{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T13:57:15Z","timestamp":1788184635228,"version":"build-2803163510"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"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":["Oncol. Rev."],"abstract":"<jats:p>\n                    This review focused on trials investigating the front-line covalent BTK inhibitors (cBTKi) and venetoclax (V) combination administered in a fixed-duration (CAPTIVATE, GLOW, AMPLIFY trials) or minimal residual disease (MRD)-guided manner (MDACC, FLAIR, ERADIC, HOVON NEXT STEP, SEQUOIA arm D trials) in patients with chronic lymphocytic leukemia (CLL). We reviewed data from these studies to highlight their therapeutic activity and toxicity profile. Despite the heterogeneity in patients\u2019 characteristics, treatment schedule, and duration, most patients achieved deep responses with undetectable MRD and prolonged progression-free survival (PFS) with BTKi + V regimens. MRD-guided treatments yielded higher PFS rates, including patients with high-risk genetic characteristics, such as those with unmutated IGHV and\n                    <jats:italic>TP<\/jats:italic>\n                    53 disruption. The cBTKi + V regimen is easy to manage and relatively well tolerated. However, cBTKi-related cardiovascular toxicities remain a limiting concern, especially for the use of cBTKi + V in some older patients.\n                  <\/jats:p>","DOI":"10.3389\/or.2025.1703228","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T06:42:30Z","timestamp":1766040150000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Lights and shades of front-line treatment with covalent BTK inhibitors combined with venetoclax in patients with chronic lymphocytic leukemia"],"prefix":"10.3389","volume":"19","author":[{"given":"Andrea","family":"Visentin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca R.","family":"Mauro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.3390\/cancers16071290","article-title":"Innovative combinations, cellular therapies and bispecific antibodies for chronic lymphocytic leukemia: a narrative review","volume":"16","author":"Visentin","year":"2024","journal-title":"Cancers"},{"key":"B2","doi-asserted-by":"publisher","first-page":"809","DOI":"10.3324\/haematol.2022.282466","article-title":"Lymphocyte migration and retention properties affected by ibrutinib in chronic lymphocytic leukemia","volume":"109","author":"Rey-Barroso","year":"2023","journal-title":"Haematologica"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2040","DOI":"10.3324\/haematol.2018.209981","article-title":"p66Shc deficiency in the E\u03bc-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape","volume":"104","author":"Patrussi","year":"2019","journal-title":"Haematologica"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1038\/s41375-023-01898-w","article-title":"Ibrutinib sensitizes CLL cells to venetoclax by interrupting TLR9-induced CD40 upregulation and protein translation","volume":"37","author":"Kielbassa","year":"2023","journal-title":"Leukemia"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2503","DOI":"10.1158\/1078-0432.CCR-18-1286","article-title":"Ibrutinib therapy releases leukemic surface IgM from antigen drive in chronic lymphocytic leukemia patients","volume":"25","author":"Drennan","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2918","DOI":"10.1182\/blood.2019004326","article-title":"Changes in Bcl-2 members after ibrutinib or venetoclax uncover functional hierarchy in determining resistance to venetoclax in CLL","volume":"136","author":"Haselager","year":"2020","journal-title":"Blood"},{"key":"B7","doi-asserted-by":"publisher","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":"B8","doi-asserted-by":"publisher","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":"B9","doi-asserted-by":"publisher","first-page":"2095","DOI":"10.1056\/NEJMoa1900574","article-title":"Ibrutinib and venetoclax for first-line treatment of CLL","volume":"380","author":"Jain","year":"2019","journal-title":"N Engl J Med"},{"key":"B10","doi-asserted-by":"publisher","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":"B11","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1056\/NEJMoa2409804","article-title":"Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia","volume":"392","author":"Brown","year":"2025","journal-title":"N Engl J Med"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2409","DOI":"10.1200\/JCO-25-00758","article-title":"Zanubrutinib and venetoclax for patients with treatment-na\u00efve chronic lymphocytic leukemia\/small lymphocytic lymphoma with and without Del(17p)\/TP53 mutation: SEQUOIA arm D results","volume":"43","author":"Shadman","year":"2025","journal-title":"JCO"},{"key":"B13","doi-asserted-by":"publisher","first-page":"4385","DOI":"10.1158\/1078-0432.CCR-22-0504","article-title":"Effective tumor debulking with ibrutinib before initiation of venetoclax: results from the CAPTIVATE minimal residual disease and fixed-duration cohorts","volume":"28","author":"Barr","year":"2022","journal-title":"Clin Cancer Res"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1056\/NEJMoa2504341","article-title":"Measurable residual disease-guided therapy for chronic lymphocytic leukemia","volume":"15","author":"Munir","year":"2025","journal-title":"N Engl J