{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:30:59Z","timestamp":1791325859993,"version":"4.3.1"},"reference-count":102,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>FMS-like tyrosine kinase 3 (FLT3) is a crucial regulator of normal hematopoiesis, with high expression in hematopoietic stem and progenitor cells. Beyond its role in stem cell survival and proliferation, FLT3 signaling is essential for immune regulation, particularly dendritic cell differentiation and NK cell expansion. In acute myeloid leukemia (AML), FLT3 mutations\u2014most commonly internal tandem duplications (FLT3-ITD) and tyrosine kinase domain (FLT3-TKD) substitutions\u2014are among the most frequent genetic alterations, driving constitutive activation of proliferative and antiapoptotic pathways and conferring adverse prognosis. The clinical development of FLT3 inhibitors has been a decades-long endeavor. Early multikinase agents established proof-of-concept but were hampered by off-target effects and incomplete efficacy. The subsequent generation of potent and selective inhibitors has transformed outcomes, culminating in FDA approvals of midostaurin, quizartinib, and gilteritinib. Together with allogeneic transplantation, these agents have reshaped the treatment paradigm for FLT3-mutant AML, converting a historically high-risk subset into one with realistic prospects for long-term survival. Despite these advances, challenges remain. Resistance emerges through cell-intrinsic mechanisms such as acquisition of secondary TKD or RAS pathway mutations, metabolic reprogramming, and antiapoptotic shifts, as well as cell-extrinsic mechanisms mediated by the bone marrow microenvironment, including cytokine support, stromal CYP3A4 metabolism, and retinoid inactivation. These pathways sustain measurable residual disease (MRD), the key predictor of relapse. Rational combination strategies and MRD-directed approaches are therefore essential to fully realize the curative potential of FLT3 inhibition.<\/jats:p>","DOI":"10.3390\/cancers17213415","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T01:35:11Z","timestamp":1761269711000},"page":"3415","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["FLT3: A 35-Year Voyage from Discovery to the Next Generation of Targeted Therapy in AML"],"prefix":"10.3390","volume":"17","author":[{"given":"Maria-Camelia","family":"Stancioaica","sequence":"first","affiliation":[{"name":"Faculty of Medicine, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 022338 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7251-6079","authenticated-orcid":false,"given":"Daniel","family":"Coriu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 022338 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3955-7944","authenticated-orcid":false,"given":"Gabriel","family":"Ghiaur","sequence":"additional","affiliation":[{"name":"The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1111\/cas.14274","article-title":"FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development","volume":"111","author":"Kiyoi","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1182\/blood-2002-02-0492","article-title":"The roles of FLT3 in hematopoiesis and leukemia","volume":"100","author":"Gilliland","year":"2002","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Cueto, F.J., and Sancho, D. (2021). The Flt3L\/Flt3 Axis in Dendritic Cell Biology and Cancer Immunotherapy. Cancers, 13.","DOI":"10.3390\/cancers13071525"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S1359-6101(97)00035-X","article-title":"FLT3: Receptor and ligand. Biology and potential clinical application","volume":"9","author":"Shurin","year":"1998","journal-title":"Cytokine Growth Factor. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.1182\/blood.V95.11.3489","article-title":"Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells","volume":"95","author":"McKenna","year":"2000","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1084\/jem.20051645","article-title":"Activation of the Flt3 signal transduction cascade rescues and enhances type I interferon-producing and dendritic cell development","volume":"203","author":"Onai","year":"2006","journal-title":"J. Exp. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1084\/jem.184.6.2185","article-title":"Dendritic cell development in culture from thymic precursor cells in the absence of granulocyte\/macrophage colony-stimulating factor","volume":"184","author":"Saunders","year":"1996","journal-title":"J. Exp. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Schlaweck, S., Radcke, A., Kampmann, S., Becker, B.V., Brossart, P., and Heine, A. (2024). The Immunomodulatory Effect of Different FLT3 Inhibitors on Dendritic Cells. Cancers, 16.","DOI":"10.3390\/cancers16213719"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.autrev.2013.09.010","article-title":"Fms-like tyrosine kinase 3 ligand-dependent dendritic cells in autoimmune inflammation","volume":"13","author":"Ramos","year":"2014","journal-title":"Autoimmun. