{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T02:05:33Z","timestamp":1781316333734,"version":"3.54.1"},"reference-count":78,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T00:00:00Z","timestamp":1679875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology, Taiwan","award":["MOST 109-2320-B-038-050"],"award-info":[{"award-number":["MOST 109-2320-B-038-050"]}]},{"name":"Ministry of Science and Technology, Taiwan","award":["110-2320-B-038-064-MY3"],"award-info":[{"award-number":["110-2320-B-038-064-MY3"]}]},{"name":"Taipei Medical University, Taiwan","award":["MOST 109-2320-B-038-050"],"award-info":[{"award-number":["MOST 109-2320-B-038-050"]}]},{"name":"Taipei Medical University, Taiwan","award":["110-2320-B-038-064-MY3"],"award-info":[{"award-number":["110-2320-B-038-064-MY3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The effectiveness and safety of combination treatments such as chemoimmunotherapies in chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL\/SLL) remain controversial. Bruton tyrosine kinase inhibitors (BTKis) are an effective therapy for CLL\/SLL patients. This meta-analysis aimed to compare the efficacy and safety of BTKis versus combination therapy in CLL\/SLL patients. We searched the PubMed, Cochrane, Medline, and Embase databases through February 2023 for relevant randomized controlled trials (RCTs). Four RCTs (including 1510 patients) were found and met the inclusion criteria. Progression-free survival (PFS) was significantly improved with BTKis when compared to the combination therapy (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.22\u20130.40), while a pooled analysis of overall survival did not favor single-agent BTKis over the combination therapy (HR, 0.87; 95% CI, 0.67\u20131.15). We observed consistent benefits for PFS among patients with high-risk disease characteristics. Although there was no difference in complete response between the two arms (risk ratio (RR), 0.54; 95% CI, 0.20\u20131.46), BTKi use was related to a better overall response rate (RR, 1.10; 95% CI, 1.04\u20131.16). The risk of grade \u22653 adverse events (AEs) was comparable between the two arms (RR, 0.82; 95% CI, 0.55\u20131.23). However, the risk of grade \u22653 AEs was significantly lower in the second-generation BTKi group than in the combination therapy group (RR, 0.73; 95% CI, 0.54\u20130.98). Overall, BTKis have superior efficacy compared to the combination regimens in patients with untreated or treated CLL\/SLL without excess toxicity. Further studies are needed to confirm these results and determine the optimal therapy for managing patients with CLL\/SLL.<\/jats:p>","DOI":"10.3390\/cancers15071996","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T07:32:09Z","timestamp":1679902329000},"page":"1996","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Efficacy and Safety of Bruton Tyrosine Kinase Inhibitor Monotherapy Compared with Combination Therapy for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5050-574X","authenticated-orcid":false,"given":"Thi Thuy","family":"Nguyen","sequence":"first","affiliation":[{"name":"International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Oncology, Hue University of Medicine and Pharmacy, Hue University, Hue 49120, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1636-6061","authenticated-orcid":false,"given":"Nguyen Thanh","family":"Nhu","sequence":"additional","affiliation":[{"name":"International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Faculty of Medicine, Can Tho University of Medicine and Pharmacy, Can Tho 94117, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Van Khoi","family":"Tran","sequence":"additional","affiliation":[{"name":"International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Surgery, Hue University of Medicine and Pharmacy, Hue University, Hue 49120, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tran Thuc Huan","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hue University of Medicine and Pharmacy, Hue University, Hue 49120, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4396-6086","authenticated-orcid":false,"given":"Chiou-Feng","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Core Laboratory of Immune Monitoring, Office of Research & Development, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,27]]},"reference":[{"key":"ref_1","first-page":"2745","article-title":"iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL","volume":"131","author":"Hallek","year":"2018","journal-title":"J. Am. Soc. Hematol."},{"key":"ref_2","first-page":"208","article-title":"Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: Updated results of the CLL8 trial","volume":"127","author":"Fischer","year":"2016","journal-title":"J. Am. Soc. Hematol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1016\/S0140-6736(18)30422-7","article-title":"Chronic lymphocytic leukaemia","volume":"391","author":"Hallek","year":"2018","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3559","DOI":"10.1200\/JCO.2010.33.8061","article-title":"Bendamustine combined with rituximab in patients with relapsed and\/or refractory chronic lymphocytic leukemia: A multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group","volume":"29","author":"Fischer","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","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":"ref_6","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1056\/NEJMoa1313984","article-title":"Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions","volume":"370","author":"Goede","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1016\/S1470-2045(20)30443-5","article-title":"Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): Follow-up results from a multicentre, open-label, randomised, phase 3 