{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T04:38:50Z","timestamp":1793335130902,"version":"4.5.0"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Ministry of Economy and Competitiveness | Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CM23\/00101"],"award-info":[{"award-number":["CM23\/00101"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["FU 356\/12-1"],"award-info":[{"award-number":["FU 356\/12-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["70115737"],"award-info":[{"award-number":["70115737"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:italic>NPM1<\/jats:italic>\n                    -mutated (\n                    <jats:italic>NPM1<\/jats:italic>\n                    -mut) acute myeloid leukemia (AML) is generally associated with a more favorable outcome, although the presence of additional gene mutations can influence patient prognosis. We analyzed intensively-treated adult\n                    <jats:italic>NPM1<\/jats:italic>\n                    -mut AML patients included in the HARMONY Alliance database. A newly developed risk classification, which included combinations of co-mutations in\n                    <jats:italic>FLT3<\/jats:italic>\n                    -ITD,\n                    <jats:italic>DNMT3A<\/jats:italic>\n                    ,\n                    <jats:italic>IDH1\/IDH2<\/jats:italic>\n                    , and\n                    <jats:italic>TET2<\/jats:italic>\n                    genes, was applied to a training cohort of\n                    <jats:italic>NPM1<\/jats:italic>\n                    -mut AML patients included in clinical trials (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20091001), an internal validation cohort more representative of real-world settings (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009762), and an external validation cohort enrolled in UK-NCRI trials (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009585). The HARMONY classification considered 51.8% of the\n                    <jats:italic>NPM1<\/jats:italic>\n                    -mut AML training cohort patients as favorable, 24.8% as intermediate, and 23.4% as adverse risk, with median overall survival (OS) of 14.4, 2.2, and 0.9 years, respectively;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001), thereby reclassifying 42.7% of\n                    <jats:italic>NPM1<\/jats:italic>\n                    -mut patients into a different European LeukemiaNet (ELN) 2022 risk category. These results were confirmed both in an internal and external validation cohort. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) showed the highest benefit in the\n                    <jats:italic>NPM1<\/jats:italic>\n                    -mut adverse-risk subgroup. The HARMONY classification provides the basis for a refined genetic risk stratification for adult\n                    <jats:italic>NPM1<\/jats:italic>\n                    -mut AML with potential clinical impact on allo-HSCT decision-making.\n                  <\/jats:p>","DOI":"10.1038\/s41375-025-02851-9","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T09:18:33Z","timestamp":1768382313000},"page":"418-428","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Unravelling co-mutational patterns with prognostic implications in NPM1 mutated adult acute myeloid leukemia \u2013 a HARMONY study"],"prefix":"10.1038","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6601-3096","authenticated-orcid":false,"given":"Alberto","family":"Hern\u00e1ndez-S\u00e1nchez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7337-7218","authenticated-orcid":false,"given":"\u00c1ngela","family":"Villaverde Ramiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Str\u00e4ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1347-3360","authenticated-orcid":false,"given":"Amin