{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T23:11:21Z","timestamp":1794611481514,"version":"4.9.1"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T00:00:00Z","timestamp":1658102400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T00:00:00Z","timestamp":1658102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["318488004"],"award-info":[{"award-number":["318488004"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008672","name":"Wilhelm Sander-Stiftung","doi-asserted-by":"publisher","award":["2021.035.1"],"award-info":[{"award-number":["2021.035.1"]}],"id":[{"id":"10.13039\/100008672","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MeDDrive, intramural funding, #60466"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Measurable residual disease (MRD) detected by multiparametric flow cytometry (MFC) is associated with unfavorable outcome in patients with AML. A simple, broadly applicable eight-color panel was implemented and analyzed utilizing a hierarchical gating strategy with fixed gates to develop a clear-cut LAIP-based DfN approach. In total, 32 subpopulations with aberrant phenotypes with\/without expression of markers of immaturity were monitored in 246 AML patients after completion of induction chemotherapy. Reference values were established utilizing 90 leukemia-free controls. Overall, 73% of patients achieved a response by cytomorphology. In responders, the overall survival was shorter for MRD<jats:sup>pos<\/jats:sup>patients (HR 3.8,<jats:italic>p<\/jats:italic>\u2009=\u20090.006). Overall survival of MRD<jats:sup>neg<\/jats:sup>non-responders was comparable to MRD<jats:sup>neg<\/jats:sup>responders. The inter-rater-reliability for MRD detection was high with a Krippendorffs \u03b1 of 0.860. The mean time requirement for MRD analyses at follow-up was very short with 04:31\u2009minutes. The proposed one-tube MFC approach for detection of MRD allows a high level of standardization leading to a promising inter-observer-reliability with a fast turnover. MRD defined by this strategy provides relevant prognostic information and establishes aberrancies outside of cell populations with markers of immaturity as an independent risk feature. Our results imply that this strategy may provide the base for multicentric immunophenotypic MRD assessment.<\/jats:p>","DOI":"10.1038\/s41375-022-01647-5","type":"journal-article","created":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T09:02:57Z","timestamp":1658134977000},"page":"2208-2217","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Reproducible measurable residual disease detection by multiparametric flow cytometry in acute myeloid leukemia"],"prefix":"10.1038","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8213-2047","authenticated-orcid":false,"given":"Maximilian A.","family":"R\u00f6hnert","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kramer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2687-9178","authenticated-orcid":false,"given":"Jonas","family":"Schadt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Ensel","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\/0000-0002-5259-4651","authenticated-orcid":false,"given":"Stefan W.","family":"Krause","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7391-7280","authenticated-orcid":false,"given":"Veit","family":"B\u00fccklein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Jaramillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard F.","family":"Schlenk","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\/0000-0002-5916-3029","authenticated-orcid":false,"given":"Martin","family":"Bornh\u00e4user","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"McCarthy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1869-180X","authenticated-orcid":false,"given":"Sylvie","family":"Freeman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uta","family":"Oelschl\u00e4gel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3828-0031","authenticated-orcid":false,"given":"Malte","family":"von Bonin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,18]]},"reference":[{"key":"1647_CR1","doi-asserted-by":"publisher","first-page":"1583","DOI":"10.1200\/JCO.1985.3.12.1583","volume":"3","author":"T B\u00fcchner","year":"1985","unstructured":"B\u00fcchner T, Urbanitz D, Hiddemann W, R\u00fchl H, Ludwig WD, Fischer J, et al. Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): Two multicenter studies of the German AML Cooperative Group. J Clin Oncol. 1985;3:1583\u20139.","journal-title":"J Clin Oncol"},{"key":"1647_CR2","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1182\/blood-2016-08-733196","volume":"129","author":"H D\u00f6hner","year":"2017","unstructured":"D\u00f6hner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, B\u00fcchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424\u201347.","journal-title":"Blood"},{"key":"1647_CR3","first-page":"2209","volume":"374","author":"E Papaemmanuil","year":"2016","unstructured":"Papaemmanuil E, Ph D, Gerstung M, Ph D, Bullinger L, Gaidzik VI, et al. Genomic classification and prognosis in acute myeloid. Leukemia. 2016;374:2209\u201321.","journal-title":"Leukemia"},{"key":"1647_CR4","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":"1647_CR5","doi-asserted-by":"publisher","first-page":"2826","DOI":"10.1182\/blood-2012-06-435669","volume":"120","author":"JA Liu Yin","year":"2012","unstructured":"Liu Yin JA, O\u2019Brien MA, Hills RK, Daly SB, Wheatley K, Burnett AK. 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. Blood. 2012;120:2826\u201335.","journal-title":"Blood"},{"key":"1647_CR6","doi-asserted-by":"publisher","first-page":"1608","DOI":"10.1182\/blood.2019001425","volume":"134","author":"FG R\u00fccker","year":"2019","unstructured":"R\u00fccker FG, Agrawal M, Corbacioglu A, Weber D, Kapp-Schwoerer S, Gaidzik VI, et al. Measurable residual disease monitoring in acute myeloid leukemia with t(8;21)(q22;q22.1): Results from the AML Study Group. Blood. 2019;134:1608\u201318.","journal-title":"Blood"},{"key":"1647_CR7","doi-asserted-by":"publisher","first-page":"328","DOI":"10.3324\/haematol.2015.131946","volume":"101","author":"C Willekens","year":"2016","unstructured":"Willekens C, Blanchet O, Renneville A, Cornillet-Lefebvre P, Pautas C, Guieze R, et al. Prospective long-term minimal residual disease monitoring using RQ-PCR in RUNX1-RUNX1T1-positive acute myeloid leukemia: Results of the French CBF-2006 trial. Haematologica. 2016;101:328\u201335.","journal-title":"Haematologica"},{"key":"1647_CR8","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.beha.2014.10.008","volume":"27","author":"GJ Ossenkoppele","year":"2014","unstructured":"Ossenkoppele GJ, Schuurhuis GJ. MRD in AML: It is time to change the definition of remission. Best Pract Res: Clin Haematol. 2014;27:265\u201371.","journal-title":"Best Pract Res: Clin Haematol"},{"key":"1647_CR9","doi-asserted-by":"publisher","first-page":"2295","DOI":"10.1182\/blood-2009-12-258178","volume":"116","author":"F Buccisano","year":"2010","unstructured":"Buccisano F, Maurillo L, Spagnoli A, Del Principe MI, Fraboni D, Panetta P, et al. Cytogenetic and molecular diagnostic characterization combined to postconsolidation minimal residual disease assessment by flow cytometry improves risk stratification in adult acute myeloid leukemia. Blood. 2010;116:2295\u2013303.","journal-title":"Blood"},{"key":"1647_CR10","doi-asserted-by":"crossref","unstructured":"Buccisano F, Dillon R, Freeman SD, Venditti A. Role of minimal (measurable) residual disease assessment in older patients with acute myeloid leukemia. Cancers. 2018;10:205.","DOI":"10.3390\/cancers10070215"},{"key":"1647_CR11","doi-asserted-by":"publisher","first-page":"4123","DOI":"10.1200\/JCO.2013.49.1753","volume":"31","author":"SD Freeman","year":"2013","unstructured":"Freeman SD, Virgo P, Couzens S, Grimwade D, Russell N, Hills RK, et al. Prognostic relevance of treatment response measured by flow cytometric residual disease detection in older patients with acute myeloid leukemia. J Clin Oncol. 