trial","volume":"21","author":"Zhang","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.3324\/haematol.2018.189837","article-title":"Efficacy of bendamustine and rituximab as first salvage treatment in chronic lymphocytic leukemia and indirect comparison with ibrutinib: A gimema, eric and UK cll forum study","volume":"103","author":"Cuneo","year":"2018","journal-title":"Haematologica"},{"key":"ref_10","first-page":"2199","article-title":"Outcomes of CLL patients treated with sequential kinase inhibitor therapy: A real world experience","volume":"128","author":"Mato","year":"2016","journal-title":"J. Am. Soc. Hematol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1093\/annonc\/mdx031","article-title":"Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: Results from a multicenter study of 683 patients","volume":"28","author":"Mato","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1200\/JCO.18.01460","article-title":"Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia","volume":"37","author":"Sharman","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.3109\/10428194.2014.957203","article-title":"Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: Distribution and clinical outcomes","volume":"56","author":"Benjamini","year":"2015","journal-title":"Leuk. Lymphoma"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s40164-019-0139-8","article-title":"Frontline therapies for untreated chronic lymphoid leukemia","volume":"8","author":"Liu","year":"2019","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2425","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":"ref_16","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_17","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1056\/NEJMoa1509981","article-title":"Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia","volume":"374","author":"Byrd","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13045-020-00884-4","article-title":"Treatment of relapsed\/refractory chronic lymphocytic leukemia\/small lymphocytic lymphoma with the BTK inhibitor zanubrutinib: Phase 2, single-arm, multicenter study","volume":"13","author":"Xu","year":"2020","journal-title":"J. Hematol. Oncol."},{"key":"ref_19","first-page":"3286","article-title":"Ibrutinib inhibits BCR and NF-\u03baB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL","volume":"123","author":"Herman","year":"2014","journal-title":"J. Am. Soc. Hematol."},{"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\u2013Dependent Adhesion of Chronic Lymphocytic Leukemia Cells In VivoIbrutinib Inhibits VLA-4\u2013Dependent Adhesion in CLL","volume":"21","author":"Herman","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_21","first-page":"1182","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":"J. Am. Soc. Hematol."},{"key":"ref_22","first-page":"1910","article-title":"Single-agent ibrutinib in treatment-na\u00efve and relapsed\/refractory chronic lymphocytic leukemia: A 5-year experience","volume":"131","author":"Furman","year":"2018","journal-title":"J. Am. Soc. Hematol."},{"key":"ref_23","unstructured":"(2015, January 01). Imbruvica\u00ae (ibrutinib) capsules, for oral use, Available online: https:\/\/www.Accessdata.Fda.Gov\/drugsatfda_docs\/label\/2015\/205552s002lbl.Pdf."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1056\/NEJMoa1817073","article-title":"Ibrutinib\u2013rituximab or chemoimmunotherapy for chronic lymphocytic leukemia","volume":"381","author":"Shanafelt","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1056\/NEJMoa1812836","article-title":"Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL","volume":"379","author":"Woyach","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"103238","DOI":"10.1016\/j.critrevonc.2021.103238","article-title":"Risk of bleeding complications and atrial fibrillation associated with ibrutinib treatment: A systematic review and meta-analysis","volume":"159","author":"Pellegrini","year":"2021","journal-title":"Crit. Rev. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1002\/ajh.25638","article-title":"Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma","volume":"94","author":"Munir","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e400","DOI":"10.3324\/haematol.2017.169334","article-title":"The specific Bruton tyrosine kinase inhibitor acalabrutinib (ACP-196) shows favorable in vitro activity against chronic lymphocytic leukemia B cells with CD20 antibodies","volume":"102","author":"Golay","year":"2017","journal-title":"Haematologica"},{"key":"ref_29","unstructured":"Food and Drug Administration (2019, November 21). FDA Takes Second Action under International Collaboration, Approves New Treatment Option for Patients with Chronic Lymphocytic Leukemia, Available online: https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-takes-second-action-under-international-collaboration-approves-new-treatment-option-patients."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1016\/S0140-6736(20)30262-2","article-title":"Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE-TN): A randomised, controlled, phase 3 trial","volume":"395","author":"Sharman","year":"2020","journal-title":"Lancet"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7923","DOI":"10.1021\/acs.jmedchem.9b00687","article-title":"Discovery of zanubrutinib (BGB-3111), a novel, potent, and selective covalent inhibitor of Bruton\u2019s tyrosine kinase","volume":"62","author":"Guo","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4216","DOI":"10.1158\/1078-0432.CCR-19-3703","article-title":"Treatment of Patients with Relapsed or Refractory Mantle\u2013Cell Lymphoma with Zanubrutinib, a Selective Inhibitor of Bruton\u2019s Tyrosine KinaseZanubrutinib for Relapsed\/Refractory MCL","volume":"26","author":"Song","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_33","first-page":"851","article-title":"Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL","volume":"134","author":"Tam","year":"2019","journal-title":"J. Am. Soc. Hematol."