Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Fixed-duration therapy of chronic lymphocytic leukemia with venetoclax and Bruton tyrosine kinase inhibitors: an insight into differences between ibrutinib and acalabrutinib

Leukemia (2025)Cite this article

Subjects

Access through your institution
Buy or subscribe

Terms such as GLOW, CAPTIVATE, and AMPLIFY have become increasingly familiar to hematologists involved in the management of chronic lymphocytic leukemia (CLL). These trials, all exploring time-limited combinations of venetoclax with Bruton tyrosine kinase inhibitors (BTKis), reflect a growing interest in fixed-duration regimens. However, differences in trial design, patient selection, and clinical endpoints complicate direct comparisons. The question of which BTKi represents the optimal partner for venetoclax remains unresolved. This perspective aims to contribute a critical analysis to this ongoing debate.

Compared to continuous BTKis, fixed-duration regimens can reduce the cumulative burden of adverse events, mitigate the risk of clonal evolution and resistance development, and potentially enable re-treatment with the same agents. Achieving deep remissions, such as undetectable minimal residual disease (uMRD), is critical in this context. High-quality responses have been consistently associated with prolonged progression-free survival (PFS) and extended time to next treatment (TTNT), underscoring the clinical value of depth of response in time-limited regimens [1].

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Possible mechanisms for the superior outcomes of fixed-duration ibrutinib-venetoclax over acalabrutinib-venetoclax in clinical trials.

References

  1. Shadman M. Diagnosis and treatment of chronic lymphocytic leukemia. JAMA. 2023;329:918–32.

    Article  CAS  PubMed  Google Scholar 

  2. Cheson BD, Shadman M. Current approaches and novel agents in the treatment of chronic lymphocytic leukemia. J Clin Oncol Oncol Pract. 2024;20:1360–66.

    Article  Google Scholar 

  3. Eichhorst B, Ghia P, Niemann CU, Kater AP, Gregor M, Hallek M, et al. ESMO clinical practice guideline interim update on new targeted therapies in the first-line and at relapse of chronic lymphocytic leukaemia. Ann Oncol. 2024;35:762–68.

    Article  CAS  PubMed  Google Scholar 

  4. Al-Sawaf O, Robrecht S, Zhang C, Olivieri S, Chang YM, Fink AM, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study. Blood. 2024;144:1924–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Fürstenau M, Kater AP, Robrecht S, Zhang C, Gregor M, Thornton P, et al. 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. Lancet Oncol. 2024;25:744–59.

    Article  PubMed  Google Scholar 

  6. Timofeeva N, Jain N, Gandhi V. Ibrutinib and venetoclax in combination for chronic lymphocytic leukemia: synergy in practice. Blood Neoplasia. 2024;1:1–21.

    Article  Google Scholar 

  7. Lu P, Wang S, Franzen CA, Venkataraman G, McClure R, Li L, et al. Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication. Blood Cancer J. 2021;11:39–59.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Tam CS, Allan JN, Siddiqi T, Kipps TJ, Jacobs R, Opat S, et al. Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort. Blood. 2022;139:3278–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kater AP, Owen C, Moreno C, Follows G, Munir T, Levin MD, et al. Fixed-duration ibrutinib-venetoclax in patients with chronic lymphocytic leukemia and comorbidities. NEJM Evid. 2022;1:1–12.

    Article  Google Scholar 

  10. Barr PM, Allan JN, Siddiqui T, Wierda WG, Tam CSL, Moreno C, et al. Fixed-duration ibrutinib + venetoclax for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): 4-y follow-up from the FD cohort of the phase 2 CAPTIVATE study. J Clin Oncol. 2023;41:7535.

    Article  Google Scholar 

  11. Wierda WG, Jacobs R, Barr PM, Allan JN, Siddiqi T, Tedeschi A, et al. Outcomes in high-risk subgroups after fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Up to 5.5 years of follow-up in the phase 2 CAPTIVATE study. J Clin Oncol. 2024;42:7009.

    Article  Google Scholar 

  12. Munir T, Moreno C, Owen C, Follows G, Benjamini O, Janssens A, et al. Impact of minimal residual disease on progression-free survival outcomes after fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in the GLOW study. J Clin Oncol. 2023;41:3689–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Niemann CU, Munir T, Moreno C, Owen C, Follows GA, Benjamini O, et al. Fixed-duration ibrutinib–venetoclax versus chlorambucil–obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24:1423–33.

    Article  CAS  PubMed  Google Scholar 

  14. Brown JR, Seymour JF, Jurczak W, Aw A, Wach M, Illes A, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. 2025;392:748–62.

