{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T01:31:02Z","timestamp":1793669462193,"version":"4.5.1"},"reference-count":91,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Bruton\u00b4s tyrosine kinase (BTK) inhibitor (BTKi)s block the B-cell receptor (BCR) signaling cascade by binding to the BTK enzyme preventing the proliferation and survival of malignant and normal B cells. During the past decade, the clinical use of BTKis for the treatment of B-cell malignancies has exponentially grown, changing the treatment landscape for chronic lymphocytic leukemia (CLL) in particular. At present, three different covalent BTKis, ibrutinib, acalabrutinib and zanubrutinib, are FDA-approved and many new inhibitors are under development. Despite having remarkable selectivity for BTK, the first-in-class BTKi ibrutinib can also bind, with various affinities, to other kinases. The combined inhibition of BTK (\u201con-target\u201d effect) and other kinases (\u201coff-target\u201d effect) can have additive or synergistic anti-tumor effects but also induce undesired side effects which might be treatment-limiting. Such \u201coff-target\u201d effects are expected to be more limited for second-generation BTKis. Moreover, the blockade of BCR signaling also indirectly affects the tumor microenvironment in CLL. Treatment with BTKis potentially impacts on both innate and adaptive immunity. Whether this affects infection susceptibility and vaccination efficacy requires further investigation. Here, we summarize the available knowledge on the impact of BTKis on the immune system and discuss the possible clinical implications. Indeed, a deeper knowledge on this topic could guide clinicians in the management and prevention of infections in patients with CLL treated with BTKis.<\/jats:p>","DOI":"10.3389\/fimmu.2021.686768","type":"journal-article","created":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T14:00:12Z","timestamp":1625148012000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":79,"title":["BTK Inhibitors in Chronic Lymphocytic Leukemia: Biological Activity and Immune Effects"],"prefix":"10.3389","volume":"12","author":[{"given":"Marzia","family":"Palma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom A.","family":"Mulder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"\u00d6sterborg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.343","article-title":"From Identification of the BTK Kinase to Effective Management of Leukemia","volume":"36","author":"Smith","year":"2017","journal-title":"Oncogene"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.191.10.1745","article-title":"Bruton\u2019s Tyrosine Kinase Is Required for Activation of IkappaB Kinase and Nuclear Factor kappaB in Response to B Cell Receptor Engagement","volume":"191","author":"Petro","year":"2000","journal-title":"J Exp Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M009137200","article-title":"Phospholipase C-Gamma 2 Couples Bruton\u2019s Tyrosine Kinase to the NF-kappaB Signaling Pathway in B Lymphocytes","volume":"276","author":"Petro","year":"2001","journal-title":"J Biol Chem"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.316","article-title":"BTK Inhibition Results in Impaired CXCR4 Chemokine Receptor Surface Expression, Signaling and Function in Chronic Lymphocytic Leukemia","volume":"30","author":"Chen","year":"2016","journal-title":"Leukemia"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-12-127688","article-title":"BCR Ligation Induced by IgM Stimulation Results in Gene Expression and Functional Changes Only in IgV H Unmutated Chronic Lymphocytic Leukemia (CLL) Cells","volume":"112","author":"Guarini","year":"2008","journal-title":"Blood"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-07-515361","article-title":"Bruton\u2019s Tyrosine Kinase (BTK) Function is Important to the Development and Expansion of Chronic Lymphocytic Leukemia (CLL)","volume":"123","author":"Woyach","year":"2014","journal-title":"Blood"},{"key":"B7","doi-asserted-by":"publisher","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":"B8","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-03-0889","article-title":"Nurselike Cells Express BAFF and APRIL, Which can Promote Survival of Chronic Lymphocytic Leukemia Cells via a Paracrine Pathway Distinct From That of SDF-1alpha","volume":"106","author":"Nishio","year":"2005","journal-title":"Blood"},{"key":"B9","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1182\/asheducation-2011.1.96","article-title":"Nurture