T.","family":"Turki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Ab\u00e1igar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2372-1663","authenticated-orcid":false,"given":"Jurjen","family":"Versluis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Sobas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5294-6162","authenticated-orcid":false,"given":"Javier","family":"Mart\u00ednez Elicegui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4892-925X","authenticated-orcid":false,"given":"Gastone","family":"Castellani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Benner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3382-3674","authenticated-orcid":false,"given":"Ra\u00fal","family":"Azibeiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0811-0824","authenticated-orcid":false,"given":"Jesse M.","family":"Tettero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9374-300X","authenticated-orcid":false,"given":"Rabea","family":"Mecklenbrauck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7908-0063","authenticated-orcid":false,"given":"Joaqu\u00edn","family":"Mart\u00ednez-L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Pratcorona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6362-4481","authenticated-orcid":false,"given":"Ken I.","family":"Mills","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2767-8191","authenticated-orcid":false,"given":"Guillermo","family":"Sanz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6164-4761","authenticated-orcid":false,"given":"Maria Teresa","family":"Voso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lehmann","family":"S\u00f6ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3791-0548","authenticated-orcid":false,"given":"Christoph","family":"R\u00f6llig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1241-2048","authenticated-orcid":false,"given":"Christian","family":"Thiede","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3920-7490","authenticated-orcid":false,"given":"Klaus H.","family":"Metzeler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2261-9862","authenticated-orcid":false,"given":"Konstanze","family":"D\u00f6hner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5318-9044","authenticated-orcid":false,"given":"Michael","family":"Heuser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0196-2837","authenticated-orcid":false,"given":"Torsten","family":"Haferlach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8857-9461","authenticated-orcid":false,"given":"Peter JM","family":"Valk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel","family":"Russell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9661-9371","authenticated-orcid":false,"given":"Jes\u00fas Mar\u00eda","family":"Hern\u00e1ndez-Rivas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0312-161X","authenticated-orcid":false,"given":"Brian","family":"Huntly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gert","family":"Ossenkoppele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2116-5536","authenticated-orcid":false,"given":"Hartmut","family":"D\u00f6hner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5890-5510","authenticated-orcid":false,"given":"Lars","family":"Bullinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,14]]},"reference":[{"key":"2851_CR1","doi-asserted-by":"publisher","first-page":"2209","DOI":"10.1056\/NEJMoa1516192","volume":"374","author":"E Papaemmanuil","year":"2016","unstructured":"Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209\u201321.","journal-title":"N Engl J Med"},{"key":"2851_CR2","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1182\/blood-2006-07-012252","volume":"109","author":"B Falini","year":"2007","unstructured":"Falini B, Nicoletti I, Martelli MF, Mecucci C. Acute myeloid leukemia carrying cytoplasmic\/mutated nucleophosmin (NPMc+ AML): Biologic and clinical features. Blood. 