2013;31:4123\u201331.","journal-title":"J Clin Oncol"},{"key":"1647_CR12","doi-asserted-by":"publisher","first-page":"1581","DOI":"10.1182\/blood-2012-02-408336","volume":"120","author":"MR Loken","year":"2012","unstructured":"Loken MR, Alonzo TA, Pardo L, Gerbing RB, Raimondi SC, Hirsch BA, et al. Residual disease detected by multidimensional flow cytometry signifies high relapse risk in patients with de novo acute myeloid leukemia: A report from Children\u2019s Oncology Group. Blood. 2012;120:1581\u20138.","journal-title":"Blood"},{"key":"1647_CR13","doi-asserted-by":"publisher","first-page":"3889","DOI":"10.1200\/JCO.2012.45.9628","volume":"31","author":"M Terwijn","year":"2013","unstructured":"Terwijn M, Kelder A, Huijgens PC, Dr\u00e4ger AM, Oussoren YJM, Scholten WJ, et al. High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: Data from the HOVON\/SAKK AML 42A study. J Clin Oncol. 2013;31:3889\u201397.","journal-title":"J Clin Oncol"},{"key":"1647_CR14","doi-asserted-by":"publisher","first-page":"1482","DOI":"10.1038\/leu.2017.113","volume":"31","author":"CS Hourigan","year":"2017","unstructured":"Hourigan CS, Gale RP, Gormley NJ, Ossenkoppele GJ, Walter RB. Measurable residual disease testing in acute myeloid leukaemia. Leukemia. 2017;31:1482\u201390.","journal-title":"Leukemia"},{"key":"1647_CR15","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1200\/JCO.2010.31.8121","volume":"29","author":"RB Walter","year":"2011","unstructured":"Walter RB, Gooley TA, Wood BL, Milano F, Fang M, Sorror ML, et al. Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia. J Clin Oncol. 2011;29:1190\u20137.","journal-title":"J Clin Oncol"},{"key":"1647_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-021-00558-5","volume":"11","author":"C Rautenberg","year":"2021","unstructured":"Rautenberg C, St\u00f6lzel F, R\u00f6llig C, Stelljes M, Gaidzik V, Lauseker M, et al. Real-world experience of CPX-351 as first-line treatment for patients with acute myeloid leukemia. Blood Cancer J. 2021;11:164.","journal-title":"Blood Cancer J"},{"key":"1647_CR17","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1056\/NEJMoa1716863","volume":"378","author":"M Jongen-Lavrencic","year":"2018","unstructured":"Jongen-Lavrencic M, Grob T, Hanekamp D, Kavelaars FG, al Hinai A, Zeilemaker A. et al. Molecular minimal residual disease in acute myeloid leukemia. N Engl J Med. 2018;378:1189\u201399.","journal-title":"N Engl J Med"},{"key":"1647_CR18","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1080\/17474086.2018.1549479","volume":"11","author":"GJ Schuurhuis","year":"2018","unstructured":"Schuurhuis GJ, Ossenkoppele GJ, Kelder A, Cloos J. Measurable residual disease in acute myeloid leukemia using flow cytometry: approaches for harmonization\/standardization. Expert Rev Hematol. 2018;11:921\u201335.","journal-title":"Expert Rev Hematol"},{"key":"1647_CR19","doi-asserted-by":"publisher","first-page":"E510","DOI":"10.3324\/haematol.2018.215236","volume":"104","author":"T K\u00f6hnke","year":"2019","unstructured":"K\u00f6hnke T, B\u00fccklein V, Rechkemmer S, Schneider S, Rothenberg-Thurley M, Metzeler KH, et al. Response assessment in acute myeloid leukemia by flow cytometry supersedes cytomorphology at time of aplasia, amends cases without molecular residual disease marker and serves as an independent prognostic marker at time of aplasia and post-induction. Haematologica. 2019;104:E510\u20133.","journal-title":"Haematologica"},{"key":"1647_CR20","doi-asserted-by":"crossref","unstructured":"Wood BL. Acute myeloid leukemia minimal residual disease detection: the difference from normal approach. Curr Protoc Cytom. 2020;93:e73.","DOI":"10.1002\/cpcy.73"},{"key":"1647_CR21","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1002\/cytob.21134","volume":"86","author":"W Zeijlemaker","year":"2013","unstructured":"Zeijlemaker W, Gratama JW, Schuurhuis GJ. Tumor heterogeneity makes AML a \u2018moving target\u2019 for detection of residual disease. Cytometry B Clin Cytom. 