{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:06:10Z","timestamp":1790877970375,"version":"4.1.0"},"reference-count":24,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    The combination of azacitidine and venetoclax (Aza\/Ven) is an effective treatment for acute myeloid leukemia (AML); however, biological factors underlying heterogeneous treatment responses across diverse genetic backgrounds remain incompletely defined. We analyzed 97 AML patients treated with Aza\/Ven in the prospective HM-SCREEN-Japan 02 study using targeted next-generation sequencing (NGS) of 53 genes, cytogenetic analyses, and clinical variables. Somatic mutations were categorized into type 1 (\n                    <jats:italic>FLT3, PTPN11, WT1, IDH1\/2, NPM1, NRAS<\/jats:italic>\n                    ) and type 2 (\n                    <jats:italic>GATA2, KRAS, TP53, RUNX1, STAG2, ASXL1, ZRSR2, TET2<\/jats:italic>\n                    ) groups based on a previously proposed framework describing clonal characteristics. Complete remission (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 53.8%, 52.1%, and 50.0% of patients treated in the first-, second-, and \u2265third-line settings, respectively. Among 53 first-line patients with pre-treatment NGS data, type 1\u2013only mutations were more frequently observed in responders (CR\/CRi 72%), whereas type 2\u2013only mutations were enriched in non-responders (CR\/CRi 33%). In the first-line setting, achievement of CR\/CRi following Aza\/Ven was associated with improved overall survival. In addition, an exploratory mathematical model integrating baseline clinical variables demonstrated strong discriminatory performance for treatment response, including in cases without established prognostic mutations. In conclusion, Aza\/Ven demonstrated consistent clinical activity across treatment lines in this real-world cohort. Mutational patterns classified by a type 1\/type 2 framework were associated with differential response patterns in the first-line setting. Integrative modeling approaches may support the interpretation of response heterogeneity, particularly in genetically uninformative AML.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0357898","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:37:17Z","timestamp":1790876237000},"page":"e0357898","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genomic and clinical determinants of response to Azacitidine plus venetoclax in acute myeloid leukemia: Results from the HM-SCREEN-Japan 02 study"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8806-5498","authenticated-orcid":true,"given":"Tomoaki","family":"Ueda","sequence":"first","affiliation":[{"name":"The University of Osaka Graduate School of Medicine","place":["Suita, Osaka, Japan"],"department":["Department of Hematology and Oncology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Fukushima","sequence":"additional","affiliation":[{"name":"The University of Osaka Graduate School of Medicine","place":["Suita, Osaka, Japan"],"department":["Department of Hematology and Oncology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunggi","family":"Chi","sequence":"additional","affiliation":[{"name":"National Cancer Center Hospital East","place":["Kashiwa, Chiba, Japan"],"department":["Department of Hematology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Haeno","sequence":"additional","affiliation":[{"name":"Tokyo University of Science","place":["Noda, Chiba, Japan"],"department":["Division of Integrated Research Research Institute for Biomedical Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goichi","family":"Yoshimoto","sequence":"additional","affiliation":[{"name":"Saga-ken Medical Centre Koseikan","place":["Kasemachi, Saga, Japan"],"department":["Department of Hematology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironori","family":"Arai","sequence":"additional","affiliation":[{"name":"Japanese Red Cross Narita Hospital","place":["Narita, Chiba, Japan"],"department":["Division of Hematology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences","place":["Kita-ku, Okayama, Japan"],"department":["Department of Hematology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoshi","family":"Ichikawa","sequence":"additional","affiliation":[{"name":"NTT Medical Center Tokyo","place":["Shinagawa-ku, Tokyo, Japan"],"department":["Department of Hematology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Nephrology and Rheumatology, Akita University Graduate School of Medicine","place":["Hondo, Akita, Japan"],"department":["Department of Hematology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoko","family":"Hosono","sequence":"additional","affiliation":[{"name":"University