2007;109:874\u201385.","journal-title":"Blood"},{"key":"2851_CR3","doi-asserted-by":"publisher","first-page":"1200","DOI":"10.1182\/blood.2022015850","volume":"140","author":"DA Arber","year":"2022","unstructured":"Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140:1200\u201328.","journal-title":"Blood"},{"key":"2851_CR4","doi-asserted-by":"publisher","first-page":"1703","DOI":"10.1038\/s41375-022-01613-1","volume":"36","author":"JD Khoury","year":"2022","unstructured":"Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic\/Dendritic Neoplasms. Leukemia. 2022;36:1703\u201319.","journal-title":"Leukemia"},{"key":"2851_CR5","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1056\/NEJMoa041974","volume":"352","author":"B Falini","year":"2005","unstructured":"Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, et al. Cytoplasmic Nucleophosmin in Acute Myelogenous Leukemia with a Normal Karyotype. N Engl J Med. 2005;352:254\u201366.","journal-title":"N Engl J Med"},{"key":"2851_CR6","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1182\/blood.2022016867","volume":"140","author":"H D\u00f6hner","year":"2022","unstructured":"D\u00f6hner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140:1345\u201377.","journal-title":"Blood"},{"key":"2851_CR7","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1182\/blood.2024024310","volume":"144","author":"J Othman","year":"2024","unstructured":"Othman J, Potter N, Ivey A, Tazi Y, Papaemmanuil E, Jovanovic J, et al. Molecular, clinical, and therapeutic determinants of outcome in NPM1-mutated AML. Blood. 2024;144:714\u201328.","journal-title":"Blood"},{"key":"2851_CR8","doi-asserted-by":"publisher","first-page":"1488","DOI":"10.1038\/nm.4210","volume":"22","author":"OA Guryanova","year":"2016","unstructured":"Guryanova OA, Shank K, Spitzer B, Luciani L, Koche RP, Garrett-Bakelman FE, et al. DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nat Med. 2016;22:1488\u201395.","journal-title":"Nat Med"},{"key":"2851_CR9","doi-asserted-by":"publisher","first-page":"2072","DOI":"10.1200\/JCO.2014.59.2022","volume":"33","author":"RE Gale","year":"2015","unstructured":"Gale RE, Lamb K, Allen C, El-Sharkawi D, Stowe C, Jenkinson S, et al. Simpson\u2019s paradox and the impact of different DNMT3A mutations on outcome in younger adults with acute myeloid leukemia. J Clin Oncol. 2015;33:2072\u201383.","journal-title":"J Clin Oncol"},{"key":"2851_CR10","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1056\/NEJMoa1507471","volume":"374","author":"A Ivey","year":"2016","unstructured":"Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;374:422\u201333.","journal-title":"N Engl J Med"},{"key":"2851_CR11","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1200\/JCO.2016.71.2208","volume":"35","author":"L Bullinger","year":"2017","unstructured":"Bullinger L, D\u00f6hner K, Dohner H. Genomics of acute myeloid leukemia diagnosis and pathways. J Clin Oncol. 2017;35:934\u201346.","journal-title":"J Clin Oncol"},{"key":"2851_CR12","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1182\/bloodadvances.2020004136","volume":"6","author":"G O\u00f1ate","year":"2022","unstructured":"O\u00f1ate G, Bataller A, Garrido A, Hoyos M, Arnan M, Vives S, et al. Prognostic impact of DNMT3A mutation in acute myeloid leukemia with mutated NPM1. Blood Adv. 2022;6:882\u201390.","journal-title":"Blood Adv"},{"key":"2851_CR13","doi-asserted-by":"publisher","first-page":"2059","DOI":"10.1056\/NEJMoa1301689","volume":"368","author":"T Ley","year":"2013","unstructured":"Ley T, Miller C, Ding L, Raphael B, Mungall A, Robertson A, et al. Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia. N Engl J Med. 2013;368:2059\u201374.","journal-title":"N Engl J Med"},{"key":"2851_CR14","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1182\/blood.2019003339","volume":"135","author":"MF Bezerra","year":"2020","unstructured":"Bezerra MF, Lima AS, Piqu\u00e9-Borr\u00e0s MR, Silveira DR, Coelho-Silva JL, Pereira-Martins DA, et al. Co-occurrence of DNMT3A, NPM1, FLT3 mutations identifies a subset of acute myeloid leukemia with adverse prognosis. Blood. 