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Employing a multi-omics approach of up to 3.2 years of follow-up, we analyzed data from 24 CLL patients, specifically focusing on nine patients treated with ibrutinib monotherapy. In this study, clonal stability was observed within the ibrutinib-treated group following an effective initial clinical response, where clonotype frequencies of residual CLL cells remained high and stable, ranging from 74.9% at 1.5 years to 87.7% at approximately 3 years. In contrast, patients treated with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax exhibited substantial reductions in clonal frequencies, approaching molecular eradication. Deep whole-exome sequencing revealed minimal genomic progression in the ibrutinib group, maintaining somatic drivers and variant allele frequencies (VAF) above 0.2 throughout treatment. At the single-cell level, the NF-\u03baB pathway inhibition and apoptotic signals were detected or even augmented during treatment in ibrutinib-treated patients. These findings may corroborate the role of ibrutinib in stabilizing the genomic landscape of CLL cells, preventing significant genomic evolution despite maintaining a high clonal burden within the residual B-cell compartment.<\/jats:p>","DOI":"10.3390\/ijms252312569","type":"journal-article","created":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T10:17:23Z","timestamp":1732270643000},"page":"12569","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Molecular Composition and Kinetics of B Cells During Ibrutinib Treatment in Patients with Chronic Lymphocytic Leukemia"],"prefix":"10.3390","volume":"25","author":[{"given":"S\u00f3lja Remisd\u00f3ttir","family":"Veyhe","sequence":"first","affiliation":[{"name":"Haematology-Pathology Research Laboratory, Research Unit for Haematology and Research Unit for Pathology, University of Southern Denmark and Odense University Hospital, 5000 Odense, Denmark"},{"name":"Centre for Cellular Immunotherapy of Haematological Cancer Odense (CITCO), Odense University Hospital, 5000 Odense, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6632-8039","authenticated-orcid":false,"given":"Oriane","family":"C\u00e9dile","sequence":"additional","affiliation":[{"name":"Haematology-Pathology Research Laboratory, Research Unit for Haematology and Research Unit for Pathology, University of Southern Denmark and Odense University Hospital, 5000 Odense, Denmark"},{"name":"Centre for Cellular Immunotherapy of Haematological Cancer Odense (CITCO), Odense University Hospital, 5000 Odense, Denmark"},{"name":"Department of Haematology, Odense University Hospital, 5000 Odense, Denmark"},{"name":"Odense Patient Data Explorative Network (OPEN), Odense University Hospital, 5000 Odense, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6427-4276","authenticated-orcid":false,"given":"Sara Kamuk","family":"Dahlmann","sequence":"additional","affiliation":[{"name":"Haematology-Pathology Research Laboratory, Research Unit for Haematology and Research Unit for Pathology, University of Southern Denmark and Odense University Hospital, 5000 Odense, Denmark"},{"name":"Centre for Cellular Immunotherapy of Haematological Cancer Odense (CITCO), Odense University Hospital, 5000 Odense, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jakub","family":"Krejcik","sequence":"additional","affiliation":[{"name":"Haematology-Pathology Research Laboratory, Research Unit for Haematology and Research Unit for Pathology, University of Southern Denmark and Odense University Hospital, 5000 Odense, Denmark"},{"name":"Centre for Cellular Immunotherapy of Haematological Cancer Odense (CITCO), Odense University Hospital, 5000 Odense, Denmark"},{"name":"Department of Haematology, Odense University Hospital, 5000 Odense, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niels","family":"Abildgaard","sequence":"additional","affiliation":[{"name":"Haematology-Pathology Research Laboratory, Research Unit for Haematology and Research Unit for Pathology, University of Southern Denmark and Odense University Hospital, 5000 Odense, Denmark"},{"name":"Centre for Cellular Immunotherapy of Haematological Cancer Odense (CITCO), Odense University Hospital, 5000 Odense, Denmark"},{"name":"Department of Haematology, Odense University Hospital, 5000 Odense, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thor","family":"H\u00f8yer","sequence":"additional","affiliation":[{"name":"Department of Hematology, Aalborg University Hospital, 9000 Aalborg, Denmark"},{"name":"Department of Clinical Medicine, Aalborg University Hospital, 9000 Aalborg, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2041-3630","authenticated-orcid":false,"given":"Michael Boe","family":"M\u00f8ller","sequence":"additional","affiliation":[{"name":"Haematology-Pathology Research Laboratory, Research Unit for Haematology and Research Unit for Pathology, University of Southern Denmark and Odense University Hospital, 5000 Odense, Denmark"},{"name":"Department of Pathology, Odense University