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/S1074-7613(03)00332-7","article-title":"STAT3 is required for Flt3L-dependent dendritic cell differentiation","volume":"19","author":"Laouar","year":"2003","journal-title":"Immunity"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1152\/physrev.00029.2018","article-title":"FMS-like Tyrosine Kinase 3\/FLT3: From Basic Science to Clinical Implications","volume":"99","author":"Kazi","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1756-8722-4-13","article-title":"Downstream molecular pathways of FLT3 in the pathogenesis of acute myeloid leukemia: Biology and therapeutic implications","volume":"4","author":"Takahashi","year":"2011","journal-title":"J. Hematol. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.arcmed.2020.10.013","article-title":"FLT3-ITD and CD135 Over-Expression are Frequent Findings of Poor Survival in Adult Patients with Acute Leukemias","volume":"52","author":"Cardenas","year":"2021","journal-title":"Arch. Med. Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kennedy, V.E., and Smith, C.C. (2020). FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.612880"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1182\/blood-2006-05-023804","article-title":"Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways","volume":"109","author":"Piloto","year":"2007","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1056\/NEJMoa1112304","article-title":"Prognostic relevance of integrated genetic profiling in acute myeloid leukemia","volume":"366","author":"Patel","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/s41375-018-0357-9","article-title":"Targeting FLT3 mutations in AML: Review of current knowledge and evidence","volume":"33","author":"Daver","year":"2019","journal-title":"Leukemia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1182\/blood.2019002697","article-title":"Impact of NPM1\/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia","volume":"135","author":"Dohner","year":"2020","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.hoc.2017.04.005","article-title":"Mechanisms of Resistance to FLT3 Inhibitors and the Role of the Bone Marrow Microenvironment","volume":"31","author":"Ghiaur","year":"2017","journal-title":"Hematol. Oncol. Clin. N. Am."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1182\/blood.2022016293","article-title":"Prognostic impact of NPM1 and FLT3 mutations in patients with AML in first remission treated with oral azacitidine","volume":"140","author":"Dohner","year":"2022","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2834","DOI":"10.1182\/blood.2024024248","article-title":"Approaching a therapeutic inflection point for FLT3-mutated AML","volume":"145","author":"Perl","year":"2025","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1002\/1878-0261.12961","article-title":"FLT3-ITD mutations in acute myeloid leukaemia\u2014Molecular characteristics, distribution and numerical variation","volume":"15","author":"Engen","year":"2021","journal-title":"Mol. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1182\/blood-2016-09-693648","article-title":"How I treat FLT3-mutated AML","volume":"129","author":"Pratz","year":"2017","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Fedorov, K., Maiti, A., and Konopleva, M. (2023). Targeting FLT3 Mutation in Acute Myeloid Leukemia: Current Strategies and Future Directions. Cancers, 15.","DOI":"10.3390\/cancers15082312"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.leukres.2010.01.001","article-title":"Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations in acute promyelocytic leukemia: A systematic review","volume":"34","author":"Beitinjaneh","year":"2010","journal-title":"Leuk. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3768","DOI":"10.1182\/blood-2005-04-1746","article-title":"Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia","volume":"106","author":"Gale","year":"2005","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Picharski, G.L., Andrade, D.P., Fabro, A., Lenzi, L., Tonin, F.S., Ribeiro, R.C., and Figueiredo, B.C. (2019). The Impact of Flt3 Gene Mutations in Acute Promyelocytic Leukemia: A Meta-Analysis. Cancers, 11.","DOI":"10.3390\/cancers11091311"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Li, A.Y., Kashanian, S.M., Hambley, B.C., Zacholski, K., Duong, V.H., El Chaer, F., Holtzman, N.G., Gojo, I., Webster, J.A., and Norsworthy, K.J. (2021). FLT3-ITD Allelic Burden and Acute Promyelocytic Leukemia Risk Stratification. Biology, 10.","DOI":"10.3390\/biology10030243"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3544","DOI":"10.1182\/blood-2003-07-2441","article-title":"FLT3 mutations in childhood