Med"},{"key":"B15","doi-asserted-by":"publisher","first-page":"3853","DOI":"10.1200\/JCO.21.00807","article-title":"Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia: primary analysis results from the minimal residual disease cohort of the randomized phase II CAPTIVATE study","volume":"39","author":"Wierda","year":"2021","journal-title":"JCO"},{"key":"B16","doi-asserted-by":"publisher","first-page":"2745","DOI":"10.1182\/blood-2017-09-806398","article-title":"iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL","volume":"131","author":"Hallek","year":"2018","journal-title":"Blood"},{"key":"B17","doi-asserted-by":"publisher","first-page":"7036","DOI":"10.1200\/jco.2025.43.16_suppl.7036","article-title":"Final analysis of fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia (CLL)\/small lymphocytic lymphoma (SLL) in the phase 2 CAPTIVATE study","volume":"43","author":"Wierda","year":"2025","journal-title":"Oral Presentation S156 EHA Congress 12-15 June"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1869","DOI":"10.1182\/blood-2024-200936","article-title":"Consistently high 5.5-Year progression-free survival (PFS) rates in patients with and without bulky baseline lymphadenopathy \u22655 cm are associated with high undetectable minimal residual disease (uMRD4) rates after first-line treatment with fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia (CLL)\/small lymphocytic lymphoma (SLL) in the phase 2 CAPTIVATE study","volume":"144","author":"Wierda","year":"2024","journal-title":"Blood"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1016\/S1470-2045(23)00452-7","article-title":"Fixed-duration ibrutinib\u2013venetoclax versus chlorambucil\u2013obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-Year follow-up from a multicentre, open-label, randomised, phase 3 trial","volume":"24","author":"Niemann","year":"2023","journal-title":"The Lancet Oncol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1871","DOI":"10.1182\/blood-2024-203269","article-title":"First-line ibrutinib plus venetoclax Vs chlorambucil plus obinutuzumab in elderly or comorbid patients (pts) with chronic lymphocytic leukemia (CLL): glow study 64-Month Follow-up (FU) and adverse event (AE)-free progression-free survival (PFS) analysis","volume":"144","author":"Niemann","year":"2024","journal-title":"Blood"},{"key":"B21","doi-asserted-by":"publisher","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":"B22","doi-asserted-by":"publisher","first-page":"4635","DOI":"10.1182\/blood-2023-189711","article-title":"Combined ibrutinib and venetoclax for first-line treatment of patients with chronic lymphocytic leukemia (CLL): 5-year Follow-up data","volume":"142","author":"Jain","year":"2023","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1182\/blood-2024-194593","article-title":"Minimal residual disease-guided combination of ibrutinib and venetoclax compared to FCR in untreated patients with CLL of intermediate risk: final results of the eradic trial from the filo group","volume":"144","author":"Michallet","year":"2024","journal-title":"Blood"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e104","DOI":"10.1002\/hem3.104","volume":"8","year":"2024","journal-title":"HemaSphere"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1182\/blood-2024-207452","article-title":"Improved efficacy with Response- and MRD-guided ibrutinib-obinutuzumab (IO) intensification after Ibrutinib-Venetoclax (IV) in first line chronic lymphocytic leukemia (CLL) patients: primary analysis of the HOVON 158\/Next STEP phase 2 trial","volume":"144","author":"Levin","year":"2024","journal-title":"Blood"},{"key":"B26","doi-asserted-by":"publisher","first-page":"2575","DOI":"10.1182\/bloodadvances.2022008643","article-title":"Racial and socioeconomic disparities in CLL\/SLL: analysis of SEER data from 2006 to 2019","volume":"7","author":"Kittai","year":"2023","journal-title":"Blood Adv"},{"key":"B27","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1182\/blood-2024-211449","article-title":"IGHV unmutated status, low tumor lysis risk disease and BRAF mutated status are predictors for early MRD responders treated with MRD defined ibrutinib with venetoclax: report of the UK NCRI FLAIR study","volume":"144","author":"Munir","year":"2024","journal-title":"Blood"},{"key":"B28","doi-asserted-by":"publisher","first-page":"2593","DOI":"10.1158\/1078-0432.CCR-22-2779","article-title":"Outcomes in patients with high-risk features after fixed-duration ibrutinib plus venetoclax: phase II CAPTIVATE study in first-line chronic lymphocytic leukemia","volume":"29","author":"Allan","year":"2023","journal-title":"Clin Cancer Res"},{"key":"B29","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1158\/1078-0432.CCR-22-3934","article-title":"Absence of BTK BCL2, and PLCG2 mutations in chronic lymphocytic leukemia relapsing after first-line treatment with fixed-duration ibrutinib plus venetoclax","volume":"30","author":"Jain","year":"2024","journal-title":"Clin Cancer Res"},{"key":"B30","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1002\/ajh.27544","article-title":"Prevalence of BTK and PLCG2 mutations in CLL patients with disease progression on BTK inhibitor therapy: a meta\u2010analysis","volume":"100","author":"Molica","year":"2025","journal-title":"Am J Hematol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"104408","DOI":"10.1016\/j.critrevonc.2024.104408","article-title":"Severe infections in patients with chronic lymphocytic leukemia included in trials investigating BTK and BCL2 inhibitors","volume":"201","author":"Mauro","year":"2024","journal-title":"Crit Rev Oncology\/Hematology."