Molecular Composition and Kinetics of B Cells During Ibrutinib Treatment in Patients with Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of B cells due to constitutive B-cell receptor (BCR) signaling, leading to apoptosis resistance and increased proliferation. This study evaluates the effects of the Bruton Tyrosine Kinase (BTK) inhibitor ibrutinib on the molecul...
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| Veröffentlicht in: | International journal of molecular sciences 2024-12, Vol.25 (23), p.12569 |
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| creator | Veyhe, Sólja Remisdóttir Cédile, Oriane Dahlmann, Sara Kamuk Krejcik, Jakub Abildgaard, Niels Høyer, Thor Møller, Michael Boe Thomassen, Mads Juul-Jensen, Karen Frederiksen, Henrik Dybkær, Karen Hansen, Marcus Høy Nyvold, Charlotte Guldborg |
| description | Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of B cells due to constitutive B-cell receptor (BCR) signaling, leading to apoptosis resistance and increased proliferation. This study evaluates the effects of the Bruton Tyrosine Kinase (BTK) inhibitor ibrutinib on the molecular composition, clonality, and kinetics of B cells during treatment in CLL patients. 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-κB 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. |
| doi_str_mv | 10.3390/ijms252312569 |
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This study evaluates the effects of the Bruton Tyrosine Kinase (BTK) inhibitor ibrutinib on the molecular composition, clonality, and kinetics of B cells during treatment in CLL patients. 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-κB pathway inhibition and apoptotic signals were detected or even augmented during treatment in ibrutinib-treated patients. 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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c274t-523af0c86ee9a45c63f56415dd941b3daf17a54c047995063535a18064375a5f3</cites><orcidid>0000-0003-3083-4850 ; 0000-0001-8905-0220 ; 0000-0002-6632-8039 ; 0000-0003-2041-3630 ; 0000-0002-6427-4276 ; 0000-0002-0411-7594 ; 0000-0003-2488-435X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39684282$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Veyhe, Sólja Remisdóttir</creatorcontrib><creatorcontrib>Cédile, Oriane</creatorcontrib><creatorcontrib>Dahlmann, Sara Kamuk</creatorcontrib><creatorcontrib>Krejcik, Jakub</creatorcontrib><creatorcontrib>Abildgaard, Niels</creatorcontrib><creatorcontrib>Høyer, Thor</creatorcontrib><creatorcontrib>Møller, Michael Boe</creatorcontrib><creatorcontrib>Thomassen, Mads</creatorcontrib><creatorcontrib>Juul-Jensen, Karen</creatorcontrib><creatorcontrib>Frederiksen, Henrik</creatorcontrib><creatorcontrib>Dybkær, Karen</creatorcontrib><creatorcontrib>Hansen, Marcus Høy</creatorcontrib><creatorcontrib>Nyvold, Charlotte Guldborg</creatorcontrib><title>Molecular Composition and Kinetics of B Cells During Ibrutinib Treatment in Patients with Chronic Lymphocytic Leukemia</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of B cells due to constitutive B-cell receptor (BCR) signaling, leading to apoptosis resistance and increased proliferation. This study evaluates the effects of the Bruton Tyrosine Kinase (BTK) inhibitor ibrutinib on the molecular composition, clonality, and kinetics of B cells during treatment in CLL patients. 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-κB pathway inhibition and apoptotic signals were detected or even augmented during treatment in ibrutinib-treated patients. 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This study evaluates the effects of the Bruton Tyrosine Kinase (BTK) inhibitor ibrutinib on the molecular composition, clonality, and kinetics of B cells during treatment in CLL patients. 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-κB 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.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>39684282</pmid><doi>10.3390/ijms252312569</doi><orcidid>https://orcid.org/0000-0003-3083-4850</orcidid><orcidid>https://orcid.org/0000-0001-8905-0220</orcidid><orcidid>https://orcid.org/0000-0002-6632-8039</orcidid><orcidid>https://orcid.org/0000-0003-2041-3630</orcidid><orcidid>https://orcid.org/0000-0002-6427-4276</orcidid><orcidid>https://orcid.org/0000-0002-0411-7594</orcidid><orcidid>https://orcid.org/0000-0003-2488-435X</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | International journal of molecular sciences, 2024-12, Vol.25 (23), p.12569 |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Adenine - analogs & derivatives Adenine - therapeutic use Agammaglobulinaemia Tyrosine Kinase - antagonists & inhibitors Agammaglobulinaemia Tyrosine Kinase - genetics Agammaglobulinaemia Tyrosine Kinase - metabolism Aged Aged, 80 and over Apoptosis B cells B-Lymphocytes - drug effects B-Lymphocytes - immunology B-Lymphocytes - metabolism Bridged Bicyclo Compounds, Heterocyclic - pharmacology Bridged Bicyclo Compounds, Heterocyclic - therapeutic use Care and treatment Cells Chronic lymphocytic leukemia Cloning Ethylenediaminetetraacetic acid Exome Sequencing Female Humans Inhibitor drugs Kinases Kinetics Leukemia Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy Leukemia, Lymphocytic, Chronic, B-Cell - genetics Leukemia, Lymphocytic, Chronic, B-Cell - metabolism Lymphocytes Male Medical research Medicine, Experimental Middle Aged Patients Piperidines - pharmacology Piperidines - therapeutic use Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Proteins Proto-Oncogene Proteins c-bcl-2 - genetics Proto-Oncogene Proteins c-bcl-2 - metabolism Pyrazoles - pharmacology Pyrazoles - therapeutic use Pyrimidines - pharmacology Pyrimidines - therapeutic use Sulfonamides - pharmacology Sulfonamides - therapeutic use Targeted cancer therapy Tyrosine |
| title | Molecular Composition and Kinetics of B Cells During Ibrutinib Treatment in Patients with Chronic Lymphocytic Leukemia |
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