Versus Nature: The Microenvironment in Chronic Lymphocytic Leukemia","volume":"2011","author":"Burger","year":"2011","journal-title":"Hematol Am Soc Hematol Educ Program"},{"key":"B10","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1182\/blood.2019003715","article-title":"Clinical and Biological Implications of Target Occupancy in CLL Treated With the BTK Inhibitor Acalabrutinib","volume":"136","author":"Sun","year":"2020","journal-title":"Blood"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-05-284984","article-title":"The Lymph Node Microenvironment Promotes B-Cell Receptor Signaling, NF-kappaB Activation, and Tumor Proliferation in Chronic Lymphocytic Leukemia","volume":"117","author":"Herishanu","year":"2011","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-2921","article-title":"Cell-Intrinsic Determinants of Ibrutinib-Induced Apoptosis in Chronic Lymphocytic Leukemia","volume":"23","author":"Amin","year":"2017","journal-title":"Clin Cancer Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-02-554220","article-title":"Kinetics of CLL Cells in Tissues and Blood During Therapy With the BTK Inhibitor Ibrutinib","volume":"123","author":"Wodarz","year":"2014","journal-title":"Blood"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1084\/jem.177.1.213","article-title":"Interferon Gamma Inhibits Apoptotic Cell Death in B Cell Chronic Lymphocytic Leukemia","volume":"177","author":"Buschle","year":"1993","journal-title":"J Exp Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1084\/jem.176.5.1319","article-title":"Interleukin 4 Protects Chronic Lymphocytic Leukemic B Cells From Death by Apoptosis and Upregulates Bcl-2 Expression","volume":"176","author":"Dancescu","year":"1992","journal-title":"J Exp Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V91.8.2689.2689_2689_2697","article-title":"Chronic Lymphocytic Leukemia B Cells can Express CD40 Ligand and Demonstrate T-Cell Type Costimulatory Capacity","volume":"91","author":"Schattner","year":"1998","journal-title":"Blood"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020005627","article-title":"miR-29 Modulates CD40 Signaling in Chronic Lymphocytic Leukemia by Targeting TRAF4: An Axis Affected by BCR Inhibitors","volume":"137","author":"Sharma","year":"2021","journal-title":"Blood"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-10-386417","article-title":"The Bruton Tyrosine Kinase Inhibitor PCI-32765 Thwarts Chronic Lymphocytic Leukemia Cell Survival and Tissue Homing In Vitro and In Vivo","volume":"119","author":"Ponader","year":"2012","journal-title":"Blood"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-11-390989","article-title":"The Clinically Active BTK Inhibitor PCI-32765 Targets B-Cell Receptor- and Chemokine-Controlled Adhesion and Migration in Chronic Lymphocytic Leukemia","volume":"119","author":"de Rooij","year":"2012","journal-title":"Blood"},{"key":"B20","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1056\/NEJMoa1215637","article-title":"Targeting BTK With Ibrutinib in Relapsed Chronic Lymphocytic Leukemia","volume":"369","author":"Byrd","year":"2013","journal-title":"N Engl J Med"},{"key":"B21","doi-asserted-by":"publisher","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":"B22","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-06-093906","article-title":"Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic Leukemia: A Report From the International Workshop on Chronic Lymphocytic Leukemia Updating the National Cancer Institute-Working Group 1996 Guidelines","volume":"111","author":"Hallek","year":"2008","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30212-1","article-title":"Ibrutinib for Patients With Relapsed or Refractory Chronic Lymphocytic Leukaemia With 17p Deletion (RESONATE-17): A Phase 2, Open-Label, Multicentre Study","volume":"17","author":"O\u2019Brien","year":"2016","journal-title":"Lancet Oncol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30019-5","article-title":"Venetoclax in Relapsed or Refractory Chronic Lymphocytic Leukaemia With 17p Deletion: A Multicentre, Open-Label, Phase 2 Study","volume":"17","author":"Stilgenbauer","year":"2016","journal-title":"Lancet Oncol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1056\/NEJMoa1315226","article-title":"Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia","volume":"370","author":"Furman","year":"2014","journal-title":"N Engl J