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A curative intent for R\/R AML usually involves chemotherapy (with or without targeted therapy) with subsequent consolidation, including allogeneic haematopoietic stem cell transplantation. Despite this, long\u2010term survival rates of R\/R AML only reach approximately 10% in adults and 40% in children. Given this great unmet clinical need, this review outlines the current and emerging paradigms for preventing and treating R\/R AML. Somatic mutations, gene expression, and functional drug testing are important for the selection of small molecule inhibitors of oncogenic signalling pathways (e.g., FLT3), menin inhibitors that disrupt leukemogenic programmes, inhibitors of isocitrate dehydrogenases to restore oncometabolic homoeostasis, and proapoptotic Bcl\u20102 homology 3 (BH3) mimetics, such as venetoclax. Targeting the recently identified resistance factor SAMHD1 promises to overcome resistance to cytarabine and fludarabine. Given the growing number of potential combinatorial drug regimens and the genetic heterogeneity of AML, real\u2010time\n                    <jats:italic>ex vivo<\/jats:italic>\n                    drug response profiling to guide individualized treatment decisions will become an important complement. We argue that better outcomes for R\/R AML critically depend on being guided by precision oncology to define the best combination of chemotherapy, targeted therapy, and immunological therapy informed by phenotypic and genotypic patient\u2010 and disease\u2010specific parameters.\n                  <\/jats:p>","DOI":"10.1111\/joim.70004","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T09:26:26Z","timestamp":1754645186000},"page":"297-318","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Precision oncology to overcome resistance in R\/R AML in children and adults requires combinations of cytotoxic, targeted, and immunological treatments"],"prefix":"10.1111","volume":"298","author":[{"given":"Martin","family":"J\u00e4dersten","sequence":"first","affiliation":[{"name":"Department of Hematology Karolinska University Hospital  Stockholm Sweden"},{"name":"Department of Medicine, Center 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