of Fukui","place":["Yoshida-gun, Fukui, Japan"],"department":["Department of Hematology and Oncology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"University of Fukui","place":["Yoshida-gun, Fukui, Japan"],"department":["Department of Hematology and Oncology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Kondo","sequence":"additional","affiliation":[{"name":"Blood Disorders Center, Aiiku Hospital","place":["Sapporo, Hokkaido, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Kusumoto","sequence":"additional","affiliation":[{"name":"Aichi Cancer Center","place":["Chikusa-ku, Nagoya, Japan"],"department":["Department of Hematology and Cell Therapy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junya","family":"Kuroda","sequence":"additional","affiliation":[{"name":"Kyoto Prefectural University of Medicine","place":["Kamigyo-ku, Kyoto, Japan"],"department":["Division of Hematology and Oncology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0863-0739","authenticated-orcid":true,"given":"Yosuke","family":"Minami","sequence":"additional","affiliation":[{"name":"National Cancer Center Hospital East","place":["Kashiwa, Chiba, Japan"],"department":["Department of Hematology"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"issue":"4","key":"pone.0357898.ref001","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1200\/JCO.2009.23.8329","article-title":"Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia","volume":"28","author":"P Fenaux","year":"2010","journal-title":"J Clin Oncol"},{"issue":"3","key":"pone.0357898.ref002","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1182\/blood-2015-01-621664","article-title":"International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts","volume":"126","author":"H Dombret","year":"2015","journal-title":"Blood"},{"issue":"5","key":"pone.0357898.ref003","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.ccr.2006.10.006","article-title":"Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia","volume":"10","author":"M Konopleva","year":"2006","journal-title":"Cancer Cell"},{"issue":"7","key":"pone.0357898.ref004","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1056\/NEJMoa2012971","article-title":"Azacitidine and venetoclax in previously untreated acute myeloid leukemia","volume":"383","author":"CD DiNardo","year":"2020","journal-title":"N Engl J Med"},{"issue":"5","key":"pone.0357898.ref005","doi-asserted-by":"crossref","DOI":"10.1016\/j.ccell.2018.10.005","article-title":"Inhibition of amino acid metabolism selectively targets human leukemia stem cells","volume":"34","author":"CL Jones","year":"2018","journal-title":"Cancer Cell"},{"issue":"12","key":"pone.0357898.ref006","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1038\/s41591-018-0233-1","article-title":"Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia","volume":"24","author":"DA Pollyea","year":"2018","journal-title":"Nat Med"},{"issue":"24","key":"pone.0357898.ref007","doi-asserted-by":"crossref","first-page":"5565","DOI":"10.1182\/bloodadvances.2021005538","article-title":"Venetoclax and azacitidine compared with induction chemotherapy for newly diagnosed patients with acute myeloid leukemia","volume":"5","author":"EM Cherry","year":"2021","journal-title":"Blood Adv"},{"issue":"10","key":"pone.0357898.ref008","first-page":"694","article-title":"Outcomes are similar after allogeneic hematopoietic stem cell transplant for newly diagnosed acute myeloid leukemia patients who received venetoclax + azacitidine versus intensive chemotherapy","volume":"28","author":"AC Winters","journal-title":"Transp Cellular Ther"},{"issue":"2","key":"pone.0357898.ref009","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/ng.3742","article-title":"Dynamics of clonal evolution in myelodysplastic syndromes","volume":"49","author":"H Makishima","year":"2017","journal-title":"Nat Genet"},{"issue":"6","key":"pone.0357898.ref010","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.3324\/haematol.2023.283790","article-title":"Multi-gene measurable residual disease assessed by digital polymerase chain reaction has clinical and biological utility in acute myeloid leukemia patients receiving venetoclax\/azacitidine","volume":"109","author":"AC Winters","year":"2024","journal-title":"Haematologica"},{"issue":"20","key":"pone.0357898.ref011","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1182\/blood-2016-03-643544","article-title":"The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia","volume":"127","author":"DA