{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T02:56:58Z","timestamp":1781233018741,"version":"3.54.1"},"reference-count":43,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous hematologic malignancy in which intensive induction chemotherapy remains the standard therapeutic platform for medically fit adults. In recent years, however, the frontline treatment paradigm has progressively evolved from a purely cytotoxic approach toward a biologically informed strategy. This shift has been driven by the identification of recurrent molecular alterations\u2014particularly FLT3 and IDH1\/2 mutations\u2014as well as renewed interest in antibody-based therapies and the growing recognition that relapse, resistance, and measurable residual disease (MRD) are shaped by clonal architecture rather than blast burden alone. This review examines the development of targeted therapies combined with intensive chemotherapy in AML. We discuss the biological rationale for combination approaches and summarize the key clinical studies that have defined current practice, including trials evaluating FLT3 inhibitors, gemtuzumab ozogamicin, IDH inhibitors, and venetoclax-based strategies. We also address the role of targeted therapy across different treatment phases, including induction, consolidation, and post-remission settings, and analyze emerging data regarding MRD-guided treatment strategies, mechanisms of resistance, and integration with allogeneic hematopoietic stem cell transplantation. The integration of targeted agents with intensive chemotherapy is reshaping frontline AML therapy and represents a critical step toward precision medicine. While genotype-directed strategies\u2014such as FLT3 inhibition\u2014have already demonstrated survival benefit, optimal patient selection, treatment sequencing, and duration remain areas of active investigation. Future progress will likely depend on MRD-driven treatment adaptation, improved understanding of clonal evolution, and the development of rational multi-agent combinations capable of achieving deeper and more durable remissions.<\/jats:p>","DOI":"10.3390\/jcm15124529","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T01:52:08Z","timestamp":1781229128000},"page":"4529","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeted Therapies Combined with Intensive Chemotherapy in Fit Acute Myeloid Leukemia: Past Developments, Current Evidence, and Future Therapeutic Paradigms"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6391-4406","authenticated-orcid":false,"given":"Matteo","family":"Molica","sequence":"first","affiliation":[{"name":"Department of Hematology-Oncology, Azienda Ospedaliera Renato Dulbecco, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9280-2023","authenticated-orcid":false,"given":"Laura","family":"De Fazio","sequence":"additional","affiliation":[{"name":"Department of Hematology-Oncology, Azienda Ospedaliera Renato Dulbecco, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Simio","sequence":"additional","affiliation":[{"name":"Department of Hematology-Oncology, Azienda Ospedaliera Renato Dulbecco, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Alati","sequence":"additional","affiliation":[{"name":"Hematology and Stem Cell Transplantation and Cellular Rerapies Unit (CTMO), Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano \u201cBianchi-Melacrino-Morelli\u201d, Presidio Morelli, 89121 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3987-419X","authenticated-orcid":false,"given":"Massimo","family":"Martino","sequence":"additional","affiliation":[{"name":"Hematology and Stem Cell Transplantation and Cellular Rerapies Unit (CTMO), Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano \u201cBianchi-Melacrino-Morelli\u201d, Presidio Morelli, 89121 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7258-475X","authenticated-orcid":false,"given":"Marco","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Hematology-Oncology, Azienda Ospedaliera Renato Dulbecco, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"ref_1","first-page":"485","article-title":"Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia","volume":"57","author":"Yates","year":"1973","journal-title":"Cancer Chemother. 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