{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:29:46Z","timestamp":1787318986731,"version":"build-2736575974"},"reference-count":77,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T00:00:00Z","timestamp":1777161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T00:00:00Z","timestamp":1777161600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European J of Haematology"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Minimal residual disease (MRD) has emerged as a central biomarker in hematologic malignancies, enabling highly sensitive detection of tumor persistence beyond conventional morphologic assessment and serving as an increasingly important surrogate endpoint in clinical trials. Despite these advances, MRD remains predominantly conceptualized as a quantitative variable reflecting residual tumor burden below assay detection thresholds. While this paradigm has enabled standardization of response criteria and cross\u2010trial comparisons, it does not fully explain key clinical observations, including heterogeneous outcomes among MRD\u2010positive patients, durable remissions despite detectable disease, and discordance between molecular and imaging\u2010based assessments. Here, we propose a conceptual framework in which MRD is redefined as a biologically determined trait\u2014a functional phenotype of persistence\u2014rather than a purely quantitative state. We review the mechanisms that shape this phenotype, including therapy\u2010driven clonal selection, epigenetic and transcriptional plasticity, metabolic adaptation, immune evasion, and microenvironmental niche protection. These processes collectively define the functional fitness of residual tumor cells and their capacity to survive therapeutic pressure, remain dormant, and ultimately drive relapse. This framework provides a mechanistic explanation for clinically observed phenomena\u2014including molecular\u2013imaging discordance and variable relapse kinetics\u2014arguing that these are not merely technical artifacts but reflect distinct, partially independent biological dimensions of residual disease. We further outline a multidimensional model of MRD integrating molecular, spatial, immune, metabolic, and functional dimensions. Operationally, we define MRD as a biological trait across five interacting axes: (i) clonal fitness, (ii) phenotypic plasticity, (iii) metabolic adaptability, (iv) immune evasion, and (v) microenvironmental dependence. Conceptualizing MRD as a dynamic biological trait offers a more comprehensive and testable model of disease persistence and supports the development of mechanism\u2010based MRD\u2010directed therapeutic strategies in hematologic malignancies.<\/jats:p>","DOI":"10.1111\/ejh.70203","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T03:56:24Z","timestamp":1777262184000},"page":"320-337","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Minimal Residual Disease as a Biological Trait: Rethinking Disease Persistence in Hematologic Malignancies"],"prefix":"10.1111","volume":"117","author":[{"given":"Santino","family":"Caserta","sequence":"first","affiliation":[{"name":"Hematology Unit, Department of Onco\u2010Hematology, AO of Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrica Antonia","family":"Martino","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco\u2010Hematology, AO of Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Vigna","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco\u2010Hematology, AO of Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamdouh","family":"Skafi","sequence":"additional","affiliation":[{"name":"Emergency and Internal Medicine Department Saint Joseph Hospital  East Jerusalem Palestine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Bruzzese","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco\u2010Hematology, AO of Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Amodio","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine University of Catanzaro  Catanzaro Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenio","family":"Lucia","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco\u2010Hematology, AO of Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graziella","family":"D'Arrigo","sequence":"additional","affiliation":[{"name":"Istituto di Fisiologia Clinica del CNR di Reggio Calabria, Consiglio Nazionale Delle Ricerche  Reggio Calabria Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Olivito","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco\u2010Hematology, AO of Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Labanca","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco\u2010Hematology, AO of Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6339-632X","authenticated-orcid":false,"given":"Francesco","family":"Mendicino","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco\u2010Hematology, AO of Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Eugenia","family":"Alvaro","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco\u2010Hematology, AO of Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Tripepi","sequence":"additional","affiliation":[{"name":"Istituto di Fisiologia Clinica del CNR di Reggio Calabria, Consiglio Nazionale Delle Ricerche  Reggio Calabria Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fortunato","family":"Morabito","sequence":"additional","affiliation":[{"name":"AIL Sezione di Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5256-0726","authenticated-orcid":false,"given":"Massimo","family":"Gentile","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco\u2010Hematology, AO of Cosenza  Cosenza Italy"},{"name":"Department of Pharmacy, Health and Nutritional Science University of Calabria  Rende Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,26]]},"reference":[{"key":"e_1_2_20_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2016.3160"},{"key":"e_1_2_20_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.0580"},{"key":"e_1_2_20_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470\u20102045(15)70106\u20103"},{"key":"e_1_2_20_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470\u20102045(16)30206\u20106"},{"key":"e_1_2_20_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021013626"},{"key":"e_1_2_20_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102018\u201006\u2010858613"},{"key":"e_1_2_20_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010019\u20101367\u20100"},{"key":"e_1_2_20_9_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2017009845"},{"key":"e_1_2_20_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019001077"},{"key":"e_1_2_20_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12061384"},{"key":"e_1_2_20_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1709866"},{"key":"e_1_2_20_13_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2022.282034"