2020;135:870\u20135.","journal-title":"Blood"},{"key":"2851_CR15","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1182\/blood.2018862383","volume":"134","author":"S Garg","year":"2019","unstructured":"Garg S, Reyes-Palomares A, He L, Bergeron A, Lavall\u00e9e VP, Lemieux S, et al. Hepatic leukemia factor is a novel leukemic stem cell regulator in DNMT3A, NPM1, and FLT3-ITD triple-mutated AML. Blood. 2019;134:263\u201376.","journal-title":"Blood"},{"key":"2851_CR16","doi-asserted-by":"publisher","first-page":"1707","DOI":"10.1182\/blood.2019004226","volume":"136","author":"B Falini","year":"2020","unstructured":"Falini B, Brunetti L, Sportoletti P, Paola Martelli M. NPM1-mutated acute myeloid leukemia: From bench to bedside. Blood. 2020;136:1707\u201321.","journal-title":"Blood"},{"key":"2851_CR17","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1200\/JCO.2016.67.1875","volume":"35","author":"M Balsat","year":"2017","unstructured":"Balsat M, Renneville A, Thomas X, De Botton S, Caillot D, Marceau A, et al. Postinduction minimal residual disease predicts outcome and benefit from allogeneic stem cell transplantation in acute myeloid leukemia with NPM1 mutation: A study by the acute leukemia French association group. J Clin Oncol. 2017;35:185\u201393.","journal-title":"J Clin Oncol"},{"key":"2851_CR18","doi-asserted-by":"publisher","first-page":"2632","DOI":"10.1200\/JCO.19.00416","volume":"37","author":"L Angenendt","year":"2019","unstructured":"Angenendt L, R\u00f6llig C, Montesinos P, Mart\u00ednez-Cuadr\u00f3n D, Barragan E, Garc\u00eda R, et al. Chromosomal abnormalities and prognosis in NPM1-mutated acute myeloid leukemia: A pooled analysis of individual patient data from nine international cohorts. J Clin Oncol. 2019;37:2632\u201342.","journal-title":"J Clin Oncol"},{"key":"2851_CR19","doi-asserted-by":"publisher","first-page":"3024","DOI":"10.1182\/blood-2009-01-197871","volume":"114","author":"C Haferlach","year":"2009","unstructured":"Haferlach C, Mecucci C, Schnittger S, Kohlmann A, Mancini M, Cuneo A, et al. AML with mutated NPM1 carrying a normal or aberrant karyotype show overlapping biologic, pathologic, immunophenotypic, and prognostic features. Blood. 2009;114:3024\u201332.","journal-title":"Blood"},{"key":"2851_CR20","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1002\/ajh.27187","volume":"99","author":"N Moukalled","year":"2024","unstructured":"Moukalled N, Labopin M, Versluis J, Soci\u00e9 G, Blaise D, Salmenniemi U, et al. Complex karyotype but not other cytogenetic abnormalities is associated with worse posttransplant survival of patients with nucleophosmin 1-mutated acute myeloid leukemia: A study from the European Society for Blood and Marrow Transplantation Acute Leukem. Am J Hematol. 2024;99:360\u20139.","journal-title":"Am J Hematol"},{"key":"2851_CR21","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1182\/blood.2022018108","volume":"141","author":"J Othman","year":"2023","unstructured":"Othman J, Meggendorfer M, Tiacci E, Thiede C, Schlenk R, Dillon R, et al. Overlapping features of therapy-related and de novo NPM1-mutated AML. Blood. 2023;141:8\u201310.","journal-title":"Blood"},{"key":"2851_CR22","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1182\/blood.2022018582","volume":"141","author":"L Angenendt","year":"2023","unstructured":"Angenendt L, R\u00f6llig C, Montesinos P, Ravandi F, Juliusson G, R\u00e9cher C, et al. Revisiting coexisting chromosomal abnormalities in NPM1-mutated AML in light of the revised ELN 2022 classification. Blood. 