acute lymphoblastic leukemia","volume":"103","author":"Armstrong","year":"2004","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/s41417-019-0120-z","article-title":"The mutational spectrum of FLT3 gene in acute lymphoblastic leukemia is different from acute myeloid leukemia","volume":"27","author":"Zhang","year":"2020","journal-title":"Cancer Gene Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1056\/NEJMoa1403088","article-title":"Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia","volume":"371","author":"Roberts","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/ng765","article-title":"MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia","volume":"30","author":"Armstrong","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Biojone, E.R., Guido, B.C., Cavalcante, L.L.M., Santos J\u00fanior, A.d.C.M.d., Pontes, R.M.d., Furtado, F.M., C\u00f3rdoba, J.C., Magalh\u00e3es, I.M.Q., de Oliveira, D.M., and Camargo, R. (2024). Prevalence of FLT3 gene mutation and its expression in Brazilian pediatric B-ALL patients: Clinical implications. Front. Pediatr., 12.","DOI":"10.3389\/fped.2024.1505060"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1182\/blood-2004-06-2498","article-title":"FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression","volume":"105","author":"Brown","year":"2005","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2360","DOI":"10.1038\/leu.2012.161","article-title":"Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia","volume":"26","author":"Chillon","year":"2012","journal-title":"Leukemia"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1182\/blood.2019004684","article-title":"13q12.2 deletions in acute lymphoblastic leukemia lead to upregulation of FLT3 through enhancer hijacking","volume":"136","author":"Yang","year":"2020","journal-title":"Blood"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/bjh.12599","article-title":"Bone marrow stroma-mediated resistance to FLT3 inhibitors in FLT3-ITD AML is mediated by persistent activation of extracellular regulated kinase","volume":"164","author":"Yang","year":"2014","journal-title":"Br. J. Haematol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Woods, A.C., and Norsworthy, K.J. (2023). Differentiation Syndrome in Acute Leukemia: APL and Beyond. Cancers, 15.","DOI":"10.3390\/cancers15194767"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3477","DOI":"10.1182\/blood-2006-04-015743","article-title":"Plasma inhibitory activity (PIA): A pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors","volume":"108","author":"Levis","year":"2006","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1007\/s40259-013-0049-y","article-title":"Sorafenib and thyroid cancer","volume":"27","author":"Fallahi","year":"2013","journal-title":"BioDrugs"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"27","DOI":"10.3324\/haematol.10692","article-title":"The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors","volume":"92","author":"Lierman","year":"2007","journal-title":"Haematologica"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7099","DOI":"10.1158\/0008-5472.CAN-04-1443","article-title":"BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF\/MEK\/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis","volume":"64","author":"Wilhelm","year":"2004","journal-title":"Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"62","DOI":"10.3324\/haematol.2010.030452","article-title":"Phase I study of sorafenib in patients with refractory or relapsed acute leukemias","volume":"96","author":"Borthakur","year":"2011","journal-title":"Haematologica"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4655","DOI":"10.1182\/blood-2013-01-480228","article-title":"Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation","volume":"121","author":"Ravandi","year":"2013","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1002\/ajh.25198","article-title":"Sorafenib Combined with 5-azacytidine in Older Patients with Untreated FLT3-ITD Mutated Acute Myeloid Leukemia","volume":"93","author":"Ohanian","year":"2018","journal-title":"Am. J. Hematol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1016\/S1470-2045(15)00362-9","article-title":"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","volume":"16","author":"Rollig","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1182\/blood.2023020301","article-title":"Sorafenib plus intensive chemotherapy in newly diagnosed FLT3-ITD AML: A randomized, placebo-controlled study by the ALLG","volume":"142","author":"Loo","year":"2023","journal-title":"Blood"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Andreeff, M. (2015). Development of Midostaurin as a Tyrosine Kinase Inhibitor. Targeted Therapy of Acute Myeloid Leukemia, Springer.","DOI":"10.1007\/978-1-4939-1393-0"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"100905","DOI":"10.1016\/j.blre.2021.100905","article-title":"A