Med"},{"key":"B26","unstructured":"Chronic Lymphocytic Leukemia Treatment"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1509388","article-title":"Ibrutinib as Initial Therapy for Patients With Chronic Lymphocytic Leukemia","volume":"373","author":"Burger","year":"2015","journal-title":"N Engl J Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.70.2282","article-title":"BTK(C481S)-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia","volume":"35","author":"Woyach","year":"2017","journal-title":"J\u00a0Clin Oncol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/S1470-2045(13)70513-8","article-title":"Ibrutinib as Initial Therapy for Elderly Patients With Chronic Lymphocytic Leukaemia or Small Lymphocytic Lymphoma: An Open-Label, Multicentre, Phase 1b\/2 Trial","volume":"15","author":"O\u2019Brien","year":"2014","journal-title":"Lancet Oncol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/leu.2017.175","article-title":"Extended Follow-Up and Impact of High-Risk Prognostic Factors From the Phase 3 RESONATE Study in Patients With Previously Treated CLL\/SLL","volume":"32","author":"Brown","year":"2018","journal-title":"Leukemia"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2014.218","article-title":"Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia","volume":"1","author":"Maddocks","year":"2015","journal-title":"JAMA Oncol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01454","article-title":"Bruton\u2019s Tyrosine Kinase: An Emerging Key Player in Innate Immunity","volume":"8","author":"Weber","year":"2017","journal-title":"Front Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2014.12","article-title":"B-Cell Receptor Pathway Inhibitors Affect CD20 Levels and Impair Antitumor Activity of Anti-CD20 Monoclonal Antibodies","volume":"28","author":"Bojarczuk","year":"2014","journal-title":"Leukemia"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2019.220590","article-title":"Differential Effects of BTK Inhibitors Ibrutinib and Zanubrutinib on NK-Cell Effector Function in Patients With Mantle Cell Lymphoma","volume":"105","author":"Flinsenberg","year":"2020","journal-title":"Haematologica"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.6.3575","article-title":"Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk","volume":"178","author":"Khurana","year":"2007","journal-title":"J Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-01-547869","article-title":"Ibrutinib Antagonizes Rituximab-Dependent NK Cell-Mediated Cytotoxicity","volume":"123","author":"Kohrt","year":"2014","journal-title":"Blood"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-04-281170","article-title":"Neutrophil Development and Function Critically Depend on Bruton Tyrosine Kinase in a Mouse Model of X-Linked Agammaglobulinemia","volume":"117","author":"Fiedler","year":"2011","journal-title":"Blood"},{"key":"B38","doi-asserted-by":"publisher","first-page":"R115","DOI":"10.1186\/ar3400","article-title":"The Bruton Tyrosine Kinase Inhibitor PCI-32765 Ameliorates Autoimmune Arthritis by Inhibition of Multiple Effector Cells","volume":"13","author":"Chang","year":"2011","journal-title":"Arthritis Res Ther"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.687251","article-title":"Analysis of the Effects of the Bruton\u2019s Tyrosine Kinase (Btk) Inhibitor Ibrutinib on Monocyte Fcgamma Receptor (FcgammaR) Function","volume":"291","author":"Ren","year":"2016","journal-title":"J Biol Chem"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.14548","article-title":"Effects of BTK Signalling in Pathogenic Microorganism Infections","volume":"23","author":"Ye","year":"2019","journal-title":"J Cell Mol Med"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2007.10.005","article-title":"Toll-Like Receptor Signaling is Impaired in Dendritic Cells From Patients With X-Linked Agammaglobulinemia","volume":"126","author":"Taneichi","year":"2008","journal-title":"Clin Immunol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1644","DOI":"10.1016\/j.jaci.2013.12.1085","article-title":"Bruton Tyrosine Kinase Mediates TLR9-Dependent Human Dendritic Cell Activation","volume":"133","author":"Lougaris","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.271247","article-title":"A Novel Role for Bruton\u2019s Tyrosine Kinase in Hepatocyte Growth Factor-Mediated Immunoregulation of Dendritic Cells","volume":"286","author":"Singhal","year":"2011","journal-title":"J\u00a0Biol