{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:09:26Z","timestamp":1778285366864,"version":"3.51.4"},"reference-count":21,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2024A1515012445"],"award-info":[{"award-number":["2024A1515012445"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003785","name":"Guangdong Medical Research Foundation","doi-asserted-by":"publisher","award":["A2024057"],"award-info":[{"award-number":["A2024057"]}],"id":[{"id":"10.13039\/501100003785","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003785","name":"Guangdong Medical Research Foundation","doi-asserted-by":"publisher","award":["B2025513"],"award-info":[{"award-number":["B2025513"]}],"id":[{"id":"10.13039\/501100003785","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Guangzhou\u00c2\u00a0Basic\u00c2\u00a0and\u00c2\u00a0Applied\u00c2\u00a0Basic\u00c2\u00a0Research\u00c2\u00a0Foundation","award":["2024A04J4686"],"award-info":[{"award-number":["2024A04J4686"]}]},{"name":"Yat-sen Excellent Young Scientists Fund","award":["2024A03J1185"],"award-info":[{"award-number":["2024A03J1185"]}]}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"\n Background<\/jats:title>\n Minimal residual disease (MRD) monitoring is a cornerstone of risk stratification in pediatric acute myeloid leukemia (AML), with a threshold of 0.1% conventionally defining positivity by flow cytometry. Advances in flow cytometric technologies, enabling detection of leukemic cells with higher sensitivity and specificity, warrant a reevaluation of whether a lower threshold improves prognostic accuracy.<\/jats:p>\n <\/jats:sec>\n \n Methods and findings<\/jats:title>\n \n We conducted a retrospective cohort study using data from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET)-AML initiative. The study population comprised 1,205 pediatric patients with de novo AML treated across Children\u2019s Oncology Group (COG) clinical trial centers. Patients were enrolled between September 1996 and December 2016, with a median follow-up of 6.2 years (range: 0.5\u201320.1 years). The primary objective was to compare the prognostic performance of the traditional MRD threshold (\u22650.1%) with a lower threshold (\u22650.05%) after induction courses 1 and 2. The main outcome measure was 5-year event-free survival (EFS). Analyses included Kaplan\u2212Meier survival estimates, Cox proportional hazards models to calculate hazard ratios (\n HR<\/jats:italic>\n ) with 95% confidence intervals (\n CI<\/jats:italic>\n ), receiver operating characteristic (ROC) curves, and net reclassification improvement (NRI). The optimal threshold for predicting 5-year EFS, determined by ROC analysis, was 0.05% after both induction course 1 (AUC: 0.840, 95%\n CI<\/jats:italic>\n [0.76,0.88]) and course 2 (AUC: 0.854, 95%\n CI<\/jats:italic>\n [0.78,0.89]). The 0.05% threshold demonstrated higher\n HR<\/jats:italic>\n for the first event than the 0.1% threshold (after course 1:\n HR<\/jats:italic>\n \u2009=\u20092.8, 95%\n CI<\/jats:italic>\n [2.3,3.3];\n P<\/jats:italic>\n \u2009<\u20090.001; after course 2:\n HR<\/jats:italic>\n \u2009=\u20093.7, 95%\n CI<\/jats:italic>\n [3.0,4.6];\n P<\/jats:italic>\n \u2009<\u20090.001). NRI analysis confirmed significant improvement in risk classification with the 0.05% threshold (overall NRI: 0.15 after course 1, 0.18 after course 2). The main limitation of this study is its retrospective design using historical data from trials conducted over 20 years, which may limit generalizability to contemporary treatments.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n A lower MRD threshold of 0.05% provides superior prognostic discrimination compared to the conventional 0.1% threshold in pediatric AML treated in previous COG trials. These findings support testing this more sensitive threshold in future clinical trial designs for improved risk-adapted therapy.<\/jats:p>\n <\/jats:sec>","DOI":"10.1371\/journal.pmed.1005088","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T23:10:17Z","timestamp":1778281817000},"page":"e1005088","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimal minimal residual disease threshold in pediatric acute myeloid leukemia: A retrospective cohort study based on the TARGET database"],"prefix":"10.1371","volume":"23","author":[{"given":"Xiong-yu","family":"Liao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian-pei","family":"Fang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dun-hua","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1809-0206","authenticated-orcid":true,"given":"Kun-yin","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"issue":"13","key":"pmed.1005088.ref001","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1182\/blood.2020009652","article-title":"CEBPA-bZip mutations are associated with favorable prognosis in de novo AML: a report from the Children\u2019s Oncology Group","volume":"138","author":"K Tarlock","year":"2021","journal-title":"Blood"},{"issue":"28","key":"pmed.1005088.ref002","doi-asserted-by":"crossref","first-page":"3149","DOI":"10.1200\/JCO.20.03048","article-title":"Gemtuzumab ozogamicin improves event-free survival and reduces relapse in pediatric KMT2A-rearranged AML: results from the phase III Children\u2019s Oncology Group trial AAML0531","volume":"39","author":"JA Pollard","year":"2021","journal-title":"J Clin Oncol"},{"issue":"17","key":"pmed.1005088.ref003","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1200\/JCO-24-01841","article-title":"Hematopoietic stem cell transplantation outcomes for high-risk AML: a report from the Children\u2019s Oncology Group","volume":"43","author":"BJ Huang","year":"2025","journal-title":"J Clin Oncol"},{"issue":"8","key":"pmed.1005088.ref004","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1038\/s41375-022-01619-9","article-title":"Relapsed acute myeloid leukemia in children and adolescents: current treatment options and future strategies","volume":"36","author":"S