Skip to main content

Advertisement

SpringerLink
Log in

The Evolution of Targeted Therapies in Chronic Lymphocytic Leukaemia

  • T-Cell and Other Lymphoproliferative Malignancies (J Zain, Section Editor)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The treatment landscape for chronic lymphocytic leukaemia (CLL) is rapidly evolving, with several targeted agents recently approved. These compounds have dramatically changed the natural history of the disease.

Recent Findings

However, with the array of effective therapies commercially available, the challenge is to define tailored treatment strategies able to realize a balance between treatment efficacy and toxicity or tolerance. New algorithms of treatment are being developed, and it appears that minimal residual disease (MRD) directed therapy will become the norm in the future.

Summary

Clinical trials are looking at various combinations of novel therapies given with a defined, fixed-period of treatment based on MRD analysis. This approach enables patients to have a period of treatment-free remission instead of continuous therapy. In this review, we summarize this evolution of targeted therapies in CLL.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. •• Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127(2):208–15 Long-term follow-up of the randomized CLL8 trial reporting safety and efficacy of FC and FCR treatment of previously untreated CLL patients.

    Article  CAS  PubMed  Google Scholar 

  2. Kutsch N, Bahlo J, Robrecht S, et al. Long term follow-up data and health-related quality of life in frontline therapy of fit patients treated with FCR versus BR (CLL10 trial of the GCLLSG). Hemasphere. 2020;4(1):e336.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. •• Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997–1007 First published phase 3 study showing the combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. •• Munir T, Brown JR, O'Brien S, et al. 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. Am J Hematol. 2019;94(12):1353–63 The Authors report the longest follow-up of CLL patients receiving an oral targeted agent.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Billard C. BH3 mimetics: status of the field and new developments. Mol Cancer Ther. 2013;12:1691–700.

    Article  CAS  PubMed  Google Scholar 

  7. •• Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107–20 The first trial investigating time-fixed therapy with oral inhibitor in CLL. Based on these results the EMA approved the combination of venetoclax with rituximab in R/R CLL patients.

    Article  CAS  PubMed  Google Scholar 

  8. •• Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial. J Clin Oncol. 2018;36:1973–80 The Authors report results of a phase 2 trial enrolling patients harbouring del(17p), mostly refractory to CIT. Based on these results venetoclax was firstly approved as monotherapy for CLL patients with del(17p) or TP53 mutation.

    Article  CAS  PubMed  Google Scholar 

  9. Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018;19:65–75.

    Article  CAS  PubMed  Google Scholar 

  10. • Mato AR, Hill BT, Lamanna N, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Ann Oncol. 2017;28(5):1050–6 Retrospective, non-randomized study on large cohort of patients treated with BTKi or BCL2i.

    Article  CAS  PubMed  Google Scholar 

  11. •• Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425–37 First published phase 3 study establishing ibrutinib as a frontline therapy for patients with CLL.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fischer K, Al-Sawaf O, Fink AM, et al. Venetoclax and obinutuzumabin chronic lymphocytic leukemia. Blood. 2017;129:2702–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. •• Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517–28 Phase 3 study establishing superior PFS with ibrutinib compared with chemoimmunotherapy in older CLL patients and establishing lack of additional efficacy of rituximab combined with ibrutinib.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicenter, randomized, open-label, phase 3 trial. Lancet Oncol. 2019;20(1):43–56.

    Article  CAS  PubMed  Google Scholar 

  15. •• Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432–43 The study showed a significant PFS benefit for the ibrutinib-rituximab regimen over FCR in unmutated IGHV patients.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. •• Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213–23 First randomized study comparing ibrutinib with ofatumumab in previously treated patients with advanced progressive CLL. Based on the results ibrutinib was approved for R/R CLL patients.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Brown JR, Hillmen P, O'Brien S, et al. Extended follow-up and impact of high risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018;32(1):83–91.

    Article  CAS  PubMed  Google Scholar 

  18. UK CLL Forum. Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: a UK and Ireland analysis of outcomes in 315 patients. Haematologica. 2016;101(12):1563–72.

    Article  PubMed Central  CAS  Google Scholar 

  19. Winqvist M, Asklid A, Andersson PO, et al. Real-world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: data from 95 consecutive patients treated in a compassionate use program. A study from the Swedish Chronic Lymphocytic Leukemia Group. Haematologica. 2016;101(12):1573–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Coutré SE, Furman RR, Flinn IW, et al. Extended treatment with single-agent Ibrutinib at the 420 mg dose leads to durable responses in chronic lymphocytic leukemia/small lymphocytic lymphoma. Clin Cancer Res. 2017;23(5):1149–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. • Burger JA, Barr PM, Robak T, et al. 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. Leukemia. 2020;4(3):787–98 The longest follow-up of first-line ibrutinib treatment for CLL patients.

    Article  CAS  Google Scholar 

  22. Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1(1):80–7.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Woyach JA. How I manage ibrutinib-refractory chronic lymphocytic leukemia. Blood. 2017;129(10):1270–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. •• Woyach JA, Ruppert AS, Guinn D, et al. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35(13):1437–43 Analysis of CLL patients treated with ibrutinib across four prospective studies characterizing prevalence of BTK and PLCG2 mutations and chronological relationship with disease progression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Quinquenel A, Fornecker LM, Letestu R, et al. Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after three years: a FILO group study. Blood. 2019;134(7):641–4.

