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Trial evidence is synthesized to characterize antitumor activity, toxicity, and patient selection. Despite heterogeneity, most patients achieve deep responses with undetectable MRD and prolonged progression-free survival; MRD-guided strategies show higher PFS, including high-risk genetics (unmutated IGHV, TP53 disruption). cBTKi+V is manageable and generally well tolerated, but cardiovascular toxicities remain 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\nMarco Bregni,  \nFondazioni Iseni, Italy  \nREVIEWED BY  \nDavid Allsup,  \nUniversity of Hull, United Kingdom Kamil Wiśniewski,  \nInstitute of Hematology and Transfusiology (IHT), Poland  \n*CORRESPONDENCE  \nFrancesca R. Mauro,  \n [mauro@bce.uniroma1.it](mauro@bce.uniroma1.it)[ ](mauro@bce.uniroma1.it)Andrea Visentin,  \n [andrea.visentin@unipd.it](andrea.visentin@unipd.it)  \nRECEIVED 11 September 2025  \nREVISED 30 November 2025  \nACCEPTED 30 November 2025  \nPUBLISHED 18 December 2025  \nCITATION  \nVisentin A and Mauro FR (2025) Lights and shades of front-line treatment with covalent BTK inhibitors combined with venetoclax inpatients with chronic lymphocytic leukemia. Oncol. Rev. 19:1703228 .  \ndoi: 10.3389/or.2025.1703228  \nCOPYRIGHT  \n© 2025 Visentin and Mauro. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.  \nLights and shades of front-line treatment with covalent BTK inhibitors combined with venetoclax in patients with chronic lymphocytic leukemia  \nAndrea Visentin 1* and Francesca R. Mauro 2*  \n1Hematology Unit, Department of Medicine, University of Padua, Padua, Italy, 2Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy  \nThis 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) inpatients with chronic lymphocytic leukemia (CLL) . We reviewed data from these studies to highlight their therapeutic activity and toxicity profile. Despite the heterogeneity in patients ’ 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 TP53 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.  \nKEYWORDS  \nacalabrutinib, chronic lymphocytic leukemia, fixed duration therapy, ibrutinib, venetoclax, zanubrutinib  \n1 Introduction  \nInhibitors of the Bruton’s Tyrosine Kinase (BTK) and BCL2 (B-cell lymphoma 2) are two highly effective classes of agents in the management of patients with chronic lymphocytic leukemia (CLL) either as single agents or in combination.  \nSeveral studies have demonstrated the increased efficacy of these agents when used in combination, due to their synergistic effects resulting from complementary mechanisms of action (1) .  \nThese drugs target distinct but interrelated pathways that promote the survival of chronic lymphocytic leukemia (CLL) cells.  \nIbrutinib (I) is the first-in-class covalent BTK inhibitor (cBTKi), which disrupts the B-cell receptor (BCR) signaling pathway, thereby inhibiting the survival and proliferation of CLL cells.  \nMoreover, I downregulates the homing receptors CXCR4 and CCR7 and upregulates egress receptors such as S1P1 (2, 3)(Figure 1) . By disrupting the adhesion ofCLL cells to the protective microenvironment of lymph nodes and bone marrow, I facilitates the mobilization and migration of these cells into the peripheral blood. In addition,  \nOncology Reviews 01 [frontiersin.org](frontiersin.org)","cbCaieyb5SCF40xB","https://ap.wps.com/l/cbCaieyb5SCF40xB","pdf",1092807,12,"English","# Introduction\n## BTK and BCL2 inhibitor rationale\n## Mechanisms of ibrutinib\n## Venetoclax mechanism and synergy","[{\"question\":\"What treatment strategies are evaluated for front-line cBTKi plus venetoclax in CLL?\",\"answer\":\"The review covers fixed-duration regimens from CAPTIVATE, GLOW, and AMPLIFY, and MRD-guided strategies from MDACC, FLAIR, ERADIC, HOVON NEXT STEP, and the SEQUOIA arm D trial.\"},{\"question\":\"How does MRD-guided treatment affect progression-free survival?\",\"answer\":\"MRD-guided treatments yielded higher progression-free survival rates, including in patients with high-risk genetic features such as unmutated IGHV and TP53 disruption.\"},{\"question\":\"What major safety limitation is highlighted for cBTKi plus venetoclax?\",\"answer\":\"Cardiovascular toxicities related to cBTKi remain a limiting concern, particularly for use in some older patients.\"}]","Lights and shades of front-line treatment with covalent BTK inhibitors combined with venetoclax in patients with chronic lymphocytic leukemia | PDF",1790587087]