2023;141:433\u20135.","journal-title":"Blood"},{"key":"2851_CR23","doi-asserted-by":"publisher","first-page":"3322","DOI":"10.1182\/bloodadvances.2019000328","volume":"3","author":"EF Mason","year":"2019","unstructured":"Mason EF, Hasserjian RP, Aggarwal N, Seegmiller AC, Pozdnyakova O. Blast phenotype and comutations in acute myeloid leukemia with mutated NPM1 influence disease biology and outcome. Blood Adv. 2019;3:3322\u201332.","journal-title":"Blood Adv"},{"key":"2851_CR24","first-page":"1","volume":"21","author":"B Wang","year":"2021","unstructured":"Wang B, Yang B, Wu W, Liu X, Li H. The correlation of next-generation sequencing-based genotypic profiles with clinicopathologic characteristics in NPM1-mutated acute myeloid leukemia. BMC Cancer. 2021;21:1\u201311.","journal-title":"BMC Cancer"},{"key":"2851_CR25","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.1182\/blood-2016-10-740613","volume":"129","author":"B L\u00f6wenberg","year":"2017","unstructured":"L\u00f6wenberg B, Pabst T, Maertens J, Van Norden Y, Biemond BJ, Schouten HC, et al. Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML. Blood. 2017;129:1636\u201345.","journal-title":"Blood"},{"key":"2851_CR26","doi-asserted-by":"publisher","first-page":"1751","DOI":"10.1038\/s41375-020-0725-0","volume":"34","author":"GJ Ossenkoppele","year":"2020","unstructured":"Ossenkoppele GJ, Breems DA, Stuessi G, van Norden Y, Bargetzi M, Biemond BJ, et al. Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS. Leukemia. 2020;34:1751\u20139.","journal-title":"Leukemia"},{"key":"2851_CR27","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1182\/bloodadvances.2020003855","volume":"5","author":"B L\u00f6wenberg","year":"2021","unstructured":"L\u00f6wenberg B, Pabst T, Maertens J, Gradowska P, Biemond BJ, Spertini O, et al. Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: The HOVON-SAKK-132 trial. Blood Adv. 2021;5:1110\u201321.","journal-title":"Blood Adv"},{"key":"2851_CR28","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1182\/blood-2016-01-693879","volume":"128","author":"KH Metzeler","year":"2016","unstructured":"Metzeler KH, Herold T, Rothenberg-Thurley M, Amler S, Sauerland MC, G\u00f6rlich D, et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood. 2016;128:686\u201398.","journal-title":"Blood"},{"key":"2851_CR29","first-page":"12","volume":"5","author":"R Belenkaya","year":"2021","unstructured":"Belenkaya R, Gurley MJ, Golozar A, Dymshyts D, Miller RT, Williams AE, et al. Extending the OMOP Common Data Model and Standardized Vocabularies to Support Observational Cancer Research. JCO Clin Cancer Inf. 2021;5:12\u201320.","journal-title":"JCO Clin Cancer Inf"},{"key":"2851_CR30","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.1182\/bloodadvances.2021004934","volume":"6","author":"JM Middeke","year":"2022","unstructured":"Middeke JM, Metzeler KH, Rollig C, Kramer M, Eckardt JN, Stasik S, et al. Differential impact of IDH1\/2 mutational subclasses on outcome in adult AML: results from a large multicenter study. Blood Adv. 2022;6:1394\u2013405.","journal-title":"Blood Adv"},{"key":"2851_CR31","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32103-8","volume":"13","author":"Y Tazi","year":"2022","unstructured":"Tazi Y, Arango-Ossa JE, Zhou Y, Bernard E, Thomas I, Gilkes A, et al. Unified classification and risk-stratification in Acute Myeloid Leukemia. Nat Commun. 2022;13:4622.","journal-title":"Nat Commun"},{"key":"2851_CR32","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1111\/1467-9868.00346","volume":"64","author":"JD Storey","year":"2002","unstructured":"Storey JD. A direct approach to false discovery rates. J R Stat Soc Ser B Stat Methodol. 2002;64:479\u201398.","journal-title":"J R Stat Soc Ser B Stat Methodol"},{"key":"2851_CR33","doi-asserted-by":"publisher","first-page":"3733","DOI":"10.1182\/blood-2005-06-2248","volume":"106","author":"S Schnittger","year":"2005","unstructured":"Schnittger S, Schoch C, Kern W, Mecucci C, Tschulik C, Martelli MF, et al. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood. 2005;106:3733\u20139.","journal-title":"Blood"},{"key":"2851_CR34","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1182\/blood-2009-07-235358","volume":"115","author":"H D\u00f6hner","year":"2010","unstructured":"D\u00f6hner H, Estey EH, Amadori S, Appelbaum FR, B\u00fcchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: Recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115:453\u201374.","journal-title":"Blood"},{"key":"2851_CR35","doi-asserted-by":"publisher","first-page":"3740","DOI":"10.1182\/blood-2005-05-2164","volume":"106","author":"K D\u00f6hner","year":"2005","unstructured":"D\u00f6hner K, Schlenk RF, Habdank M, Scholl C, R\u00fccker FG, Corbacioglu A, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: Interaction with other gene mutations. Blood. 2005;106:3740\u20136.","journal-title":"Blood"},{"key":"2851_CR36","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1182\/blood-2017-09-807438","volume":"131","author":"J Straube","year":"2018","unstructured":"Straube J, Ling VY, Hill GR, Lane SW. The impact of age, NPM1mut, and FLT3ITD allelic ratio in patients with acute myeloid leukemia. Blood. 2018;131:1148\u201353.","journal-title":"Blood"},{"key":"2851_CR37","doi-asserted-by":"publisher","first-page":"3636","DOI":"10.1200\/JCO.2010.28.3762","volume":"28","author":"P Paschka","year":"2010","unstructured":"Paschka P, Schlenk RF, Gaidzik VI, Habdank M, Kr\u00f6nke J, Bullinger L, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol. 2010;28:3636\u201343.","journal-title":"J Clin Oncol"},{"key":"2851_CR38","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1038\/s41375-020-0920-z","volume":"35","author":"M Alfayez","year":"2021","unstructured":"Alfayez M, Issa GC, Patel KP, Wang F, Wang X, Short NJ, et al. The Clinical impact of PTPN11 mutations in adults with acute myeloid leukemia. Leukemia. 2021;35:691\u2013700.","journal-title":"Leukemia"},{"key":"2851_CR39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-019-09745-2","volume":"10","author":"S Cocciardi","year":"2019","unstructured":"Cocciardi S, Dolnik A, Kapp-Schwoerer S, R\u00fccker FG, Lux S, Bl\u00e4tte TJ, et al. Clonal evolution patterns in acute myeloid leukemia with NPM1 mutation. Nat Commun. 2019;10:1\u201311.","journal-title":"Nat Commun"},{"key":"2851_CR40","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1007\/s12185-013-1407-8","volume":"98","author":"SM Chan","year":"2013","unstructured":"Chan SM, Majeti R. Role of DNMT3A, TET2, and IDH1\/2 mutations in pre-leukemic stem cells in acute myeloid leukemia. Int J Hematol. 2013;98:648\u201357.","journal-title":"Int J Hematol"},{"key":"2851_CR41","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1158\/2159-8290.CD-16-1032","volume":"7","author":"JL Glass","year":"2017","unstructured":"Glass JL, Hassane D, Wouters BJ, Kunimoto H, Avellino R, Garrett-Bakelman FE, et al. Epigenetic identity in AML depends on disruption of nonpromoter regulatory elements and is affected by antagonistic effects of mutations in epigenetic modifiers. Cancer Discov. 2017;7:868\u201383.","journal-title":"Cancer Discov"},{"key":"2851_CR42","doi-asserted-by":"publisher","first-page":"2282","DOI":"10.1038\/s41375-023-02016-6","volume":"37","author":"JN Eckardt","year":"2023","unstructured":"Eckardt JN, Bill M, Rausch C, Metzeler K, Spiekermann K, Stasik S, et al. Secondary-type mutations do not impact outcome in NPM1-mutated acute myeloid leukemia \u2013 implications for the European LeukemiaNet risk classification. Leukemia. 