Lights and shades of front-line treatment with covalent BTK inhibitors combined with venetoclax in patients with chronic lymphocytic leukemia

Sep 28, 2026

Uploaded by Melati

Review of trials assessing front-line combinations of covalent BTK inhibitors (cBTKi) with venetoclax in chronic lymphocytic leukemia (CLL), using either fixed-duration regimens (CAPTIVATE, GLOW, AMPLIFY) or minimal residual disease (MRD)-guided approaches (MDACC, FLAIR, ERADIC, HOVON NEXT STEP, SEQUOIA arm D). 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 limiting.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Introduction

BTK and BCL2 inhibitor rationale

Mechanisms of ibrutinib

Venetoclax mechanism and synergy

TYPE Review PUBLISHED 18 December 2025 DOI 10.3389/or.2025.1703228 OPEN ACCESS EDITED BY Marco Bregni, Fondazioni Iseni, Italy REVIEWED BY David Allsup, University of Hull, United Kingdom Kamil Wiśniewski, Institute of Hematology and Transfusiology (IHT), Poland *CORRESPONDENCE Francesca R. Mauro, [mauro@bce.uniroma1.it](mauro@bce.uniroma1.it)[ ](mauro@bce.uniroma1.it)Andrea Visentin, [andrea.visentin@unipd.it](andrea.visentin@unipd.it) RECEIVED 11 September 2025 REVISED 30 November 2025 ACCEPTED 30 November 2025 PUBLISHED 18 December 2025 CITATION Visentin 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 . doi: 10.3389/or.2025.1703228 COPYRIGHT © 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. Lights and shades of front-line treatment with covalent BTK inhibitors combined with venetoclax in patients with chronic lymphocytic leukemia Andrea Visentin 1* and Francesca R. Mauro 2* 1Hematology Unit, Department of Medicine, University of Padua, Padua, Italy, 2Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy 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) 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. KEYWORDS acalabrutinib, chronic lymphocytic leukemia, ﬁxed duration therapy, ibrutinib, venetoclax, zanubrutinib 1 Introduction Inhibitors 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. Several 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) . These drugs target distinct but interrelated pathways that promote the survival of chronic lymphocytic leukemia (CLL) cells. Ibrutinib (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. Moreover, 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, Oncology Reviews 01 [frontiersin.org](frontiersin.org)

FAQs

What treatment strategies are evaluated for front-line cBTKi plus venetoclax in CLL?

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.

How does MRD-guided treatment affect progression-free survival?

MRD-guided treatments yielded higher progression-free survival rates, including in patients with high-risk genetic features such as unmutated IGHV and TP53 disruption.

What major safety limitation is highlighted for cBTKi plus venetoclax?

Cardiovascular toxicities related to cBTKi remain a limiting concern, particularly for use in some older patients.

Sep 28, 2026

Uploaded by Melati