{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T03:04:21Z","timestamp":1789009461685,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,10,30]],"date-time":"2020-10-30T00:00:00Z","timestamp":1604016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["GR-2013-02358238"],"award-info":[{"award-number":["GR-2013-02358238"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["21267"],"award-info":[{"award-number":["21267"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Legato Zottola","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Acute myeloid leukemia (AML) \u201cwith myelodysplasia-related changes (MRC)\u201d is considered a separate entity by the World Health Organization (WHO) classification of myeloid neoplasms. While anamnestic and cytogenetic criteria provide objective attribution to this subset, with clear unfavorable prognostic significance, the actual role of multi-lineage dysplasia (MLD) as assessed by morphology is debated. The aim of our work was to study MLD by a technique alternative to morphology, which is multiparameter flow cytometry (MFC), in a large series of 302 AML patients intensively treated at our Center. The correlation with morphology we observed in the unselected analysis reiterated the capability of the MFC-based approach at highlighting dysplasia. MLD data, estimated through an immune-phenotypic score (IPS), provided no insight into prognosis when considered overall nor within well-defined genetic categories. Of interest, IPS-related dysplasia conveyed significant prognostic information when we focused on genetically undefined patients, triple-negative for NPM1, FLT3 and CEBPA (TN-AML). In this context, the lack of dysplastic features (IPS_0) correlated with a significantly higher CR rate and longer survival compared to patients showing dysplasia in one or both (neutrophil and erythroid) cell lineages. The impact of IPS category maintained its validity after censoring at allogeneic HSCT and in a multivariate analysis including baseline and treatment-related covariates. In a subgroup featured by the lack of genetic determinants, our data could help address the relative unmet needs in terms of risk assessment and treatment strategy, and provide insight into prediction of response in the rapidly evolving therapeutic scenario of AML.<\/jats:p>","DOI":"10.3390\/cancers12113196","type":"journal-article","created":{"date-parts":[[2020,10,30]],"date-time":"2020-10-30T09:29:32Z","timestamp":1604050172000},"page":"3196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Multilineage Dysplasia as Assessed by Immunophenotype in Acute Myeloid Leukemia: A Prognostic Tool in a Genetically Undefined Category"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4810-6501","authenticated-orcid":false,"given":"Francesco","family":"Mannelli","sequence":"first","affiliation":[{"name":"Struttura Operativa Dipartimentale Ematologia, Azienda Ospedaliero-Universitaria Careggi, 50134 Firenze, Italy"},{"name":"Centro Ricerca e Innovazione Malattie Mieloproliferative (CRIMM), AOU Careggi, 50134 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Bencini","sequence":"additional","affiliation":[{"name":"Struttura Operativa Dipartimentale Ematologia, Azienda Ospedaliero-Universitaria Careggi, 50134 Firenze, Italy"},{"name":"Centro Diagnostico di Citofluorimetria e Immunoterapia, AOU Careggi, 50134 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Piccini","sequence":"additional","affiliation":[{"name":"Struttura Operativa Dipartimentale Ematologia, Azienda Ospedaliero-Universitaria Careggi, 50134 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Gianfaldoni","sequence":"additional","affiliation":[{"name":"Struttura Operativa Dipartimentale Ematologia, Azienda Ospedaliero-Universitaria Careggi, 50134 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Ida","family":"Bonetti","sequence":"additional","affiliation":[{"name":"Struttura Operativa Dipartimentale Ematologia, Azienda Ospedaliero-Universitaria Careggi, 50134 Firenze, Italy"},{"name":"Centro Diagnostico di Citofluorimetria e Immunoterapia, AOU Careggi, 50134 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedetta","family":"Peruzzi","sequence":"additional","affiliation":[{"name":"Centro Diagnostico di Citofluorimetria e Immunoterapia, AOU Careggi, 50134 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Caporale","sequence":"additional","affiliation":[{"name":"Centro Diagnostico di Citofluorimetria e Immunoterapia, AOU Careggi, 50134 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Scappini","sequence":"additional","affiliation":[{"name":"Struttura Operativa Dipartimentale Ematologia, Azienda Ospedaliero-Universitaria Careggi, 50134 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiana","family":"Pancani","sequence":"additional","affiliation":[{"name":"Struttura Operativa Dipartimentale Ematologia, Azienda Ospedaliero-Universitaria Careggi, 50134 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Ponziani","sequence":"additional","affiliation":[{"name":"Struttura Operativa Dipartimentale Ematologia, Azienda Ospedaliero-Universitaria Careggi, 50134 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3360-572X","authenticated-orcid":false,"given":"Leonardo","family":"Signori","sequence":"additional","affiliation":[{"name":"Struttura Operativa Dipartimentale Ematologia, Azienda Ospedaliero-Universitaria Careggi, 50134 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Zizza","sequence":"additional","affiliation":[{"name":"Struttura Operativa Dipartimentale Ematologia, Azienda Ospedaliero-Universitaria