2013;86:3\u201314.","journal-title":"Cytometry B Clin Cytom"},{"key":"1647_CR22","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1002\/1097-0320(20000815)42:4<247::AID-CYTO5>3.0.CO;2-V","volume":"42","author":"U Oelschl\u00e4gel","year":"2000","unstructured":"Oelschl\u00e4gel U, Nowak R, Schaub A, K\u00f6ppel C, Herbst R, Mohr B, et al. Shift of aberrant antigen expression at relapse or at treatment failure in acute leukemia. Cytometry. 2000;42:247\u201353.","journal-title":"Cytometry"},{"key":"1647_CR23","doi-asserted-by":"publisher","DOI":"10.1038\/bcj.2013.27","volume":"3","author":"N Feller","year":"2013","unstructured":"Feller N, Van Der Velden VHJ, Brooimans RA, Boeckx N, Preijers F, Kelder A, et al. Defining consensus leukemia-associated immunophenotypes for detection of minimal residual disease in acute myeloid leukemia in a multicenter setting. Blood Cancer J. 2013;3:e129.","journal-title":"Blood Cancer J"},{"key":"1647_CR24","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.leukres.2018.11.014","volume":"76","author":"RA Brooimans","year":"2019","unstructured":"Brooimans RA, van der Velden VHJ, Boeckx N, Slomp J, Preijers F, te Marvelde JG, et al. Immunophenotypic measurable residual disease (MRD) in acute myeloid leukemia: Is multicentric MRD assessment feasible? Leuk Res. 2019;76:39\u201347.","journal-title":"Leuk Res"},{"key":"1647_CR25","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1016\/j.pathol.2019.03.010","volume":"51","author":"AE Camburn","year":"2019","unstructured":"Camburn AE, Petrasich M, Ruskova A, Chan G. Myeloblasts in normal bone marrows expressing leukaemia-associated immunophenotypes. Pathology. 2019;51:502\u20136.","journal-title":"Pathology"},{"key":"1647_CR26","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1002\/cyto.b.21846","volume":"98","author":"AM Eckel","year":"2020","unstructured":"Eckel AM, Cherian S, Miller V, Soma L. CD33 expression on natural killer cells is a potential confounder for residual disease detection in acute myeloid leukemia by flow cytometry. Cytometry B Clin Cytom. 2020;98:174\u20138.","journal-title":"Cytometry B Clin Cytom"},{"key":"1647_CR27","doi-asserted-by":"publisher","first-page":"1973","DOI":"10.1080\/10428194.2021.1889539","volume":"62","author":"A Rosso","year":"2021","unstructured":"Rosso A, Juliusson G, Lorenz F, Lehmann S, Derolf \u00c5, Deneberg S, et al. Is there an impact of measurable residual disease as assessed by multiparameter flow cytometry on survival of AML patients treated in clinical practice? A population-based study. Leuk Lymphoma. 2021;62:1973\u201381.","journal-title":"Leuk Lymphoma"},{"key":"1647_CR28","doi-asserted-by":"publisher","first-page":"2358","DOI":"10.1038\/s41375-021-01126-3","volume":"35","author":"B Paiva","year":"2021","unstructured":"Paiva B, Vidriales MB, Sempere A, Tar\u00edn F, Colado E, Benavente C, et al. Impact of measurable residual disease by decentralized flow cytometry: a PETHEMA real-world study in 1076 patients with acute myeloid leukemia. Leukemia. 2021;35:2358\u201370.","journal-title":"Leukemia"},{"key":"1647_CR29","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1182\/blood-2017-09-801498","volume":"131","author":"GJ Schuurhuis","year":"2018","unstructured":"Schuurhuis GJ, Heuser M, Freeman S, B\u00e9ne MC, Buccisano F, Cloos J, et al. Minimal\/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018;131:1275\u201391.","journal-title":"Blood"},{"key":"1647_CR30","first-page":"EP566","volume":"06\/12\/20","author":"M R\u00f6hnert","year":"2020","unstructured":"R\u00f6hnert M, von Bonin M, Kramer M, Ensel P, Holtschke N, R\u00f6llig C, et al. Standardized identification of measurable residual disease (MRD) by multicolor flow cytometry (MFC) in patients with acute myeloid leukemia (AML). EHA Libr. 2020;06\/12\/20:EP566.","journal-title":"EHA Libr"},{"key":"1647_CR31","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1159\/000495474","volume":"42","author":"M R\u00f6hnert","year":"2019","unstructured":"R\u00f6hnert M, von Bonin M, Bu\u0308cklein V, Krause S, V\u00f6lkl S, Rieger M, et al. Comparison of leukemia-associated immunophenotype (LAIP)-based and different-from-normal (DfN)-based analysis of measurable residual disease (MRD) in patients with AML. Oncol Res Treat. 