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The loss of functional p53 compromises DNA repair, apoptosis, and genomic stability, rendering both conventional and novel therapies largely ineffective. This review evaluates the efficacy of various treatment approaches, including intensive chemotherapy (IC), hypomethylating agents (HMAs), venetoclax\u2010based regimens, and immune checkpoint inhibitors. Additionally, we discuss emerging strategies such as p53 reactivation, multi\u2010targeted inhibition, and novel immunotherapies, including bispecific T\u2010cell engagers (BiTEs) and CAR\u2010T cell therapy. Current treatment options provide limited benefits in\n                    <jats:italic>TP53<\/jats:italic>\n                    \u2010mutated AML, with complete remission rates ranging from 13% to 46% and median overall survival of only 6.1\u20136.5\u00a0months. Allogeneic stem cell transplantation (allo\u2010SCT) offers minimal survival advantage due to high relapse rates. Despite promising preclinical data, checkpoint inhibitors and TIM\u20103 blockade have failed to demonstrate significant clinical efficacy, likely due to the immunosuppressive tumor microenvironment. Novel approaches, such as APR\u2010246 (eprenetapopt) and MCL\u20101\/CHK1 inhibitors, are under investigation, but their therapeutic impact remains uncertain. The failure of single\u2010agent therapies underscores the need for combination strategies targeting multiple resistance mechanisms. Future research should focus on integrating targeted inhibitors with immunotherapy and bone marrow microenvironment modifiers. While\n                    <jats:italic>TP53<\/jats:italic>\n                    \u2010mutated AML remains a formidable challenge, ongoing advances in precision medicine and immunotherapy hold the potential to improve patient outcomes.\n                  <\/jats:p>","DOI":"10.1002\/hon.70106","type":"journal-article","created":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T07:35:39Z","timestamp":1748936139000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["<i>TP53<\/i>\n                    \u2010Mutated Acute Myeloid Leukemia: Unanswered Questions"],"prefix":"10.1002","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9456-2404","authenticated-orcid":false,"given":"Antonella","family":"Bruzzese","sequence":"first","affiliation":[{"name":"Hematology Unit Department of Onco\u2010Hematology AO of Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Vigna","sequence":"additional","affiliation":[{"name":"Hematology Unit Department of Onco\u2010Hematology AO of Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrica Antonia","family":"Martino","sequence":"additional","affiliation":[{"name":"Hematology Unit Department of Onco\u2010Hematology AO of Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Labanca","sequence":"additional","affiliation":[{"name":"Hematology Unit Department of Onco\u2010Hematology AO of Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Carid\u00e0","sequence":"additional","affiliation":[{"name":"Hematology Unit Department of Onco\u2010Hematology AO of Cosenza  Cosenza Italy"},{"name":"Department of Experimental and Clinical Medicine University of Catanzaro  Catanzaro Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6339-632X","authenticated-orcid":false,"given":"Francesco","family":"Mendicino","sequence":"additional","affiliation":[{"name":"Hematology Unit Department of Onco\u2010Hematology AO of Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenio","family":"Lucia","sequence":"additional","affiliation":[{"name":"Hematology Unit Department of Onco\u2010Hematology AO of Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Olivito","sequence":"additional","affiliation":[{"name":"Hematology Unit Department of Onco\u2010Hematology AO of Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noemi","family":"Puccio","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Reserach Azienda USL\u2010IRCSS di Reggio Emilia  Reggio Emilia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonino","family":"Neri","sequence":"additional","affiliation":[{"name":"Scientific Directorate Azienda USL\u2010IRCCS di Reggio Emilia  Reggio Emilia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fortunato","family":"Morabito","sequence":"additional","affiliation":[{"name":"Gruppo Amici Dell'Ematologia Foundation\u2010GrADE  Reggio Emilia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Gentile","sequence":"additional","affiliation":[{"name":"Hematology Unit Department of Onco\u2010Hematology AO of Cosenza  Cosenza Italy"},{"name":"Department of Pharmacy Health and Nutritional Science University of Calabria  Rende Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,3]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102010\u201005\u2010282632"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102011\u201004\u2010347872"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022015850"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375\u2010022\u201001613\u20101"},{"key":"e_1_2_11_6_1","unstructured":"National Cancer Institute.Surveillance Epidemiology and End Results Program (SEER). 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