review of FLT3 inhibitors in acute myeloid leukemia","volume":"52","author":"Zhao","year":"2022","journal-title":"Blood Rev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1182\/blood-2004-03-0891","article-title":"Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412","volume":"105","author":"Stone","year":"2005","journal-title":"Blood"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4339","DOI":"10.1200\/JCO.2010.28.9678","article-title":"Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3","volume":"28","author":"Fischer","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1056\/NEJMoa1614359","article-title":"Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation","volume":"377","author":"Stone","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1002\/ajh.23924","article-title":"Phase I\/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome","volume":"90","author":"Strati","year":"2015","journal-title":"Am. J. Hematol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1007\/s10637-017-0470-z","article-title":"Gilteritinib, a FLT3\/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia","volume":"35","author":"Mori","year":"2017","journal-title":"Investig. New Drugs"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5319","DOI":"10.1073\/pnas.1320661111","article-title":"Crenolanib is a selective type I pan-FLT3 inhibitor","volume":"111","author":"Smith","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1182\/blood-2016-10-745133","article-title":"Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor","volume":"129","author":"Lee","year":"2017","journal-title":"Blood"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1182\/blood-2013-10-529313","article-title":"Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants","volume":"123","author":"Galanis","year":"2014","journal-title":"Blood"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2390","DOI":"10.1038\/leu.2015.165","article-title":"FLT3 D835 mutations confer differential resistance to type II FLT3 inhibitors","volume":"29","author":"Smith","year":"2015","journal-title":"Leukemia"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/S1470-2045(17)30416-3","article-title":"Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: A multicentre, first-in-human, open-label, phase 1-2 study","volume":"18","author":"Perl","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1056\/NEJMoa1902688","article-title":"Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML","volume":"381","author":"Perl","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4236","DOI":"10.1200\/JCO.22.02721","article-title":"Gilteritinib in Combination with Induction and Consolidation Chemotherapy and as Maintenance Therapy: A Phase IB Study in Patients with Newly Diagnosed AML","volume":"41","author":"Pratz","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1182\/blood.2021014586","article-title":"Phase 3 trial of gilteritinib plus azacitidine vs. azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy","volume":"140","author":"Wang","year":"2022","journal-title":"Blood"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1200\/JCO.23.01911","article-title":"Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory FLT3-Mutated AML","volume":"42","author":"Short","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/s41408-021-00410-w","article-title":"Triplet therapy with venetoclax, FLT3 inhibitor and decitabine for FLT3-mutated acute myeloid leukemia","volume":"11","author":"Maiti","year":"2021","journal-title":"Blood Cancer J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2984","DOI":"10.1182\/blood-2009-05-222034","article-title":"AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML)","volume":"114","author":"Zarrinkar","year":"2009","journal-title":"Blood"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3681","DOI":"10.1200\/JCO.2013.48.8783","article-title":"Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status","volume":"31","author":"Cortes","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1038\/leu.2012.52","article-title":"Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: A model for emerging clinical resistance patterns","volume":"26","author":"Moore","year":"2012","journal-title":"Leukemia"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/S1470-2045(18)30240-7","article-title":"Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: An open-label, multicentre, single-arm, phase 2 trial","volume":"19","author":"Cortes","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1182\/blood-2018-01-821629","article-title":"Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD-mutated, relapsed or refractory AML","volume":"132","author":"Cortes","year":"2018","journal-title":"Blood"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1016\/S1470-2045(19)30150-0","article-title":"Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): A