2019;42:87\u201388.","journal-title":"Oncol Res Treat"},{"key":"1647_CR32","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1182\/blood-2020-138683","volume":"136","author":"M R\u00f6hnert","year":"2020","unstructured":"R\u00f6hnert M, von Bonin M, Kramer M, Ensel P, Holtschke N, R\u00f6llig C, et al. Identification of prognostic immunophenotypes at first diagnosis in patients with acute myeloid leukemia (AML) by a standardized multicolor flow cytometry (MFC) panel originally designed to detect measurable residual disease (MRD) at follow-up. Blood. 2020;136:35.","journal-title":"Blood"},{"key":"1647_CR33","doi-asserted-by":"publisher","first-page":"2753","DOI":"10.1182\/blood.2021013626","volume":"138","author":"M Heuser","year":"2021","unstructured":"Heuser M, Freeman SD, Ossenkoppele GJ, Buccisano F, Hourigan CS, Ngai LL. et al. 2021 update measurable residual disease in acute myeloid leukemia: european leukemianet working party consensus document. Blood. 2021;138:2753\u201367.","journal-title":"Blood"},{"key":"1647_CR34","doi-asserted-by":"crossref","first-page":"e66","DOI":"10.1002\/cpcy.66","volume":"91","author":"W Zeijlemaker","year":"2019","unstructured":"Zeijlemaker W, Kelder A, Cloos J, Schuurhuis GJ. Immunophenotypic detection of measurable residual (Stem Cell) disease using LAIP approach in acute myeloid leukemia. Curr Protoc Cytom. 2019;91:e66.","journal-title":"Curr Protoc Cytom"},{"key":"1647_CR35","doi-asserted-by":"publisher","first-page":"1769","DOI":"10.1038\/leu.2016.44","volume":"30","author":"F Lacombe","year":"2016","unstructured":"Lacombe F, Bernal E, Bloxham D, Couzens S, Porta MGD, Johansson U, et al.\u00a0Harmonemia: a universal strategy for flow cytometry immunophenotyping-A European LeukemiaNet WP10 study. Leukemia. 2016;30:1769\u201372.","journal-title":"Leukemia"},{"key":"1647_CR36","doi-asserted-by":"publisher","first-page":"1908","DOI":"10.1038\/leu.2012.120","volume":"26","author":"JJM Van Dongen","year":"2012","unstructured":"Van Dongen JJM, Lhermitte L, B\u00f6ttcher S, Almeida J, Van Der Velden VHJ, Flores-Montero J, et al. EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia. 2012;26:1908\u201375.","journal-title":"Leukemia"},{"key":"1647_CR37","doi-asserted-by":"crossref","unstructured":"Gorczyca W. Flow Cytometry in Neoplastic Hematology: Morphologic--Immunophenotypic Correlation (2nd ed.). (CRC Press, 2010).","DOI":"10.3109\/9781841847443"},{"key":"1647_CR38","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1038\/leu.2014.186","volume":"29","author":"T K\u00f6hnke","year":"2015","unstructured":"K\u00f6hnke T, Sauter D, Ringel K, Hoster E, Laubender RP, Hubmann M, et al. Early assessment of minimal residual disease in AML by flow cytometry during aplasia identifies patients at increased risk of relapse. Leukemia. 2015;29:377\u201386.","journal-title":"Leukemia"},{"key":"1647_CR39","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1200\/JCO.20.02308","volume":"39","author":"C Craddock","year":"2021","unstructured":"Craddock C, Jackson A, Loke J, Siddique S, Hodgkinson A, Mason J, et al. Augmented reduced-intensity regimen does not improve postallogeneic transplant outcomes in acute myeloid leukemia. J Clin Oncol. 2021;39:768\u201378.","journal-title":"J Clin Oncol"},{"key":"1647_CR40","unstructured":"Mccarthy N, Loke J, Andrew G, Jackson A, Hodgkinson A, Mason J et al. Validation and application of an unsupervised analysis approach to measurable residual disease testing in acute myeloid leukemia. EHA Libr. 2021;06\/09\/21:EP432."},{"key":"1647_CR41","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1080\/19312450709336664","volume":"1","author":"AF Hayes","year":"2007","unstructured":"Hayes AF, Krippendorff K. Answering the call for a standard reliability measure for coding data. Commun Methods Measures. 