Hospital, 5000 Odense, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mads","family":"Thomassen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark"},{"name":"Clinical Genome Center, Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"Juul-Jensen","sequence":"additional","affiliation":[{"name":"Haematology-Pathology Research Laboratory, Research Unit for Haematology and Research Unit for Pathology, University of Southern Denmark and Odense University Hospital, 5000 Odense, Denmark"},{"name":"Department of Haematology, Odense University Hospital, 5000 Odense, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8905-0220","authenticated-orcid":false,"given":"Henrik","family":"Frederiksen","sequence":"additional","affiliation":[{"name":"Haematology-Pathology Research Laboratory, Research Unit for Haematology and Research Unit for Pathology, University of Southern Denmark and Odense University Hospital, 5000 Odense, Denmark"},{"name":"Department of Haematology, Odense University Hospital, 5000 Odense, 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Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/s41375-019-0602-x","article-title":"Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL\/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study","volume":"34","author":"Burger","year":"2020","journal-title":"Leukemia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/S1470-2045(24)00070-6","article-title":"Activity of venetoclax in patients with relapsed or refractory chronic lymphocytic leukaemia: Analysis of the VENICE-1 multicentre, open-label, single-arm, phase 3b trial","volume":"25","author":"Kater","year":"2024","journal-title":"Lancet Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1038\/leu.2017.32","article-title":"Bruton\u2019s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia","volume":"31","author":"Deng","year":"2017","journal-title":"Leukemia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3278","DOI":"10.1182\/blood.2021014488","article-title":"Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: Primary analysis of the CAPTIVATE FD cohort","volume":"139","author":"Tam","year":"2022","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"EVIDoa2200006","DOI":"10.1056\/EVIDoa2200006","article-title":"Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities","volume":"1","author":"Kater","year":"2022","journal-title":"NEJM Evid."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1001\/jamaoncol.2021.1649","article-title":"Ibrutinib Plus Venetoclax for First-line Treatment of Chronic Lymphocytic Leukemia: A Nonrandomized Phase 2 Trial","volume":"7","author":"Jain","year":"2021","journal-title":"JAMA Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2722","DOI":"10.1200\/JCO.19.00894","article-title":"Ibrutinib Plus Venetoclax in Relapsed\/Refractory Chronic Lymphocytic Leukemia: The CLARITY Study","volume":"37","author":"Hillmen","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4642","DOI":"10.1158\/1078-0432.CCR-15-0781","article-title":"Treatment with Ibrutinib Inhibits BTK- and VLA-4-Dependent Adhesion of Chronic Lymphocytic Leukemia Cells In Vivo","volume":"21","author":"Herman","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.1038\/leu.2014.122","article-title":"Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: Correlative analyses from a phase II study","volume":"28","author":"Herman","year":"2014","journal-title":"Leukemia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1182\/blood-2013-09-527853","article-title":"Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy","volume":"123","author":"Woyach","year":"2014","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1080\/10428194.2018.1512710","article-title":"Characterizing the kinetics of lymphocytosis in patients with chronic lymphocytic leukemia treated with single-agent ibrutinib","volume":"60","author":"Barrientos","year":"2019","journal-title":"Leuk. Lymphoma"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1182\/blood-2014-10-606038","article-title":"Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib","volume":"125","author":"Byrd","year":"2015","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4042","DOI":"10.1200\/JCO.20.00948","article-title":"Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study","volume":"38","author":"Kater","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1182\/blood-2018-08-870238","article-title":"Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab","volume":"133","author":"Byrd","year":"2019","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1182\/blood.2019003570","article-title":"Achieving complete remission in CLL patients treated with ibrutinib: Clinical significance and predictive factors","volume":"135","author":"Strati","year":"2020","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1056\/NEJMoa1713976","article-title":"Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia","volume":"378","author":"Seymour","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1182\/blood-2016-04-709519","article-title":"Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4\/SDF-1 