Zarnegar-Lumley","year":"2022","journal-title":"Leukemia"},{"issue":"26","key":"pmed.1005088.ref005","doi-asserted-by":"crossref","first-page":"2753","DOI":"10.1182\/blood.2021013626","article-title":"2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party","volume":"138","author":"M Heuser","year":"2021","journal-title":"Blood"},{"issue":"6","key":"pmed.1005088.ref006","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1007\/s11899-018-0479-1","article-title":"Minimal\/measurable residual disease detection in acute leukemias by multiparameter flow cytometry","volume":"13","author":"F Fuda","year":"2018","journal-title":"Curr Hematol Malig Rep"},{"issue":"4","key":"pmed.1005088.ref007","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1080\/14737140.2021.1860763","article-title":"Measurable residual disease in pediatric acute myeloid leukemia: a systematic review","volume":"21","author":"WH Segerink","year":"2021","journal-title":"Expert Rev Anticancer Ther"},{"issue":"1","key":"pmed.1005088.ref008","doi-asserted-by":"crossref","DOI":"10.1097\/HS9.0000000000000676","article-title":"Technical aspects of flow cytometry-based measurable residual disease quantification in acute myeloid leukemia: experience of the European LeukemiaNet MRD Working Party","volume":"6","author":"JM Tettero","year":"2021","journal-title":"Hemasphere"},{"issue":"20","key":"pmed.1005088.ref009","doi-asserted-by":"crossref","first-page":"5050","DOI":"10.1182\/bloodadvances.2020002070","article-title":"Morphologic remission status is limited compared to \u0394N flow cytometry: a Children\u2019s Oncology Group AAML0531 report","volume":"4","author":"LE Brodersen","year":"2020","journal-title":"Blood Adv"},{"issue":"8","key":"pmed.1005088.ref010","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1038\/s41375-024-02300-z","article-title":"Pre-emptive detection and evolution of relapse in acute myeloid leukemia by flow cytometric measurable residual disease surveillance","volume":"38","author":"N McCarthy","year":"2024","journal-title":"Leukemia"},{"issue":"4","key":"pmed.1005088.ref011","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1182\/bloodadvances.2024013826","article-title":"Impact of measurable residual disease clearance kinetics in patients with AML undergoing intensive chemotherapy","volume":"9","author":"W-Y Jen","year":"2025","journal-title":"Blood Adv"},{"key":"pmed.1005088.ref012","article-title":"Diagnosis and management of AML in pediatric patients: consensus recommendations from an international expert panel","author":"CM Zwaan","year":"2025","journal-title":"Blood"},{"issue":"9","key":"pmed.1005088.ref013","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1182\/blood.2019002959","article-title":"Molecular MRD status and outcome after transplantation in NPM1-mutated AML","volume":"135","author":"R Dillon","year":"2020","journal-title":"Blood"},{"issue":"4","key":"pmed.1005088.ref014","doi-asserted-by":"crossref","first-page":"789","DOI":"10.3390\/cancers13040789","article-title":"Second relapse of pediatric patients with acute myeloid leukemia: a report on current treatment strategies and outcome of the AML-BFM study group","volume":"13","author":"M Rasche","year":"2021","journal-title":"Cancers (Basel)"},{"issue":"13","key":"pmed.1005088.ref015","doi-asserted-by":"crossref","first-page":"3284","DOI":"10.1182\/bloodadvances.2022009391","article-title":"Undetectable measurable residual disease is associated with improved outcomes in AML irrespective of treatment intensity","volume":"7","author":"A Bazinet","year":"2023","journal-title":"Blood Adv"},{"issue":"4","key":"pmed.1005088.ref016","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1200\/JCO.22.00715","article-title":"Prognostic value of FLT3-internal tandem duplication residual disease in acute myeloid leukemia","volume":"41","author":"T Grob","year":"2023","journal-title":"J Clin Oncol"},{"issue":"14","key":"pmed.1005088.ref017","doi-asserted-by":"crossref","first-page":"2826","DOI":"10.1182\/blood-2012-06-435669","article-title":"Minimal residual disease monitoring by quantitative RT-PCR in core binding factor AML allows risk stratification and predicts relapse: results of the United Kingdom MRC AML-15 trial","volume":"120","author":"JAL Yin","year":"2012","journal-title":"Blood"},{"issue":"19","key":"pmed.1005088.ref018","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1182\/blood.2019001425","article-title":"Measurable residual disease monitoring in acute myeloid leukemia with t(8;21)(q22;q22.1): results from the AML Study Group","volume":"134","author":"FG R\u00fccker","year":"2019","journal-title":"Blood"},{"issue":"12","key":"pmed.1005088.ref019","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.1182\/blood-2012-10-462879","article-title":"Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia","volume":"121","author":"E Jourdan","year":"2013","journal-title":"Blood"},{"issue":"1","key":"pmed.1005088.ref020","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1111\/bjh.16857","article-title":"Acute myeloid leukemia with NPM1 mutation and favorable European LeukemiaNet category: outcome after preemptive intervention based on measurable residual disease","volume":"191","author":"A Bataller","year":"2020","journal-title":"Br J Haematol"},{"issue":"4","key":"pmed.1005088.ref021","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1111\/bjh.70038","article-title":"Measurable residual disease-guided therapy in acute myeloid leukaemia: practical insights","volume":"207","author":"B Nachmias","year":"2025","journal-title":"Br J Haematol"}],"container-title":["PLOS Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pmed.1005088","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T23:10:25Z","timestamp":1778281825000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pmed.1005088"}},"subtitle":[],"editor":[{"given":"Paschalis","family":"Evangelidis","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,5,8]]},"references-count":21,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pmed.1005088","relation":{},"ISSN":["1549-1676"],"issn-type":[{"value":"1549-1676","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,8]]}}}