Arber","year":"2016","journal-title":"Blood"},{"issue":"3","key":"pone.0357898.ref012","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1007\/s12185-024-03895-w","article-title":"A practice-oriented genome-profiling study for acute myeloid leukemia using the novel HANDLE system: HM-screen-JAPAN02","volume":"121","author":"H Arai","year":"2025","journal-title":"Int J Hematol"},{"issue":"3","key":"pone.0357898.ref013","doi-asserted-by":"crossref","first-page":"837","DOI":"10.2307\/2531595","article-title":"Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach","volume":"44","author":"ER DeLong","year":"1988","journal-title":"Biometrics"},{"issue":"3","key":"pone.0357898.ref014","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/bmt.2012.244","article-title":"Investigation of the freely available easy-to-use software \u201cEZR\u201d for medical statistics","volume":"48","author":"Y Kanda","year":"2013","journal-title":"Bone Marrow Transplant"},{"issue":"12","key":"pone.0357898.ref015","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1182\/blood.2022016867","article-title":"Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN","volume":"140","author":"H D\u00f6hner","year":"2022","journal-title":"Blood"},{"issue":"21","key":"pone.0357898.ref016","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1182\/blood.2024025409","article-title":"Genetic risk classification for adults with AML receiving less-intensive therapies: the 2024 ELN recommendations","volume":"144","author":"H D\u00f6hner","year":"2024","journal-title":"Blood"},{"issue":"21","key":"pone.0357898.ref017","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1182\/blood.2024024944","article-title":"Genetic risk stratification and outcomes among treatment-naive patients with AML treated with venetoclax and azacitidine","volume":"144","author":"H D\u00f6hner","year":"2024","journal-title":"Blood"},{"issue":"3","key":"pone.0357898.ref018","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S1470-2045(09)70003-8","article-title":"Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study","volume":"10","author":"P Fenaux","year":"2009","journal-title":"Lancet Oncol"},{"issue":"4","key":"pone.0357898.ref019","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1182\/bloodadvances.2023011757","article-title":"Prognostic risk signature in patients with acute myeloid leukemia treated with hypomethylating agents and venetoclax","volume":"8","author":"A Bataller","year":"2024","journal-title":"Blood Adv"},{"issue":"1","key":"pone.0357898.ref020","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1038\/s41408-024-01054-2","article-title":"RAS mutations in myeloid malignancies: revisiting old questions with novel insights and therapeutic perspectives","volume":"14","author":"D Alawieh","year":"2024","journal-title":"Blood Cancer J"},{"issue":"5","key":"pone.0357898.ref021","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1080\/10428194.2023.2190432","article-title":"Impact of KRAS and NRAS mutations on outcomes in acute myeloid leukemia","volume":"64","author":"MK Mustafa Ali","year":"2023","journal-title":"Leuk Lymphoma"},{"issue":"4","key":"pone.0357898.ref022","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1038\/s41375-024-02175-0","article-title":"Hypomethylating agents plus venetoclax compared with intensive induction chemotherapy regimens in molecularly defined secondary AML","volume":"38","author":"S Shimony","year":"2024","journal-title":"Leukemia"},{"issue":"7","key":"pone.0357898.ref023","doi-asserted-by":"crossref","first-page":"2548","DOI":"10.1073\/pnas.1324297111","article-title":"Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission","volume":"111","author":"MR Corces-Zimmerman","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"18","key":"pone.0357898.ref024","doi-asserted-by":"crossref","first-page":"4861","DOI":"10.1158\/0008-5472.CAN-21-0985","article-title":"Mathematical modeling and mutational analysis reveal optimal therapy to prevent malignant transformation in Grade II IDH-mutant gliomas","volume":"81","author":"K Aoki","year":"2021","journal-title":"Cancer Res"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0357898","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:37:21Z","timestamp":1790876241000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0357898"}},"subtitle":[],"editor":[{"given":"Francesco","family":"Bertolini","sequence":"first","affiliation":[{"name":"European Institute of Oncology","place":["ITALY"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":24,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,10,1]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0357898","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]}}}