2007;1:77\u201389.","journal-title":"Commun Methods Measures"},{"key":"1647_CR42","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1109\/TAC.1974.1100705","volume":"19","author":"H Akaike","year":"1974","unstructured":"Akaike H. A new look at the statistical model identification. IEEE Trans Autom Control. 1974;19:716\u201323.","journal-title":"IEEE Trans Autom Control"},{"key":"1647_CR43","first-page":"111","volume":"5","author":"S Portet","year":"2020","unstructured":"Portet S. A primer on model selection using the Akaike Information Criterion. Infect Dis Model. 2020;5:111\u201328.","journal-title":"Infect Dis Model"},{"key":"1647_CR44","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.1016\/S1470-2045(18)30580-1","volume":"19","author":"U Platzbecker","year":"2018","unstructured":"Platzbecker U, Middeke JM, Sockel K, Herbst R, Wolf D, Baldus CD, et al. Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial. Lancet Oncol. 2018;19:1668\u201379.","journal-title":"Lancet Oncol"},{"key":"1647_CR45","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.1038\/sj.leu.2403405","volume":"18","author":"N Feller","year":"2004","unstructured":"Feller N, van der Pol MA, van Stijn A, Weijers GWD, Westra AH, Evertse BW, et al. MRD parameters using immunophenotypic detection methods are highly reliable in predicting survival in acute myeloid leukaemia. Leukemia. 2004;18:1380\u201390.","journal-title":"Leukemia"},{"key":"1647_CR46","doi-asserted-by":"publisher","first-page":"603636","DOI":"10.3389\/fonc.2020.603636","volume":"10","author":"LL Ngai","year":"2021","unstructured":"Ngai LL, Kelder A, Janssen JJWM, Ossenkoppele GJ, Cloos J. MRD tailored therapy in AML: what we have learned so far. Front Oncol. 2021;10:603636.","journal-title":"Front Oncol"},{"key":"1647_CR47","doi-asserted-by":"publisher","first-page":"1783","DOI":"10.1038\/sj.leu.2404313","volume":"20","author":"F Buccisano","year":"2006","unstructured":"Buccisano F, Maurillo L, Gattei V, Del Poeta G, Del Principe MI, Cox MC, et al. The kinetics of reduction of minimal residual disease impacts on duration of response and survival of patients with acute myeloid leukemia. Leukemia. 2006;20:1783\u20139.","journal-title":"Leukemia"},{"key":"1647_CR48","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1111\/ijlh.12193","volume":"36","author":"W Cui","year":"2014","unstructured":"Cui W, Zhang D, Cunningham MT, Tilzer L. Leukemia-associated aberrant immunophenotype in patients with acute myeloid leukemia: Changes at refractory disease or first relapse and clinicopathological findings. Int J Lab Hematol. 2014;36:636\u201349.","journal-title":"Int J Lab Hematol"},{"key":"1647_CR49","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1309\/FY0UMAMM91VPMR2W","volume":"129","author":"A Al-Mawali","year":"2008","unstructured":"Al-Mawali A, Gillis D, Hissaria P, Lewis I. Incidence, sensitivity, and specificity of leukemia-associated phenotypes in acute myeloid leukemia using specific five-color multiparameter flow cytometry. Am J Clin Pathol. 2008;129:934\u201345.","journal-title":"Am J Clin Pathol"},{"key":"1647_CR50","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1002\/ajh.25431","volume":"94","author":"JN Sui","year":"2019","unstructured":"Sui JN, Chen QS, Zhang YX, Sheng Y, Wu J, Li JM, et al. Identifying leukemia-associated immunophenotype-based individualized minimal residual disease in acute myeloid leukemia and its prognostic significance. Am J Hematol. 2019;94:528\u201338.","journal-title":"Am J Hematol"},{"key":"1647_CR51","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1046\/j.1365-2141.2002.03599.x","volume":"118","author":"T Haferlach","year":"2002","unstructured":"Haferlach T, Schoch C, Schnittger S, Kern W, L\u00f6ffler H, Hiddemann W. Distinct genetic patterns can be identified in acute monoblastic and acute monocytic leukaemia (FAB AML M5a and M5b): a study of 124 patients. Br J Haematol. 