{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T05:06:11Z","timestamp":1789189571571,"version":"build-2803163510"},"reference-count":14,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"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"],"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Clonal cytopenia of undetermined significance (CCUS) is a premalignant condition characterized by persistent cytopenias with somatic mutations but no morphologic evidence of overt myeloid neoplasia. While CCUS confers an elevated risk of progression to myeloid malignancies, the timing and biology of this transformation remain unpredictable. We hypothesized that the type of mutated gene and tracking clonal expansion over time via serial variant allele frequency (VAF) measurements may uncover early evolutionary signatures of malignant progression.<\/jats:p>\n <\/jats:sec>\n \n Design<\/jats:title>\n \n We retrospectively analyzed 55 CCUS patients who underwent serial next\u2010generation sequencing (NGS) testing. Patients were stratified by their final clinical course at the time of this study as non\u2010progressor (\n n<\/jats:italic>\n \u2009=\u200926) or progressor (\n n<\/jats:italic>\n \u2009=\u200929). Baseline clinicopathologic variables, mutation burden, and the presence of \u2265\u20091 high\u2010risk mutation, which was defined in prior studies as\n SF3B1<\/jats:italic>\n ,\n SRSF2<\/jats:italic>\n ,\n ZRSR2<\/jats:italic>\n ,\n JAK2<\/jats:italic>\n ,\n TP53<\/jats:italic>\n ,\n RUNX1<\/jats:italic>\n ,\n FLT3<\/jats:italic>\n ,\n IDH1<\/jats:italic>\n , and\n IDH2<\/jats:italic>\n , were compared between groups. The maximum annualized VAF slope across all tracked mutations was used as the primary dynamic clonal expansion metric. Baseline risk was assessed using the Clonal Hematopoiesis Risk Score (CHRS), and maximum VAF slope was evaluated across CHRS categories to determine whether serial clonal kinetics provided additional prognostic value beyond baseline risk stratification.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Compared with non\u2010progressors, progressors had a higher baseline mutation burden (\n p<\/jats:italic>\n \u2009<\u20090.01), more frequently harbored \u2265\u20091 high\u2010risk mutation at baseline (\n p<\/jats:italic>\n \u2009<\u20090.01), and also more acquired new mutations during follow\u2010up (\n p<\/jats:italic>\n \u2009<\u20090.01). Across longitudinally tracked mutations, progressor\u2010associated clones more frequently demonstrated positive annualized VAF slopes, particularly involving\n RUNX1<\/jats:italic>\n (12.70%\/year),\n STAG2<\/jats:italic>\n (13.09%\/year),\n ASXL1<\/jats:italic>\n (6.44%\/year),\n SRSF2<\/jats:italic>\n (4.29%\/year), and\n U2AF1<\/jats:italic>\n (8.21%\/year). Maximum annualized VAF slope correlated with CHRS risk category but also identified increased clonal expansion among progressors within the non\u2010high CHRS subgroup (\n p<\/jats:italic>\n \u2009=\u20090.006), suggesting added dynamic prognostic value beyond static baseline risk classification.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Serial VAF kinetics are helpful in predicting progression and complement baseline clinicopathologic features and CHRS risk stratification in CCUS. Expanding VAF trajectories, particularly involving\n RUNX1<\/jats:italic>\n , spliceosome genes, and cohesin\u2010related genes, may reflect biologically active clonal evolution toward progression to myeloid neoplasm, whereas stable or declining VAFs were more often observed in stable CCUS. These findings support that longitudinal VAF monitoring could be a practical dynamic approach to identify patients who require closer surveillance or repeat marrow evaluation.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/ejh.70320","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:13:20Z","timestamp":1789186400000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Serial\n VAF<\/scp>\n Kinetics Reveal Dynamic Clonal Evolution Associated With Progression in Clonal Cytopenia of Undetermined Significance"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4671-2148","authenticated-orcid":false,"given":"Zohre","family":"Sadeghian","sequence":"first","affiliation":[{"name":"Department of Pathology & Laboratory Medicine Cleveland Clinic Florida Weston Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1169-563X","authenticated-orcid":false,"given":"Mark Jinan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Cleveland Clinic Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9983-9735","authenticated-orcid":false,"given":"Kirill A.","family":"Lyapichev","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine Cleveland Clinic Florida Weston Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3664-3449","authenticated-orcid":false,"given":"Chieh\u2010Lin","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Cleveland Clinic Florida Weston Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4641-2217","authenticated-orcid":false,"given":"Chakra","family":"Chaulagain","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Cleveland Clinic Florida Weston Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2405-4527","authenticated-orcid":false,"given":"Maria Julia","family":"Diacovo","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine Cleveland Clinic Florida Weston Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Bosler","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Cleveland Clinic Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Behdad","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine Cleveland Clinic Florida Weston Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1038\/s41375-022-01613-1","article-title":"The 5th Edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic\/Dendritic Neoplasms","volume":"36","author":"Khoury J. 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A.","year":"2022","journal-title":"Nature Medicine"},{"key":"e_1_2_14_14_1","doi-asserted-by":"crossref","first-page":"e70014","DOI":"10.1002\/hem3.70014","article-title":"Comprehensive Sequential Genetic Analysis Delineating Frequency, Patterns, and Prognostic Impact of Genomic Dynamics in a Real\u2010World Cohort of Patients With Lower\u2010Risk MDS","volume":"8","author":"Mazzeo P.","year":"2024","journal-title":"HemaSphere"},{"key":"e_1_2_14_15_1","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41588-023-01472-1","article-title":"Multiparameter Prediction of Myeloid Neoplasia Risk","volume":"55","author":"Gu M.","year":"2023","journal-title":"Nature Genetics"}],"container-title":["European Journal of Haematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ejh.70320","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/ejh.70320","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ejh.70320","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:13:22Z","timestamp":1789186402000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/ejh.70320"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,11]]},"references-count":14,"alternative-id":["10.1111\/ejh.70320"],"URL":"https:\/\/doi.org\/10.1111\/ejh.70320","archive":["Portico"],"relation":{},"ISSN":["0902-4441","1600-0609"],"issn-type":[{"value":"0902-4441","type":"print"},{"value":"1600-0609","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,11]]},"assertion":[{"value":"2026-07-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"ejh.70320"}}