Chem"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400395","article-title":"Immunoregulation of Dendritic Cells by the Receptor T Cell Ig and Mucin Protein-3 via Bruton\u2019s Tyrosine Kinase and C-Src","volume":"193","author":"Maurya","year":"2014","journal-title":"J Immunol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"e1057385","DOI":"10.1080\/2162402X.2015.1057385","article-title":"Ibrutinib Enhances IL-17 Response by Modulating the Function of Bone Marrow Derived Dendritic Cells","volume":"5","author":"Natarajan","year":"2016","journal-title":"Oncoimmunology"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-12-823393","article-title":"Ibrutinib Blocks Btk-Dependent NF-kB and NFAT Responses in Human Macrophages During Aspergillus Fumigatus Phagocytosis","volume":"132","author":"Bercusson","year":"2018","journal-title":"Blood"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.02158","article-title":"BTK Inhibition Impairs the Innate Response Against Fungal Infection in Patients With Chronic Lymphocytic Leukemia","volume":"11","author":"Fiorcari","year":"2020","journal-title":"Front Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-11-818286","article-title":"Early-Onset Invasive Aspergillosis and Other Fungal Infections in Patients Treated With Ibrutinib","volume":"131","author":"Ghez","year":"2018","journal-title":"Blood"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1111\/myc.13001","article-title":"Ibrutinib-Associated Invasive Fungal Diseases in Patients With Chronic Lymphocytic Leukaemia and non-Hodgkin Lymphoma: An Observational Study","volume":"62","author":"Ruchlemer","year":"2019","journal-title":"Mycoses"},{"key":"B50","doi-asserted-by":"publisher","first-page":"100635","DOI":"10.1016\/j.blre.2019.100635","article-title":"Immunomodulatory Effect of Ibrutinib: Reducing the Barrier Against Fungal Infections","volume":"40","author":"Maffei","year":"2020","journal-title":"Blood Rev"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.16836","article-title":"The Bruton\u2019s Tyrosine Kinase Inhibitor Ibrutinib Exerts Immunomodulatory Effects Through Regulation of Tumor-Infiltrating Macrophages","volume":"8","author":"Ping","year":"2017","journal-title":"Oncotarget"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-1490","article-title":"Myeloid-Derived Suppressor Cells Express Bruton\u2019s Tyrosine Kinase and Can Be Depleted in Tumor-Bearing Hosts by Ibrutinib Treatment","volume":"76","author":"Stiff","year":"2016","journal-title":"Cancer Res"},{"key":"B53","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1002\/hon.2667","article-title":"The Impacts of Zanubrutinib on Immune Cells in Patients With Chronic Lymphocytic Leukemia\/Small Lymphocytic Lymphoma","volume":"37","author":"Zou","year":"2019","journal-title":"Hematol Oncol"},{"key":"B54","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1159\/000078339","article-title":"The Role of Tec Family Kinases in Myeloid Cells","volume":"134","author":"Schmidt","year":"2004","journal-title":"Int Arch Allergy Immunol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200838839","article-title":"The Protein Tyrosine Kinase Tec Regulates Mast Cell Function","volume":"39","author":"Schmidt","year":"2009","journal-title":"Eur J Immunol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.165613","article-title":"Absence of Tec Family Kinases Interleukin-2 Inducible T Cell Kinase (Itk) and Bruton\u2019s Tyrosine Kinase (Btk) Severely Impairs Fc epsilonRI-Dependent Mast Cell Responses","volume":"286","author":"Iyer","year":"2011","journal-title":"J Biol Chem"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2020.1753043","article-title":"The Effect of Ibrutinib on Neutrophil and Gammadelta T Cell Functions","volume":"61","author":"Risnik","year":"2020","journal-title":"Leuk Lymphoma"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.3816\/CLM.2009.n.071","article-title":"Infectious Complications in Patients With Chronic Lymphocytic Leukemia: Pathogenesis, Spectrum of Infection, and Approaches to Prophylaxis","volume":"9","author":"Morrison","year":"2009","journal-title":"Clin Lymphoma Myeloma"},{"key":"B59","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1007\/s00262-005-0015-8","article-title":"Immune Defects in Patients With Chronic Lymphocytic Leukemia","volume":"55","author":"Ravandi","year":"2006","journal-title":"Cancer Immunol Immunother"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-04-639203","article-title":"Partial