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1056\/NEJMoa2213093","article-title":"First-line venetoclax combinations in chronic lymphocytic leukemia","volume":"388","author":"Eichhorst","year":"2023","journal-title":"N Engl J Med"},{"key":"B33","doi-asserted-by":"publisher","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":"B34","doi-asserted-by":"publisher","first-page":"2147","DOI":"10.1038\/s41467-023-37648-w","article-title":"Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia","volume":"14","author":"Al-Sawaf","year":"2023","journal-title":"Nat Commun"},{"key":"B35","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1016\/S1470-2045(24)00196-7","article-title":"First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA\/CLL13): 4-Year follow-up from a multicentre, open-label, randomised, phase 3 trial","volume":"25","author":"F\u00fcrstenau","year":"2024","journal-title":"Lancet Oncol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1200\/JCO-24-02503","article-title":"Phase II study of acalabrutinib, venetoclax, and obinutuzumab in a treatment-na\u00efve chronic lymphocytic leukemia population enriched for high-risk disease","volume":"43","author":"Davids","year":"2025","journal-title":"JCO"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1867","DOI":"10.1182\/blood-2024-205697","article-title":"Multicenter phase II trial of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in treatment-na\u00efve chronic lymphocytic leukemia: 5-year follow up, retreatment outcomes, and impact of MRD kinetics (\u0394MRD400)","volume":"144","author":"Soumerai","year":"2024","journal-title":"Blood"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1182\/blood-2024-211454","article-title":"Combined pirtobrutinib, venetoclax, and obinutuzumab as first-line treatment of patients with chronic lymphocytic leukemia (CLL)","volume":"144","author":"Jain","year":"2024","journal-title":"Blood"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/hem3.70151","article-title":"Updated results from the phase 1 study of sonrotoclax (BGB-11417), A novel BCL2 inhibitor, in combination with zanubrutinib for relapsed\/refractory CLL\/SLL demonstrate deep and durable responses","author":"Cheah","year":"2025","journal-title":"Oral Presentation S159 EHA Congress, 12-15 June"},{"key":"B40","doi-asserted-by":"publisher","first-page":"4614","DOI":"10.1182\/blood-2024-207408","article-title":"Lisaftoclax (APG-2575) demonstrates activity and safety when given with accelerated ramp-up and then combined with acalabrutinib or rituximab in patients (pts) with chronic lymphocytic leukemia\/small lymphocytic lymphoma (CLL\/SLL), including those with prior exposure to venetoclax","volume":"144","author":"Davids","year":"2024","journal-title":"Blood"},{"key":"B41","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1016\/j.annonc.2024.06.016","article-title":"ESMO clinical practice guideline interim update on new targeted therapies in the first line and at relapse of chronic lymphocytic leukaemia","volume":"35","author":"Eichhorst","year":"2024","journal-title":"Ann Oncol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"175","DOI":"10.6004\/jnccn.2024.0018","article-title":"Chronic lymphocytic leukemia\/small lymphocytic lymphoma, version 2.2024, NCCN clinical practice guidelines in oncology","volume":"22","author":"Wierda","year":"2024","journal-title":"J Natl Compr Canc Netw"},{"key":"B43","article-title":"CLL17 trial investigators. Fixed-duration versus continuous treatment for chronic lymphocytic leukemia","volume-title":"N Engl J Med","author":"Al-Sawaf","year":""},{"key":"B44","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1111\/bjh.19986.f","article-title":"Management strategies for patients with chronic lymphocytic leukaemia harbouring complex karyotype","volume":"206","author":"Serafin","year":"2025","journal-title":"Br J Haematol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1002\/hon.2655","article-title":"A scoring system to predict the risk of atrial fibrillation in chronic lymphocytic leukemia","volume":"37","author":"Visentin","year":"2019","journal-title":"Hematol Oncol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"105045","DOI":"10.1016\/j.critrevonc.2025.105045","article-title":"Venetoclax and ibrutinib: two partners for the front-line treatment of chronic lymphocytic leukemia","volume":"217","author":"Visentin","year":"2025","journal-title":"Crit Rev Oncology\/Hematology"}],"container-title":["Oncology Reviews"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/or.2025.1703228\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T06:42:34Z","timestamp":1766040154000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/or.2025.1703228\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,18]]},"references-count":46,"alternative-id":["10.3389\/or.2025.1703228"],"URL":"https:\/\/doi.org\/10.3389\/or.2025.1703228","relation":{},"ISSN":["1970-5557"],"issn-type":[{"value":"1970-5557","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,18]]},"article-number":"1703228"}}