Careggi, 50134 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Annunziato","sequence":"additional","affiliation":[{"name":"Centro Diagnostico di Citofluorimetria e Immunoterapia, AOU Careggi, 50134 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Bosi","sequence":"additional","affiliation":[{"name":"Struttura Operativa Dipartimentale Ematologia, Azienda Ospedaliero-Universitaria Careggi, 50134 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1182\/blood-2009-03-209262","article-title":"The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes","volume":"114","author":"Vardiman","year":"2009","journal-title":"Blood"},{"key":"ref_2","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":"Arber","year":"2016","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1309\/EM7KCQR4GLMHRCX4","article-title":"Prognostic impact of acute myeloid leukemia classification. Importance of detection of recurring cytogenetic abnormalities and multilineage dysplasia on survival","volume":"119","author":"Arber","year":"2003","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1182\/blood-2007-08-101162","article-title":"MLD according to the WHO classification in AML has no correlation with age and no independent prognostic relevance as analyzed in 1766 patients","volume":"111","author":"Wandt","year":"2008","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2742","DOI":"10.1182\/blood-2010-04-279794","article-title":"Multilineage dysplasia (MLD) in acute myeloid leukemia (AML) correlates with MDS-related cytogenetic abnormalities and a prior history of MDS or MDS\/MPN but has no independent prognostic relevance: A comparison of 408 cases classified as \u201cAML not otherwise specified\u201d (AML-NOS) or \u201cAML with myelodysplasia-related changes\u201d (AML-MRC)","volume":"116","author":"Miesner","year":"2010","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1182\/blood-2008-10-182782","article-title":"Clinical characterization of acute myeloid leukemia with myelodysplasia-related changes as defined by the 2008 WHO classification system","volume":"113","author":"Weinberg","year":"2009","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1007\/s00277-014-2100-6","article-title":"Multilineage dysplasia is associated with a poorer prognosis in patients with de novo acute myeloid leukemia with intermediate-risk cytogenetics and wild-type NPM","volume":"93","author":"Rozman","year":"2014","journal-title":"Ann. Hematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3776","DOI":"10.1182\/blood-2009-08-240457","article-title":"Multilineage dysplasia has no impact on biologic, clinicopathologic, and prognostic features of AML with mutated nucleophosmin (NPM1)","volume":"115","author":"Falini","year":"2010","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6147","DOI":"10.1182\/blood-2010-09-307314","article-title":"The prognostic value of multilineage dysplasia in de novo acute myeloid leukemia patients with intermediate-risk cytogenetics is dependent on NPM1 mutational status","volume":"116","author":"Rozman","year":"2010","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4719","DOI":"10.1182\/blood-2011-12-395574","article-title":"Multilineage dysplasia does not influence prognosis in CEBPA-mutated AML, supporting the WHO proposal to classify these patients as a unique entity","volume":"119","author":"Bacher","year":"2012","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.exphem.2015.06.003","article-title":"Multilineage dysplasia as assessed by immunophenotype has no impact on clinical-biological features and outcome of NPM1-mutated acute myeloid leukemia","volume":"43","author":"Mannelli","year":"2015","journal-title":"Exp. Hematol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"529","DOI":"10.3324\/haematol.2016.151910","article-title":"CEBPA\u2013double-mutated acute myeloid leukemia displays a unique phenotypic profile: A reliable screening method and insight into biological features","volume":"102","author":"Mannelli","year":"2016","journal-title":"Haematologica"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1002\/ajh.25769","article-title":"Outcomes of acute myeloid leukemia with myelodysplasia related changes depend on diagnostic criteria and therapy","volume":"95","author":"Class","year":"2020","journal-title":"Am. J. Hematol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1002\/cyto.b.20513","article-title":"Bone marrow cells from myelodysplastic syndromes show altered immunophenotypic profiles that may contribute to the diagnosis and prognostic stratification of the disease: A pilot study on a series of 56 patients","volume":"78","author":"Matarraz","year":"2010","journal-title":"Cytom. Part B Clin. Cytom."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.3324\/haematol.2009.005801","article-title":"Standardization of flow cytometry in myelodysplastic syndromes: Report from the first European LeukemiaNet working conference on flow cytometry in myelodysplastic syndromes","volume":"94","author":"Alhan","year":"2009","journal-title":"Haematologica"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1182\/blood-2005-12-4916","article-title":"Diagnostic application of flow cytometric characteristics of CD34+ cells in low-grade myelodysplastic syndromes","volume":"108","author":"Ogata","year":"2006","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.3324\/haematol.2011.048421","article-title":"Multicenter validation of a reproducible flow cytometric score for the diagnosis of low-grade myelodysplastic syndromes: Results of a European LeukemiaNET study","volume":"97","author":"Porta","year":"2012","journal-title":"Haematologica"},{"key":"ref_18","unstructured":"Mitelman, F. (1994). ISCN 1995: An International System for Human Cytogenetic Nomenclature (1995): Recommendations of the International Standing Committee on Human Cytogenetic Nomenclature, Karger Medical and Scientific Publishers."