multicentre, randomised, controlled, open-label, phase 3 trial","volume":"20","author":"Cortes","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1016\/S0140-6736(23)00464-6","article-title":"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","volume":"401","author":"Erba","year":"2023","journal-title":"Lancet"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.3324\/haematol.2020.263392","article-title":"A phase I\/II study of the combination of quizartinib with azacitidine or low-dose cytarabine for the treatment of patients with acute myeloid leukemia and myelodysplastic syndrome","volume":"106","author":"Swaminathan","year":"2021","journal-title":"Haematologica"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e19019","DOI":"10.1200\/JCO.2021.39.15_suppl.e19019","article-title":"Quizartinib with decitabine and venetoclax (triplet) is highly active in patients with FLT3-ITD mutated acute myeloid leukemia (AML)","volume":"39","author":"Yilmaz","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s13045-024-01617-7","article-title":"Quizartinib: A potent and selective FLT3 inhibitor for the treatment of patients with FLT3-ITD\u2013positive AML","volume":"17","author":"Cortes","year":"2024","journal-title":"J. Hematol. Oncol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3695","DOI":"10.1182\/blood.V126.23.3695.3695","article-title":"Population Pharmacokinetics of Crenolanib, a Type I FLT3 Inhibitor, in Patients with Relapsed\/Refractory AML","volume":"126","author":"Panetta","year":"2015","journal-title":"Blood"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1038\/s41467-018-08263-x","article-title":"Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms","volume":"10","author":"Zhang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1182\/blood.V124.21.389.389","article-title":"Results of a Phase II Study of Crenolanib in Relapsed\/Refractory Acute Myeloid Leukemia Patients (Pts) with Activating FLT3 Mutations","volume":"124","author":"Randhawa","year":"2014","journal-title":"Blood"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1200\/JCO.23.01061","article-title":"Crenolanib and Intensive Chemotherapy in Adults with Newly Diagnosed FLT3-Mutated AML","volume":"42","author":"Wang","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3366","DOI":"10.1182\/blood.2021011583","article-title":"Follow-up of patients with R\/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial","volume":"139","author":"Perl","year":"2022","journal-title":"Blood"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e600","DOI":"10.1016\/S2352-3026(23)00117-5","article-title":"Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: Long-term follow-up of an open-label, multicentre, randomised, phase 3 trial","volume":"10","author":"Xuan","year":"2023","journal-title":"Lancet Haematol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2993","DOI":"10.1200\/JCO.19.03345","article-title":"Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia with FLT3-Internal Tandem Duplication Mutation (SORMAIN)","volume":"38","author":"Burchert","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1016\/S1470-2045(20)30455-1","article-title":"Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: An open-label, multicentre, randomised phase 3 trial","volume":"21","author":"Xuan","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1038\/s41409-020-01153-1","article-title":"Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia","volume":"56","author":"Maziarz","year":"2021","journal-title":"Bone Marrow Transpl."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1200\/JCO.23.02474","article-title":"Gilteritinib as Post-Transplant Maintenance for AML with Internal Tandem Duplication Mutation of FLT3","volume":"42","author":"Levis","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1182\/blood.2024025154","article-title":"Measurable residual disease and posttransplantation gilteritinib maintenance for patients with FLT3-ITD\u2013mutated AML","volume":"145","author":"Levis","year":"2025","journal-title":"Blood"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"5123","DOI":"10.1182\/bloodadvances.2025016306","article-title":"Impact of transplant conditioning, NPM1 mutations, and measurable residual disease in FLT3-ITD acute myeloid leukemia","volume":"9","author":"Levis","year":"2025","journal-title":"Blood Adv."