axis","volume":"128","author":"Pavlasova","year":"2016","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1038\/s41467-017-02329-y","article-title":"The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy","volume":"8","author":"Landau","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.exphem.2023.01.002","article-title":"Reproducibility of low-level residual myeloma immunoglobulin detection using ultra-deep sequencing","volume":"119\u2013120","author":"Cedile","year":"2023","journal-title":"Exp. Hematol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/ng1180","article-title":"PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","author":"Mootha","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1056\/NEJMoa1400376","article-title":"Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia","volume":"371","author":"Byrd","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2357","DOI":"10.1182\/blood-2017-12-820910","article-title":"Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study","volume":"131","author":"Ahn","year":"2018","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1056\/NEJMoa2211582","article-title":"Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia","volume":"388","author":"Brown","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1182\/blood.2023021959","article-title":"Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL","volume":"143","author":"Woyach","year":"2024","journal-title":"Blood"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1182\/blood.2021014960","article-title":"Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: Updated results of the E1912 trial","volume":"140","author":"Shanafelt","year":"2022","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/nature14666","article-title":"Non-coding recurrent mutations in chronic lymphocytic leukaemia","volume":"526","author":"Puente","year":"2015","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1016\/S1470-2045(14)70335-3","article-title":"Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: A single-arm, phase 2 study","volume":"15","author":"Burger","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3286","DOI":"10.1182\/blood-2014-02-548610","article-title":"Ibrutinib inhibits BCR and NF-kappaB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL","volume":"123","author":"Herman","year":"2014","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/s41467-019-14081-6","article-title":"Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib response in CLL","volume":"11","author":"Rendeiro","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.1182\/bloodadvances.2022008821","article-title":"BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib","volume":"7","author":"Bonfiglio","year":"2023","journal-title":"Blood Adv."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41408-020-0305-6","article-title":"Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice","volume":"10","author":"Scourzic","year":"2020","journal-title":"Blood Cancer J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1038\/leu.2012.122","article-title":"EuroFlow standardization of flow cytometer instrument settings and immunophenotyping protocols","volume":"26","author":"Kalina","year":"2012","journal-title":"Leukemia"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1038\/leu.2012.120","article-title":"EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes","volume":"26","author":"Lhermitte","year":"2012","journal-title":"Leukemia"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"W34","DOI":"10.1093\/nar\/gkt382","article-title":"IgBLAST: An immunoglobulin variable domain sequence analysis tool","volume":"41","author":"Ye","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","article-title":"Fast and accurate long-read alignment with Burrows-Wheeler transform","volume":"26","author":"Li","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Cingolani, P., Patel, V.M., Coon, M., Nguyen, T., Land, S.J., Ruden, D.M., and Lu, X. (2012). Using Drosophila melanogaster as a Model for Genotoxic Chemical Mutational Studies with a New Program, SnpSift. Front. Genet., 3.","DOI":"10.3389\/fgene.2012.00035"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: Improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"D941","DOI":"10.1093\/nar\/gky1015","article-title":"COSMIC: The Catalogue Of Somatic Mutations In Cancer","volume":"47","author":"Tate","year":"2019","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/12569\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:37:47Z","timestamp":1760114267000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/12569"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,22]]},"references-count":53,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ijms252312569"],"URL":"https:\/\/doi.org\/10.3390\/ijms252312569","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,11,22]]}}}