myeloid leukemia; Ara-C: citarabina; AZA: azacitidine; CT: chemotherapy; DEC: decitabine; GILT: gilteritinib; IIC: intensive induction chemotherapy; LD: low dose; MIDO: midostaurin; N/A: not available; QUIZ: quizartinib; R/R: relapsed or refractory; SC: standard care.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Table 2. Risk of Bias Assessment.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"1002\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy ID\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRandomization\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntended Intervention\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMissing Outcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMeasurement of the Outcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReported results\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOther\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eADMIRAL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003eSome concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003eSome Concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCOMMODORE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003eSome concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eSome concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003eSome Concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHOVON-155\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003eSome concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eSome concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003eSome Concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLACEWING\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003eSome concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003eSome Concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eQuANTUM-R\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003eSome concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eSome Concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003eSome Concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAML-LI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003eSome concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eSome concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003eSome Concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\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":"AML, FLT3 mutation, chemotherapy, FLT3 inhibitors","lastPublishedDoi":"10.21203/rs.3.rs-5760913/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5760913/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFLT3 inhibitors have demonstrated increased efficacy in patients with FLT3-mutated acute myeloid leukemia (AML). However, their effects on patients unfit for intensive chemotherapy remain undefined. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of FLT3 inhibitors in AML patients unfit for intensive chemotherapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA systematic search was conducted between October 2024 and December 2024 across PubMed, Embase, and Cochrane Central. Studies included patients with AML who were unfit for intensive chemotherapy, treated with FLT3 inhibitors as monotherapy or in combination with low-intensity regimens, compared to standard low-intensity chemotherapy regimens. The primary outcome was the OS, defined as the proportion of patients alive at a specified time after treatment initiation or diagnosis. Statistical analysis was performed under a random effects model using Review Manager 8.11.0. Heterogeneity was assessed using I² statistics.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e745 patients from six randomized controlled trials (RCTs) were included. FLT3 inhibitors were used in 421 (56.51%) AML patients unfit for intensive chemotherapy. Among the six studies, one reported quizartinib combined with low-dose cytarabine, two reported gilteritinib monotherapy, one reported gilteritinib with azacitidine, one reported quizartinib monotherapy, and one reported decitabine with midostaurin. Follow-up ranged from 6.5 to 48 months.\u003c/p\u003e\n\u003cp\u003eFLT3 inhibitors significantly improved OS (HR 0.52; 95% CI 0.35–0.78, P = 0.001; I² = 51%) compared to standard chemotherapy. However, the risk of grade ≥3 adverse events (RR 1.42; 95% CI 1.03–1.96, P = 0.03; I² = 0%) and QT interval prolongation (RR 3.49; 95% CI 1.43–8.51, P = 0.006; I² = 0%) was significantly higher in the FLT3 inhibitors group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFLT3 inhibitors, used either as monotherapy or in combination with low-intensity chemotherapy, improve OS in FLT3-mutated AML patients unfit for intensive chemotherapy. However, the increased risk of grade ≥3 adverse events and QT interval prolongation warrants careful monitoring in clinical practice.\u003c/p\u003e","manuscriptTitle":"Efficacy of FLT3 Inhibitors in Patients with FLT3-Mutated Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-14 15:24:15","doi":"10.21203/rs.3.rs-5760913/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-02-19T13:11:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-02-17T11:26:20+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-02-13T21:50:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"134340099989572805071397637178623315418","date":"2025-02-02T05:25:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"233332924928889276963315223243867248618","date":"2025-01-16T19:23:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-01-15T20:10:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-01-09T12:30:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-01-09T12:29:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2025-01-04T02:02:12+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":"26a4aa58-2659-4900-8522-263c0deb1377","owner":[],"postedDate":"January 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-03-15T07:53:28+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-14 15:24:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5760913","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5760913","identity":"rs-5760913","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}