},{"key":"ref_34","unstructured":"Hillmen, P., Eichhorst, B., Brown, J.R., Lamanna, N., O\u2019Brien, S., Tam, C.S., Qiu, L., Kazmierczak, M., Zhou, K., and \u0160imkovi\u010d, M. (2021, January 7). First interim analysis of ALPINE study: Results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed\/refractory chronic lymphocytic leukemia\/small lymphocytic lymphoma. Proceedings of the 2021 European Hematology Association Virtual Congress, Virtual."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"Br. Med. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.annonc.2020.09.019","article-title":"Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"32","author":"Eichhorst","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Higgins, J., Thomas, J., Chandler, J., Cumpston, M., Li, T., Page, M., and Welch, V. (2019, September 23). Cochrane Handbook for Systematic Reviews of Interventions Version 6.3 (Updated February 2022); Cochrane. Available online: www.training.cochrane.org\/handbook.","DOI":"10.1002\/9781119536604"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5446","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\u2013Working Group 1996 guidelines","volume":"111","author":"Hallek","year":"2008","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1200\/JCO.2013.54.8800","article-title":"Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification","volume":"32","author":"Cheson","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1745-6215-8-16","article-title":"Practical methods for incorporating summary time-to-event data into meta-analysis","volume":"8","author":"Tierney","year":"2007","journal-title":"Trials"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2854","DOI":"10.1038\/s41375-021-01342-x","article-title":"Adverse event burden in older patients with CLL receiving bendamustine plus rituximab or ibrutinib regimens: Alliance A041202","volume":"35","author":"Ruppert","year":"2021","journal-title":"Leukemia"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.1200\/JCO.19.03355","article-title":"ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia","volume":"38","author":"Ghia","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"E801","DOI":"10.1097\/HS9.0000000000000801","article-title":"Acalabrutinib Versus Investigator\u2019s Choice in Relapsed\/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results","volume":"6","author":"Ghia","year":"2022","journal-title":"HemaSphere"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1038\/s41375-021-01485-x","article-title":"Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-na\u00efve chronic lymphocytic leukemia","volume":"36","author":"Sharman","year":"2022","journal-title":"Leukemia"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/S1470-2045(22)00293-5","article-title":"Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): A randomised, controlled, phase 3 trial","volume":"23","author":"Tam","year":"2022","journal-title":"Lancet Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1056\/NEJMc2005943","article-title":"Ibrutinib for chronic lymphocytic leukemia with TP53 alterations","volume":"383","author":"Ahn","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1002\/ajh.25595","article-title":"Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment","volume":"94","author":"Hallek","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.clml.2019.07.004","article-title":"Long-term studies assessing outcomes of ibrutinib therapy in patients with del (11q) chronic lymphocytic leukemia","volume":"19","author":"Kipps","year":"2019","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1056\/NEJMoa1815281","article-title":"Venetoclax and obinutuzumab in patients with CLL and coexisting conditions","volume":"380","author":"Fischer","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S1470-2045(18)30788-5","article-title":"Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): A multicentre, randomised, open-label, phase 3 trial","volume":"20","author":"Moreno","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_51","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_52","doi-asserted-by":"crossref","first-page":"e610","DOI":"10.3747\/co.26.4957","article-title":"Descriptive analysis of dosing and outcomes for patients with ibrutinib-treated relapsed or refractory chronic lymphocytic leukemia in a Canadian centre","volume":"26","author":"Uminski","year":"2019","journal-title":"Curr. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1182\/blood-2017-08-764712","article-title":"How I treat CLL patients with ibrutinib","volume":"131","author":"Brown","year":"2018","journal-title":"Blood"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"874","DOI":"10.3324\/haematol.2017.182907","article-title":"Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: A real-world analysis","volume":"103","author":"Mato","year":"2018","journal-title":"Haematologica"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1177\/2040620715592569","article-title":"Ibrutinib in mantle cell lymphoma patients: Glass half full? Evidence and opinion","volume":"6","author":"Stephens","year":"2015","journal-title":"Ther. Adv. Hematol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1124\/jpet.117.242909","article-title":"Acalabrutinib (ACP-196): A covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile","volume":"363","author":"Barf","year":"2017","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1200\/JCO.21.01210","article-title":"Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial","volume":"39","author":"Byrd","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/S1470-2045(16)30051-1","article-title":"First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): An