Reconstitution of Humoral Immunity and Fewer Infections in Patients With Chronic Lymphocytic Leukemia Treated With Ibrutinib","volume":"126","author":"Sun","year":"2015","journal-title":"Blood"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2016.151100","article-title":"T Cells in Chronic Lymphocytic Leukemia Display Dysregulated Expression of Immune Checkpoints and Activation Markers","volume":"102","author":"Palma","year":"2017","journal-title":"Haematologica"},{"key":"B62","doi-asserted-by":"publisher","first-page":"e1432328","DOI":"10.1080\/2162402X.2018.1432328","article-title":"Restricted T Cell Receptor Repertoire in CLL-Like Monoclonal B Cell Lymphocytosis and Early Stage CLL","volume":"7","author":"Blanco","year":"2018","journal-title":"Oncoimmunology"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21010068","article-title":"Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy Against CLL","volume":"21","author":"Mhibik","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-1965","article-title":"Disruption of In Vivo Chronic Lymphocytic Leukemia Tumor-Microenvironment Interactions by Ibrutinib\u2013Findings From an Investigator-Initiated Phase II Study","volume":"22","author":"Niemann","year":"2016","journal-title":"Clin Cancer Res"},{"key":"B65","doi-asserted-by":"publisher","first-page":"e564","DOI":"10.1097\/HS9.0000000000000564","article-title":"Ibrutinib Has Time-Dependent On- and Off-Target Effects on Plasma Biomarkers and Immune Cells in Chronic Lymphocytic Leukemia","volume":"5","author":"Mulder","year":"2021","journal-title":"Hemasphere"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1172\/JCI89756","article-title":"Ibrutinib Treatment Improves T Cell Number and Function in CLL Patients","volume":"127","author":"Long","year":"2017","journal-title":"J Clin Invest"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601190","article-title":"Ibrutinib Therapy Increases T Cell Repertoire Diversity in Patients With Chronic Lymphocytic Leukemia","volume":"198","author":"Yin","year":"2017","journal-title":"J Immunol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2018884940","article-title":"Acalabrutinib Monotherapy in Patients With Relapsed\/Refractory Chronic Lymphocytic Leukemia: Updated Phase 2 Results","volume":"135","author":"Byrd","year":"2020","journal-title":"Blood"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-06-507947","article-title":"Ibrutinib is an Irreversible Molecular Inhibitor of ITK Driving a Th1-Selective Pressure in T Lymphocytes","volume":"122","author":"Dubovsky","year":"2013","journal-title":"Blood"},{"key":"B70","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1182\/blood-2018-99-109847","article-title":"Ibrutinib Increases the Clonality of TCR Repertoire in Patients With Chronic Lymphocytic Leukemia","volume":"132","author":"Baptista","year":"2018","journal-title":"Blood"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019001319","article-title":"Novel Mouse Model Resistant to Irreversible BTK Inhibitors: A Tool Identifying New Therapeutic Targets and Side Effects","volume":"4","author":"Estupinan","year":"2020","journal-title":"Blood Adv"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2005.12.1330","article-title":"Reduced Airway Hyperresponsiveness and Tracheal Responses During Allergic Asthma in Mice Lacking Tyrosine Kinase Inducible T-Cell Kinase","volume":"117","author":"Ferrara","year":"2006","journal-title":"J Allergy Clin Immunol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.16148","article-title":"Changes in T-Cell Subpopulations and Cytokine Network During Early Period of Ibrutinib Therapy in Chronic Lymphocytic Leukemia Patients: The Significant Decrease in T Regulatory Cells Number","volume":"8","author":"Podhorecka","year":"2017","journal-title":"Oncotarget"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.4065\/75.10.1039","article-title":"Infection and Immunity in Chronic Lymphocytic Leukemia","volume":"75","author":"Tsiodras","year":"2000","journal-title":"Mayo Clin Proc"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1111\/ejh.13020","article-title":"Systematic Review of Infectious Events With the Bruton Tyrosine Kinase Inhibitor Ibrutinib in the Treatment of Hematologic Malignancies","volume":"100","author":"Tillman","year":"2018","journal-title":"Eur J Haematol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-019-0481-1","article-title":"Incidence of Opportunistic Infections During