2023;37:2282\u20135.","journal-title":"Leukemia"},{"key":"2851_CR43","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1182\/bloodadvances.2023011173","volume":"8","author":"O Chan","year":"2024","unstructured":"Chan O, Al Ali N, Tashkandi H, Ellis A, Ball S, Grenet J, et al. Mutations highly specific for secondary AML are associated with poor outcomes in ELN favorable risk NPM1-mutated AML. Blood Adv. 2024;8:1075\u201383.","journal-title":"Blood Adv"},{"key":"2851_CR44","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1038\/s41586-018-0623-z","volume":"562","author":"JW Tyner","year":"2018","unstructured":"Tyner JW, Tognon CE, Bottomly D, Wilmot B, Kurtz SE, Savage SL, et al. Functional genomic landscape of acute myeloid leukaemia. Nature. 2018;562:526\u201331.","journal-title":"Nature"},{"key":"2851_CR45","first-page":"1095","volume":"109","author":"S Park","year":"2024","unstructured":"Park S, Kim TY, Cho BS, Kwag D, Lee JM, Kim M, et al. Prognostic value of European LeukemiaNet 2022 criteria and genomic clusters using machine learning in older adults with acute myeloid leukemia. Haematologica. 2024;109:1095\u2013106.","journal-title":"Haematologica"},{"key":"2851_CR46","doi-asserted-by":"publisher","first-page":"4084","DOI":"10.1200\/JCO.23.02631","volume":"42","author":"J Versluis","year":"2024","unstructured":"Versluis J, Metzner M, Wang A, Gradowska P, Thomas A, Jakobsen NA, et al. Risk Stratification in Older Intensively Treated Patients With AML. J Clin Oncol. 2024;42:4084\u201394.","journal-title":"J Clin Oncol"},{"key":"2851_CR47","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1056\/NEJMoa1614359","volume":"377","author":"RM Stone","year":"2017","unstructured":"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;377:454\u201364.","journal-title":"N Engl J Med"},{"key":"2851_CR48","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-023-00839-1","volume":"13","author":"G O\u00f1ate","year":"2023","unstructured":"O\u00f1ate G, Pratcorona M, Garrido A, Artigas-Baleri A, Bataller A, Tormo M, et al. Survival improvement of patients with FLT3 mutated acute myeloid leukemia: results from a prospective 9 years cohort. Blood Cancer J. 2023;13:69.","journal-title":"Blood Cancer J"},{"key":"2851_CR49","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1200\/JCO.19.01406","volume":"38","author":"RF Schlenk","year":"2020","unstructured":"Schlenk RF, Paschka P, Krzykalla J, Weber D, Kapp-Schwoerer S, Gaidzik VI, et al. Gemtuzumab ozogamicin in NPM1-mutated acute myeloid leukemia: Early results from the prospective randomized AMLSG 09-09 Phase III study. J Clin Oncol. 2020;38:623\u201332.","journal-title":"J Clin Oncol"},{"key":"2851_CR50","doi-asserted-by":"publisher","first-page":"3041","DOI":"10.1182\/blood.2020005998","volume":"136","author":"S Kapp-Schwoerer","year":"2020","unstructured":"Kapp-Schwoerer S, Weber D, Corbacioglu A, Gaidzik VI, Paschka P, Kr\u00f6nke J, et al. Impact of gemtuzumab ozogamicin on MRD and relapse risk in patients with NPM1-mutated AML: Results from the AMLSG 09-09 trial. Blood. 2020;136:3041\u201350.","journal-title":"Blood"},{"key":"2851_CR51","doi-asserted-by":"publisher","first-page":"1931","DOI":"10.1182\/blood.2023023096","volume":"143","author":"J Othman","year":"2024","unstructured":"Othman J, Potter N, Ivey A, Jovanovic J, Runglall M, Freeman SD, et al. Postinduction molecular MRD identifies patients with NPM1 AML who benefit from allogeneic transplant in first remission. Blood. 2024;143:1931\u20136.","journal-title":"Blood"},{"key":"2851_CR52","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1200\/JCO.23.00943","volume":"42","author":"NH Russell","year":"2024","unstructured":"Russell NH, Wilhelm-Benartzi C, Othman J, Dillon R, Knapper S, Batten LM, et al. Fludarabine, Cytarabine, Granulocyte Colony-Stimulating Factor, and Idarubicin With Gemtuzumab Ozogamicin Improves Event-Free Survival in Younger Patients With Newly Diagnosed AML and Overall Survival in Patients With NPM1 and FLT3 Mutations. J Clin Oncol. 