2002;118:426\u201331.","journal-title":"Br J Haematol"},{"key":"1647_CR52","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1182\/blood-2002-09-2768","volume":"102","author":"DA Wells","year":"2003","unstructured":"Wells DA, Benesch M, Loken MR, Vallejo C, Myerson D, Leisenring WM, et al. Myeloid and monocytic dyspoiesis as determined by flow cytometric scoring in myelodysplastic syndrome correlates with the IPSS and with outcome after hematopoietic stem cell transplantation. Blood. 2003;102:394\u2013403.","journal-title":"Blood"},{"key":"1647_CR53","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1002\/cncr.30361","volume":"123","author":"F Ravandi","year":"2017","unstructured":"Ravandi F, Jorgensen J, Borthakur G, Jabbour E, Kadia T, Pierce S, et al. Persistence of minimal residual disease assessed by multiparameter flow cytometry is highly prognostic in younger patients with acute myeloid leukemia. Cancer. 2017;123:426\u201335.","journal-title":"Cancer"},{"key":"1647_CR54","doi-asserted-by":"publisher","first-page":"859","DOI":"10.3324\/haematol.11118","volume":"92","author":"C Lacronique-Gazaille","year":"2007","unstructured":"Lacronique-Gazaille C, Chaury MP, Le Guyader A, Faucher JL, Bordessoule D, Feuillard J. A simple method for detection of major phenotypic abnormalities in myelodysplastic syndromes: Expression of CD56 in CMML. Haematologica. 2007;92:859\u201360.","journal-title":"Haematologica"},{"key":"1647_CR55","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.trsl.2008.03.001","volume":"151","author":"D Subira","year":"2008","unstructured":"Subira D, Font P, Villal\u00f3n L, Serrano C, Askari E, G\u00f3ngora E, et al. Immunophenotype in chronic myelomonocytic leukemia: is it closer to myelodysplastic syndromes or to myeloproliferative disorders? Transl Res. 2008;151:240\u20135.","journal-title":"Transl Res"},{"key":"1647_CR56","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1002\/cyto.b.21721","volume":"94","author":"R Feng","year":"2018","unstructured":"Feng R, Bhatt VR, Fu K, Pirruccello S, Yuan J. Application of immunophenotypic analysis in distinguishing chronic myelomonocytic leukemia from reactive monocytosis. Cytometry B Clin Cytom. 2018;94:901\u20139.","journal-title":"Cytometry B Clin Cytom"},{"key":"1647_CR57","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1002\/cyto.b.21744","volume":"72","author":"Y Zhou","year":"2019","unstructured":"Zhou Y, Moon A, Hoyle E, Fromm JR, Chen X, Soma L. et al. Pattern associatedleukemia immunophenotypes and measurable disease detection in acute myeloidleukemia or myelodysplastic syndrome with mutated NPM1. Cytometry B Clin Cytom. 2019;72:67\u201372.","journal-title":"Cytometry B Clin Cytom"},{"key":"1647_CR58","doi-asserted-by":"publisher","first-page":"2813","DOI":"10.1182\/blood.V95.9.2813.009k20_2813_2820","volume":"95","author":"L Gallacher","year":"2000","unstructured":"Gallacher L, Murdoch B, Wu DM, Karanu FN, Keeney M, Bhatia M. Isolation and characterization of human CD34-Lin- and CD34+Lin- hematopoietic stem cells using cell surface markers AC133 and CD7. Blood. 2000;95:2813\u201320.","journal-title":"Blood"},{"key":"1647_CR59","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1002\/gcc.22806","volume":"58","author":"S Vosberg","year":"2019","unstructured":"Vosberg S, Greif PA. Clonal evolution of acute myeloid leukemia from diagnosis to relapse. Genes Chromosomes Cancer. 2019;58:839\u201349.","journal-title":"Genes Chromosomes Cancer"},{"key":"1647_CR60","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/cyto.b.20008","volume":"60","author":"EG Van Lochem","year":"2004","unstructured":"Van Lochem EG, Van Der Velden VHJ, Wind HK, Te Marvelde JG, Westerdaal NAC, Van Dongen JJM. Immunophenotypic differentiation patterns of normal hematopoiesis in human bone marrow: Reference patterns for age-related changes and disease-induced shifts. Cytometry B Clin Cytom. 