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1200\/JCO.21.01612","article-title":"Sorafenib in Combination with Standard Chemotherapy for Children with High Allelic Ratio FLT3\/ITD+ Acute Myeloid Leukemia: A Report From the Children\u2019s Oncology Group Protocol AAML1031","volume":"40","author":"Pollard","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e30584","DOI":"10.1002\/pbc.30584","article-title":"Children\u2019s Oncology Group\u2019s 2023 blueprint for research: Myeloid neoplasms","volume":"70","author":"Cooper","year":"2023","journal-title":"Pediatr Blood Cancer"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1007\/s12185-023-03681-0","article-title":"FLT3 targeting in the modern era: From clonal selection to combination therapies","volume":"120","author":"Kennedy","year":"2024","journal-title":"Int. J. Hematol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1093\/toxsci\/kfaa098","article-title":"Nonclinical Safety Assessment of AMG 553, an Investigational Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Acute Myeloid Leukemia","volume":"177","author":"Karbowski","year":"2020","journal-title":"Toxicol. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Popescu, B., Jones, M.F., Piao, M., Tran, E., Koh, A., Lomeli, I., Peretz, C.A.C., Murad, N., Abelson, S., and Morales, C. (bioRxiv, 2025). Multi-selective RAS(ON) Inhibition Targets Oncogenic RAS Mutations and Overcomes RAS\/MAPK-Mediated Resistance to FLT3 and BCL2 Inhibitors in Acute Myeloid Leukemia, bioRxiv, preprint.","DOI":"10.1101\/2025.06.10.658786"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"5945","DOI":"10.1182\/blood-2023-190801","article-title":"A Phase 1b Multi-Center Study of the FLT3 Inhibitor Gilteritinib in Combination with the IDH1 Inhibitor Ivosidenib or the IDH2 Inhibitor Enasidenib for Patients with Relapsed or Refractory Acute Myeloid Leukemia Who Have Co-Occurring FLT3\/IDH1 or FLT3\/IDH2 Mutations","volume":"142","author":"Stein","year":"2023","journal-title":"Blood"},{"key":"ref_93","first-page":"1034","article-title":"Venetoclax combines synergistically with FLT3 inhibition to effectively target leukemic cells in FLT3-ITD+ acute myeloid leukemia models","volume":"106","author":"Zhang","year":"2021","journal-title":"Haematologica"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"4048","DOI":"10.1200\/JCO.22.00602","article-title":"Venetoclax Plus Gilteritinib for FLT3-Mutated Relapsed\/Refractory Acute Myeloid Leukemia","volume":"40","author":"Daver","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1182\/bloodadvances.2018029850","article-title":"Hematopoietic cytokines mediate resistance to targeted therapy in FLT3-ITD acute myeloid leukemia","volume":"3","author":"Sung","year":"2019","journal-title":"Blood Adv."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1182\/bloodadvances.2023010619","article-title":"A phase 1 study of the irreversible FLT3 inhibitor FF-10101 in relapsed or refractory acute myeloid leukemia","volume":"8","author":"Levis","year":"2024","journal-title":"Blood Adv."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1182\/blood-2017-05-786657","article-title":"A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutations","volume":"131","author":"Yamaura","year":"2018","journal-title":"Blood"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1182\/bloodadvances.2018022921","article-title":"Role of CYP3A4 in bone marrow microenvironment-mediated protection of FLT3\/ITD AML from tyrosine kinase inhibitors","volume":"3","author":"Chang","year":"2019","journal-title":"Blood Adv."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1182\/blood-2015-05-646786","article-title":"All-trans retinoic acid synergizes with FLT3 inhibition to eliminate FLT3\/ITD+ leukemia stem cells in vitro and in vivo","volume":"127","author":"Ma","year":"2016","journal-title":"Blood"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"16121","DOI":"10.1073\/pnas.1305937110","article-title":"Regulation of human hematopoietic stem cell self-renewal by the microenvironment\u2019s control of retinoic acid signaling","volume":"110","author":"Ghiaur","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Su, M., Alonso, S., Jones, J.W., Yu, J., Kane, M.A., Jones, R.J., and Ghiaur, G. (2015). All-Trans Retinoic Acid Activity in Acute Myeloid Leukemia: Role of Cytochrome P450 Enzyme Expression by the Microenvironment. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0127790"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"e70191","DOI":"10.1002\/hem3.70191","article-title":"Arsenic trioxide for reprogramming the bone marrow microenvironment to eliminate acute myeloid leukemia blasts","volume":"9","author":"Kegyes","year":"2025","journal-title":"Hemasphere"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/21\/3415\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T08:58:39Z","timestamp":1761296319000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/21\/3415"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,23]]},"references-count":102,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["cancers17213415"],"URL":"https:\/\/doi.org\/10.3390\/cancers17213415","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,23]]}}}