2024;42:1158\u201368.","journal-title":"J Clin Oncol"},{"key":"2851_CR53","doi-asserted-by":"publisher","DOI":"10.1002\/hem3.70060","volume":"9","author":"S Cocciardi","year":"2025","unstructured":"Cocciardi S, Saadati M, Wei\u00df N, Sp\u00e4th D, Kapp-Schwoerer S, Schneider I, et al. Impact of myelodysplasia-related and additional gene mutations in intensively treated patients with NPM1-mutated AML. Hemasphere. 2025;9:e70060.","journal-title":"Hemasphere"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02851-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02851-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02851-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T08:03:16Z","timestamp":1770278596000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02851-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,14]]},"references-count":53,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["2851"],"URL":"https:\/\/doi.org\/10.1038\/s41375-025-02851-9","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,14]]},"assertion":[{"value":"24 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 November 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 December 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 January 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"ATT: Consultancy for CSL Behring, Maat Pharma, Biomarin, and Onkowissen; travel reimbursements from Neovii Biotech and Novartis. MS: honoraria from Novartis, Celgene, AOP Orphan, and AbbVie. KHM: honoraria from AbbVie, Bristol Myers Squibb, Celgene, Janssen, Novartis, Pfizer, Otsuka; research funding from AbbVie. RA: honoraria from Astellas, Bristol Myers Squibb, Incyte, and Novartis. MP: honoraria from Novartis. GS: honoraria from Takeda and has participated in Ad-Boards from Novartis, Celgene, AbbVie, Helsinn, and Takeda. CR: honoraria from AbbVie, Astellas, Bristol-Meyer-Squibb, Daiichi Sankyo, Jazz, Janssen, Novartis, Otsuka, Pfizer, Servier; institutional research funding from AbbVie, Astellas, Novartis, Pfizer. CT: co-owner and CEO of AgenDix GmbH and has received lecture fees and\/or participated in Ad-Boards from Novartis, Jazz Pharmaceuticals, Astellas, Janssen, Illumina; research funding from Novartis, Bayer. KD: honoraria from Novartis, Jazz Pharmaceuticals, AbbVie; has participated in Ad-Boards from Novartis, Bristol Myers Squibb, Jazz Pharmaceuticals, AbbVie; research funding from Novartis, Astellas, Agios, Bristol Myers Squibb, Kronos. MH: honoraria from Astellas, Daiichi Sankyo, Janssen, Miltenyi, Otsuka, Qiagen, Servier, and has participated in Ad-Boards from AbbVie, AvenCell, Ascentage Pharma, Bristol Myers Squibb, Janssen, Jazz Pharmaceuticals, LabDelbert, Novartis, Pfizer, Servier; research funding from AbbVie, Bayer Pharma AG, Jazz Pharmaceuticals, Glycostem, Karyopharm, PinotBio, Servier, Toray. TH: current employment at Munich Leukemia Laboratory, with part ownership. JMHR: honoraria from Bristol Myers Squibb, Pfizer, Amgen, Celgene, GSK, Novartis; Advisory role for Bristol Myers Squibb, Pfizer, Amgen, Celgene, Novartis, Janssen, Roche, AbbVie, AstraZeneca, Beigene, Lilly, Gilead, Takeda, Jazz Pharmaceuticals, Rovi, Incyte; research funding from Bristol Myers Squibb, Celgene, Novartis. BH: honoraria from Pfizer, Bristol Myers Squibb, Novartis; research funding from AstraZeneca. GO: honoraria from AbbVie, Jazz Pharmaceuticals, Astellas, Gilead, Bristol Myers Squibb, Servier, Roche. HD: Advisory role for AbbVie, Agios, Amgen, Astellas, AstraZeneca, BERLIN-CHEMIE, Bristol Myers Squibb, Celgene, GEMoaB, Gilead Sciences, Janssen, Jazz Pharmaceuticals, Novartis, Syndax; research funding from AbbVie, Agios, Amgen, Astellas, Bristol Myers Squibb, Jazz Pharmaceuticals, Kronos-Bio, Novartis. LB: honoraria from AbbVie, Amgen, Astellas, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Otsuka, Pfizer, Roche, and Sanofi; research funding from Bayer, Jazz Pharmaceuticals.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}