},{"key":"e_1_2_20_14_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2018.78.5246"},{"key":"e_1_2_20_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hoc.2025.12.001"},{"key":"e_1_2_20_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2025016752"},{"key":"e_1_2_20_17_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.53.5229"},{"key":"e_1_2_20_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10762"},{"key":"e_1_2_20_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf2784"},{"key":"e_1_2_20_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.02.027"},{"key":"e_1_2_20_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.10.005"},{"key":"e_1_2_20_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00911-1"},{"key":"e_1_2_20_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-0441"},{"key":"e_1_2_20_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejh.14308"},{"key":"e_1_2_20_25_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1400029"},{"key":"e_1_2_20_26_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aal2380"},{"key":"e_1_2_20_27_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.93019"},{"key":"e_1_2_20_28_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2020.4600"},{"key":"e_1_2_20_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2714"},{"key":"e_1_2_20_30_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1801445"},{"key":"e_1_2_20_31_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-08-665679"},{"key":"e_1_2_20_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16101881"},{"key":"e_1_2_20_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature24297"},{"key":"e_1_2_20_34_1","article-title":"Emerging Technologies for Minimal Residual Disease Detection in Hematologic Malignancies","volume":"1963","author":"Groso D. J.","year":"2026","journal-title":"Seminars in Hematology"},{"key":"e_1_2_20_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.27582"},{"key":"e_1_2_20_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-024-01102-x"},{"key":"e_1_2_20_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10738"},{"key":"e_1_2_20_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-00302-4"},{"key":"e_1_2_20_39_1","doi-asserted-by":"crossref","DOI":"10.1111\/bjh.70619","article-title":"Minimal Residual Disease in Diffuse Large B\u2010Cell Lymphoma: From Metabolic Remission to Molecular Clearance in First\u2010Line Theraphy","author":"Caserta S.","year":"2026","journal-title":"British Journal of Haematology"},{"key":"e_1_2_20_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4040"},{"key":"e_1_2_20_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3646"},{"key":"e_1_2_20_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2012.12.013"},{"key":"e_1_2_20_43_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-08-172734"},{"key":"e_1_2_20_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13611"},{"key":"e_1_2_20_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4399"},{"key":"e_1_2_20_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.01.021"},{"key":"e_1_2_20_47_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.22.012703.104803"},{"key":"e_1_2_20_48_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1203486"},{"key":"e_1_2_20_49_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1604958"},{"key":"e_1_2_20_50_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.60.2383"},{"key":"e_1_2_20_51_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-0839"},{"key":"e_1_2_20_52_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar6711"},{"key":"e_1_2_20_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0146-z"},{"key":"e_1_2_20_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30864-7"},{"key":"e_1_2_20_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2009.175"},{"key":"e_1_2_20_56_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI66517"},{"key":"e_1_2_20_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2015.02.019"},{"key":"e_1_2_20_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010018\u20100014\u2010x"},{"key":"e_1_2_20_59_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-06-361386"},{"key":"e_1_2_20_60_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-08-3182"},{"key":"e_1_2_20_61_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-10-383406"},{"key":"e_1_2_20_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2026.105267"},{"key":"e_1_2_20_63_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1407003"},{"key":"e_1_2_20_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-018-0071-5"},{"key":"e_1_2_20_65_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2025031480"},{"key":"e_1_2_20_66_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-25-0572"},{"key":"e_1_2_20_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40966-8"},{"key":"e_1_2_20_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2025.06.004"},{"key":"e_1_2_20_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2026.108179"},{"key":"e_1_2_20_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.11.002"},{"key":"e_1_2_20_71_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-024-00967-y"},{"key":"e_1_2_20_72_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2023.1172108"},{"key":"e_1_2_20_73_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-022-10075-x"},{"key":"e_1_2_20_74_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-006284"},{"key":"e_1_2_20_75_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-026-01461-7"},{"key":"e_1_2_20_76_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-025-01673-7"},{"issue":"7","key":"e_1_2_20_77_1","first-page":"1573","article-title":"Molecular Measurable Residual Disease by Immunoglobulin Gene Rearrangements on Circulating Tumor DNA Predicts Outcome in Diffuse Large B\u2010Cell Lymphoma","volume":"110","author":"Soscia R.","year":"2025","journal-title":"Haematologica"},{"key":"e_1_2_20_78_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2025016332"}],"container-title":["European Journal of Haematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ejh.70203","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/ejh.70203","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ejh.70203","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T16:31:14Z","timestamp":1783009874000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/ejh.70203"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,26]]},"references-count":77,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1111\/ejh.70203"],"URL":"https:\/\/doi.org\/10.1111\/ejh.70203","archive":["Portico"],"relation":{},"ISSN":["0902-4441","1600-0609"],"issn-type":[{"value":"0902-4441","type":"print"},{"value":"1600-0609","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,26]]},"assertion":[{"value":"2026-04-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}