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1182\/blood-2009-11-254441","article-title":"On behalf of the Refinement of cytogenetic classification in acute myeloid leukemia: Determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials","volume":"116","author":"Grimwade","year":"2010","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1056\/NEJMoa041974","article-title":"Cytoplasmic Nucleophosmin in Acute Myelogenous Leukemia with a Normal Karyotype","volume":"352","author":"Falini","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1038\/sj.leu.2403846","article-title":"Simultaneous detection of NPM1 and FLT3-ITD mutations by capillary electrophoresis in acute myeloid leukemia","volume":"19","author":"Noguera","year":"2005","journal-title":"Leukemia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1182\/blood.V98.6.1752","article-title":"The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: Analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials","volume":"98","author":"Kottaridis","year":"2001","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/85820","article-title":"Dominant-negative mutations of CEBPA, encoding CCAAT\/enhancer binding protein-\u03b1 (C\/EBP\u03b1), in acute myeloid leukemia","volume":"27","author":"Pabst","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4642","DOI":"10.1200\/JCO.2003.04.036","article-title":"Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia","volume":"21","author":"Cheson","year":"2003","journal-title":"J. Clin. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1182\/blood-2009-07-235358","article-title":"Diagnosis and management of acute myeloid leukemia in adults: Recommendations from an international expert panel, on behalf of the European LeukemiaNet","volume":"115","author":"Estey","year":"2010","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1182\/blood-2016-08-733196","article-title":"Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel","volume":"129","author":"Estey","year":"2017","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1056\/NEJMoa1614359","article-title":"Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation","volume":"377","author":"Stone","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1016\/S0140-6736(12)60485-1","article-title":"Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): A randomised, open-label, phase 3 study","volume":"379","author":"Castaigne","year":"2012","journal-title":"Lancet"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/S1470-2045(14)70281-5","article-title":"Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: A meta-analysis of individual patient data from randomised controlled trials","volume":"15","author":"Hills","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3924","DOI":"10.1200\/JCO.2012.42.2964","article-title":"Addition of Gemtuzumab Ozogamicin to Induction Chemotherapy Improves Survival in Older Patients with Acute Myeloid Leukemia","volume":"30","author":"Burnett","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4854","DOI":"10.1182\/blood-2013-01-466706","article-title":"A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia","volume":"121","author":"Petersdorf","year":"2013","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3239","DOI":"10.1182\/blood-2013-12-540971","article-title":"Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine\/daunorubicin, vs cytarabine\/daunorubicin in older adults with untreated AML","volume":"123","author":"Lancet","year":"2014","journal-title":"Blood"},{"key":"ref_33","first-page":"2684","article-title":"CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia","volume":"34","author":"Lancet","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_34","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":"DiNardo","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s00277-015-2580-z","article-title":"Transplant outcomes of the triple-negative NPM1\/FLT3-ITD\/CEBPA mutation subgroup are equivalent to those of the favourable ELN risk group, but significantly better than the intermediate-I risk group after allogeneic transplant in normal-karyotype AML","volume":"95","author":"Ahn","year":"2016","journal-title":"Ann. Hematol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1182\/blood-2015-06-651562","article-title":"Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation","volume":"126","author":"Schmid","year":"2015","journal-title":"Blood"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2793","DOI":"10.1093\/annonc\/mdx500","article-title":"Allogeneic hematopoietic cell transplantation in intermediate risk acute myeloid leukemia negative forFLT3-ITD, NPM1- or biallelic CEBPA mutations","volume":"28","author":"Heidrich","year":"2017","journal-title":"Ann. Oncol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/11\/3196\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:26:56Z","timestamp":1760178416000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/11\/3196"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,30]]},"references-count":37,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["cancers12113196"],"URL":"https:\/\/doi.org\/10.3390\/cancers12113196","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,30]]}}}