international, open-label, randomised, phase 3, non-inferiority trial","volume":"17","author":"Eichhorst","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_59","first-page":"4326","article-title":"Pooled analysis of safety data from clinical trials evaluating acalabrutinib monotherapy in hematologic malignancies","volume":"130","author":"Byrd","year":"2017","journal-title":"Leukemia"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3197","DOI":"10.1038\/s41375-020-0987-6","article-title":"Second cancer incidence in CLL patients receiving BTK inhibitors","volume":"34","author":"Bond","year":"2020","journal-title":"Leukemia"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1038\/bjc.2013.381","article-title":"Increased risk of second malignancies in chronic lymphocytic leukaemia patients as compared with follicular lymphoma patients: A Canadian population-based study","volume":"109","author":"Beiggi","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_62","first-page":"2581","article-title":"Ventricular arrhythmias and sudden death in patients taking ibrutinib","volume":"129","author":"Lampson","year":"2017","journal-title":"J. Am. Soc. Hematol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.amjcard.2015.05.045","article-title":"Economic burden of undiagnosed nonvalvular atrial fibrillation in the United States","volume":"116","author":"Turakhia","year":"2015","journal-title":"Am. J. Cardiol."},{"key":"ref_64","first-page":"2038","article-title":"A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenstr\u00f6m macroglobulinemia: The ASPEN study","volume":"136","author":"Tam","year":"2020","journal-title":"J. Am. Soc. Hematol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"4679","DOI":"10.1002\/cncr.26091","article-title":"Nonmyeloablative allogeneic stem cell transplantation in relapsed\/refractory chronic lymphocytic leukemia: Long-term follow-up, prognostic factors, and effect of human leukocyte histocompatibility antigen subtype on outcome","volume":"117","author":"Khouri","year":"2011","journal-title":"Cancer"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3284","DOI":"10.1182\/blood-2012-11-469627","article-title":"TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: Six-year follow-up of the GCLLSG CLL3X trial","volume":"121","author":"Dreger","year":"2013","journal-title":"Blood"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"303ra139","DOI":"10.1126\/scitranslmed.aac5415","article-title":"Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia","volume":"7","author":"Porter","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1182\/blood-2015-11-679134","article-title":"Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia","volume":"127","author":"Fraietta","year":"2016","journal-title":"Blood"},{"key":"ref_69","unstructured":"Nct (2021, August 27). A Study of Pirtobrutinib (LOXO-305) Versus Bendamustine Plus Rituximab (BR) in Untreated Patients with Chronic Lymphocytic Leukemia (CLL)\/Small Lymphocytic Lymphoma (SLL), Available online: https:\/\/clinicaltrials.gov\/show\/NCT05023980."},{"key":"ref_70","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_71","doi-asserted-by":"crossref","first-page":"332","DOI":"10.3390\/curroncol28010037","article-title":"Impact of Oral Targeted Therapy on the Economic Burden of Chronic Lymphocytic Leukemia in Canada","volume":"28","author":"Lachaine","year":"2021","journal-title":"Curr. Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/bjh.13933","article-title":"The Dohner fluorescence in situ hybridization prognostic classification of chronic lymphocytic leukaemia (CLL): The CLL Research Consortium experience","volume":"173","author":"Werner","year":"2016","journal-title":"Br. J. Haematol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3247","DOI":"10.1182\/blood-2014-01-546150","article-title":"Gene mutations and treatment outcome in chronic lymphocytic leukemia: Results from the CLL8 trial","volume":"123","author":"Stilgenbauer","year":"2014","journal-title":"Blood"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.beha.2009.12.003","article-title":"Moving from prognostic to predictive factors in chronic lymphocytic leukaemia (CLL)","volume":"23","author":"Zenz","year":"2010","journal-title":"Best Pract. Res. Clin. Haematol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1038\/s41375-020-0714-3","article-title":"CRISPR\/Cas9-generated models uncover therapeutic vulnerabilities of del(11q) CLL cells to dual BCR and PARP inhibition","volume":"34","author":"Herrero","year":"2020","journal-title":"Leukemia"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1437","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. Clin. Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1182\/blood.2019000854","article-title":"Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: A FILO group study","volume":"134","author":"Quinquenel","year":"2019","journal-title":"Blood"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1182\/blood-2019-127674","article-title":"Resistance to acalabrutinib in CLL is mediated primarily by BTK mutations","volume":"134","author":"Woyach","year":"2019","journal-title":"Blood"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/7\/1996\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:04:04Z","timestamp":1760123044000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/7\/1996"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,27]]},"references-count":78,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["cancers15071996"],"URL":"https:\/\/doi.org\/10.3390\/cancers15071996","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,27]]}}}