    Article  CAS  PubMed  Google Scholar 

  15. Munir T, Hernández-Rivas JA, Tedeschi A, Ysebaert L, Allen J, Schioppa C, et al. Cross-study comparison of ibrutinib in combination with venetoclax (I+V) vs acalabrutinib in combination with venetoclax (A+V) in subjects with previously untreated chronic lymphocytic leukemia (CLL). Poster presentation at 2025 European Hematology Association (EHA) Congress; June 12–15, 2025.

  16. Wierda WG, Allan JN, Siddiqi T, Kipps TJ, Opat S, Tedeschi A, et al. 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. J Clin Oncol. 2021;39:3853–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Patrussi L, Capitani N, Cattaneo F, Manganaro N, Gamberucci A, Frezzato F, et al. p66Shc deficiency enhances CXCR4 and CCR7 recycling in CLL B cells by facilitating their dephosphorylation-dependent release from β-arrestin at early endosomes. Oncogene. 2018;37:1534–50.

    Article  CAS  PubMed  Google Scholar 

  18. Alsadhan AF, Chen J, Gaglione EM, Underbayev C, Tuma PL, Tian X, et al. CD49d expression identifies a biologically distinct subtype of chronic lymphocytic leukemia with Inferior progression-free survival on BTK Inhibitor Therapy. Clin Cancer Res. 2023;29:3612–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Innocenti I, Mosca A, Tommaso A, Galitzia A, Scarfò L, Morelli F, et al. Kinetics of lymphocytosis in naïve chronic lymphocytic leukemia patients treated with covalent Bruton’s tyrosine kinase inhibitors: an Italian multicenter real-life experience. Hemasphere. 2024;8:e144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Deng J, Isik E, Fernandes SM, Brown JR, Letai A, Davids MS, et al. Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia. 2017;31:2075–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Haselager MV, Kielbassa K, Ter Burg J, Bax DJC, Fernandes SM, Borst J, et al. Changes in Bcl-2 members after ibrutinib or venetoclax uncover functional hierarchy in determining resistance to venetoclax in CLL. Blood. 2020;136:2918–26.

    Article  PubMed  Google Scholar 

  22. Seymour JF, Byrd JC, Ghia P, Kater AP, Chanan-Khan A, Furman RR, et al. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial. Blood. 2023;142:687–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy

    Alessandra Tedeschi & Anna Maria Frustaci

  2. Department of Science and Technology for Sustainable Development and One Health, Campus Bio-Medico University, and Unit of Clinical Pharmacology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy

    Pierantonio Menna

  3. Department of Medicine, Campus Bio-Medico University, and Unit of Clinical Pharmacology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy

    Giorgio Minotti

Authors
  1. Alessandra Tedeschi
    View author publications

    Search author on:PubMed Google Scholar

  2. Anna Maria Frustaci
    View author publications

    Search author on:PubMed Google Scholar

  3. Pierantonio Menna
    View author publications

    Search author on:PubMed Google Scholar

  4. Giorgio Minotti
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Alessandra Tedeschi conceived the work, drafted the manuscript, and approved the final version. Annamaria Frustaci drafted and revised the manuscript, and approved the final version. Pierantonio Menna drafted and revised the manuscript, and approved the final version. Giorgio Minotti conceived the work, drafted the manuscript, and approved the final version.

Corresponding author

Correspondence to Giorgio Minotti.

Ethics declarations

Competing interests

AT has received honoraria for participation in advisory boards from AbbVie, AstraZeneca, BeiGene, Johnson & Johnson, Lilly, and is a participant in speaker bureaus for AbbVie, BeiGene, and Johnson & Johnson. AMF has received honoraria for participation in advisory boards and has received sponsorships for congresses from AbbVie, AstraZeneca, BeiGene, Johnson & Johnson. PM is a participant in speaker bureaus for Johnson & Johnson. GM has received honoraria for participation in advisory boards from BeiGene, Incyte, Johnson & Johnson, Lilly, and Servier, and is a participant in speaker bureaus for AbbVie, BeiGene, and Johnson & Johnson.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tedeschi, A., Frustaci, A.M., Menna, P. et al. Fixed-duration therapy of chronic lymphocytic leukemia with venetoclax and Bruton tyrosine kinase inhibitors: an insight into differences between ibrutinib and acalabrutinib. Leukemia (2025). https://doi.org/10.1038/s41375-025-02778-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41375-025-02778-1

Search

Advanced search

Quick links