2004;60:1\u201313.","journal-title":"Cytometry B Clin Cytom"},{"key":"1647_CR61","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1182\/bloodadvances.2019001157","volume":"4","author":"JF Soerensen","year":"2020","unstructured":"Soerensen JF, Aggerholm A, Kerndrup GB, Hansen MC, Ewald IKL, Bill M, et al. Clonal hematopoiesis predicts development of therapy-related myeloid neoplasms post-autologous stem cell transplantation. Blood Adv. 2020;4:885\u201392.","journal-title":"Blood Adv"},{"key":"1647_CR62","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1111\/bjh.17347","volume":"192","author":"S Loghavi","year":"2021","unstructured":"Loghavi S, DiNardo CD, Furudate K, Takahashi K, Tanaka T, Short NJ, et al. Flow cytometric immunophenotypic alterations of persistent clonal haematopoiesis in remission bone marrows of patients with NPM1-mutated acute myeloid leukaemia. Br J Haematol. 2021;192:1054\u201363.","journal-title":"Br J Haematol"},{"key":"1647_CR63","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1007\/s11899-017-0419-5","volume":"12","author":"Y Zhou","year":"2017","unstructured":"Zhou Y, Wood BL. Methods of detection of measurable residual disease in AML. Curr Hematologic Malignancy Rep. 2017;12:557\u201367.","journal-title":"Curr Hematologic Malignancy Rep"},{"key":"1647_CR64","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1200\/JCO.19.03011","volume":"38","author":"CS Hourigan","year":"2020","unstructured":"Hourigan CS, Dillon LW, Gui G, Logan BR, Fei M, Ghannam J, et al. Impact of conditioning intensity of allogeneic transplantation for acute myeloid leukemia with genomic evidence of residual disease. J Clin Oncol. 2020;38:1273\u201383.","journal-title":"J Clin Oncol"},{"key":"1647_CR65","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1182\/blood.2018886960","volume":"134","author":"A Venditti","year":"2019","unstructured":"Venditti A, Piciocchi A, Candoni A, Melillo L, Calafiore V, Cairoli R, et al. GIMEMA AML1310 trial of risk-adapted, MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia. Blood. 2019;134:935\u201345.","journal-title":"Blood"},{"key":"1647_CR66","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.ebiom.2018.10.042","volume":"37","author":"BS Ko","year":"2018","unstructured":"Ko BS, Wang YF, Li JL, Li CC, Weng PF, Hsu SC, et al. Clinically validated machine learning algorithm for detecting residual diseases with multicolor flow cytometry analysis in acute myeloid leukemia and myelodysplastic syndrome. EBioMedicine. 2018;37:91\u2013100.","journal-title":"EBioMedicine"},{"key":"1647_CR67","doi-asserted-by":"publisher","first-page":"1191","DOI":"10.1002\/cyto.a.23897","volume":"95","author":"F Lacombe","year":"2019","unstructured":"Lacombe F, Lechevalier N, Vial JP, B\u00e9n\u00e9 MC. An R-derived FlowSOM process to analyze unsupervised clustering of normal and malignant human bone marrow classical flow cytometry data. Cytom A. 2019;95:1191\u20137.","journal-title":"Cytom A"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-022-01647-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-022-01647-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-022-01647-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T17:55:20Z","timestamp":1700848520000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-022-01647-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,18]]},"references-count":67,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2022,9]]}},"alternative-id":["1647"],"URL":"https:\/\/doi.org\/10.1038\/s41375-022-01647-5","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,18]]},"assertion":[{"value":"5 January 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 June 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 July 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 July 2022","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"CT is CEO and part ownership of AgenDix GmbH, a company performing molecular diagnostics. All other authors have nothing to disclose.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}