Ibrutinib Treatment for B-Cell Malignancies","volume":"33","author":"Rogers","year":"2019","journal-title":"Leukemia"},{"key":"B77","doi-asserted-by":"publisher","first-page":"4164","DOI":"10.1182\/blood-2018-99-111518","article-title":"Infections in Patients With Lymphoproliferative Diseases Treated With Target Therapy. Italian Multicentric Retrospective Study Seifem 2017","volume":"132","author":"Nadali","year":"2018","journal-title":"Blood"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciy175","article-title":"Serious Infections in Patients Receiving Ibrutinib for Treatment of Lymphoid Cancer","volume":"67","author":"Varughese","year":"2018","journal-title":"Clin Infect Dis"},{"key":"B79","doi-asserted-by":"publisher","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":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2018.05.012","article-title":"Pneumococcal Conjugate Vaccine Triggers a Better Immune Response Than Pneumococcal Polysaccharide Vaccine in Patients With Chronic Lymphocytic Leukemia A Randomized Study by the Swedish CLL Group","volume":"36","author":"Svensson","year":"2018","journal-title":"Vaccine"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2010.032664","article-title":"Repeated Vaccination is Required to Optimize Seroprotection Against H1N1 in the Immunocompromised Host","volume":"96","author":"de Lavallade","year":"2011","journal-title":"Haematologica"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.164285","article-title":"Ibrutinib may Impair Serological Responses to Influenza Vaccination","volume":"102","author":"Douglas","year":"2017","journal-title":"Haematologica"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2016.2437","article-title":"Seasonal Influenza Vaccination in Patients With Chronic Lymphocytic Leukemia Treated With Ibrutinib","volume":"2","author":"Sun","year":"2016","journal-title":"JAMA Oncol"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020008758","article-title":"Effect of Bruton Tyrosine Kinase Inhibitor on Efficacy of Adjuvanted Recombinant Hepatitis B and Zoster Vaccines","volume":"137","author":"Pleyer","year":"2021","journal-title":"Blood"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-020-01074-4","article-title":"Short Term Results of Vaccination With Adjuvanted Recombinant Varicella Zoster Glycoprotein E During Initial BTK Inhibitor Therapy for CLL or Lymphoplasmacytic Lymphoma","author":"Zent","year":"2020","journal-title":"Leukemia"},{"key":"B86","first-page":"49","article-title":"Immunogenicity of a Recombinant Herpes Zoster Vaccine in Patients With Chronic Lymphocytic Leukemia","volume-title":"Blood","author":"Muchtar","year":"2020"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-020-0884-z","article-title":"Response to the Conjugate Pneumococcal Vaccine (PCV13) in Patients With Chronic Lymphocytic Leukemia (CLL)","author":"Mauro","year":"2020","journal-title":"Leukemia"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14855","article-title":"Lack of Adequate Pneumococcal Vaccination Response in Chronic Lymphocytic Leukaemia Patients Receiving Ibrutinib","volume":"182","author":"Andrick","year":"2018","journal-title":"Br J Haematol"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-020-0959-x","article-title":"COVID-19 Severity and Mortality in Patients With Chronic Lymphocytic Leukemia: A Joint Study by ERIC, the European Research Initiative on CLL, and CLL Campus","volume":"34","author":"Scarfo","year":"2020","journal-title":"Leukemia"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020006965","article-title":"Outcomes of COVID-19 in Patients With CLL: A Multicenter International Experience","volume":"136","author":"Mato","year":"2020","journal-title":"Blood"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.03.062","article-title":"The Development of Bruton\u2019s Tyrosine Kinase (BTK) Inhibitors From 2012 to 2017: A Mini-Review","volume":"151","author":"Liang","year":"2018","journal-title":"Eur J Med Chem"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.686768\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T14:00:16Z","timestamp":1625148016000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.686768\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,1]]},"references-count":91,"alternative-id":["10.3389\/fimmu.2021.686768"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.686768","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,1]]},"article-number":"686768"}}