    Article  CAS  PubMed  Google Scholar 

  26. Molica S, Giannarelli D, Shanafelt TD. Comparison of venetoclax plus rituximab with B-cell receptor inhibitors in patients with relapsed/refractory chronic lymphocytic leukemia: a systematic review and network meta-analysis. Leuk Lymphoma. 2020 Apr;61(4):955–8.

    Article  PubMed  Google Scholar 

  27. Kater AP, Seymour JF, Hillmen P, et al. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study. J Clin Oncol. 2019;37(4):269–77.

    Article  CAS  PubMed  Google Scholar 

  28. Bottcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012;30(9):980–8.

    Article  PubMed  Google Scholar 

  29. Kovacs G, Robrecht S, Fink AM, et al. Minimal residual disease assessment improves prediction of outcome in patients with chronic lymphocytic leukemia (CLL) who achieve partial response: comprehensive analysis of two phase III studies of the German CLL study group. J Clin Oncol. 2016;34(31):3758–65.

    Article  CAS  PubMed  Google Scholar 

  30. Deng J, Isik E, Fernandes SM, et al. Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic. Leukemia. 2017;31(10):2075–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Roberts AW, Ma S, Kipps TJ, et al. Efficacy of venetoclax in relapsed chronic lymphocytic leukaemia is influenced by disease and response variables. Blood. 2019;134(2):111–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hillmen P, Rawstron AC, Brock K, et al. Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: the CLARITY study. J Clin Oncol. 2019;37(30):2722–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019;380(22):2095–103.

    Article  CAS  PubMed  Google Scholar 

  34. Tam CS, Siddiqi T, Allan JN, et al. Ibrutinib (Ibr) plus venetoclax (ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Results from the MRD cohort of the phase 2 CAPTIVATE study. Blood. 2019;134(1):35.

    Article  Google Scholar 

  35. Davids MS, Kim HT, Nicotra A, et al. Umbralisib in combination with ibrutinib in patients with relapsed or refractory chronic lymphocytic leukaemia or mantle cell lymphoma: a multicentre phase 1-1b study. Lancet Haematol. 2019;6(1):e38–47.

    Article  PubMed  Google Scholar 

  36. Rogers KA, Huang Y, Ruppert AS, et al. Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. Blood. 2018;132(15):1568–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lampson BL, Tyekucheva S, Crombie JL, et al. Preliminary safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL). [Abstract]. Blood. 2019;134(S1):32.

    Article  Google Scholar 

  38. Coutré SE, Byrd JC, Hillmen P, et al. Long- term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies. Blood Adv. 2019;3(12):1799–807.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Awan FT, Schuh A, Brown JR, et al. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv. 2019;3(9):1553–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. • Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: Phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients (Pts) with treatment-naive chronic lymphocytic leukemia (CLL). [Abstract]. Blood. 2019;134(S1):31 Based on these results FDA approved acalabrutinib for untreated CLL patients.

    Article  Google Scholar 

  41. • Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelasib (IDR) or bendamustine (BR) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). [Abstract]. EHA Library. 2019;LB2606. Based on these results FDA approved acalabrutinib for R/R CLL patients.

  42. U.S. Food and Drug Administration. Project Orbis: FDA approves acalabrutinib for CLL and SLL. https://www.fda.gov/drugs/resources-information-approved-drugs/project-orbis-fda-approves-acalabrutinib-cll-and-sll. [Accessed 26 November 2019].

  43. Tam CS, Trotman J, Opat S, et al. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019;134(11):851–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Walter HS, Rule SA, Dyer MJ, et al. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood. 2016;127(4):411–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tam CS, Robak T, Ghia P, et al. Efficacy and safety of zanubrutinib in patients with treatment-naive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with del(17p): initial results from arm C of the Sequoia (BGB-3111-304) trial. [Abstract]. Blood. 2019;134(S1):499.

    Article  Google Scholar 

  46. Molica S, Giannarelli D, Baumann T, Montserrat E. Ibrutinib as initial therapy in chronic lymphocytic leukemia: a systematic review and meta-analysis. Eur J Haematol. 2020. https://doi.org/10.1111/ejh.13387.

  47. Molica S, Giannarelli D, Montserrat E. Minimal residual disease and survival outcomes in patients with chronic lymphocytic leukemia: a systematic review and meta-analysis. Clin Lymphoma Myeloma Leuk. 2019;19(7):423–30.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department Hematology-Oncology, Azienda Ospedaliera Pugliese-Ciaccio, 88100, Catanzaro, Italy

    Valentina Gianfelici, Luciano Levato & Stefano Molica

Authors
  1. Valentina Gianfelici
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luciano Levato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stefano Molica
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefano Molica.

Ethics declarations

Conflict of Interest

Valentina Gianfelici, Luciano Levato, and Stefano Molica do not declare any conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

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

This article is part of the Topical Collection on T-Cell and Other Lymphoproliferative Malignancies

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gianfelici, V., Levato, L. & Molica, S. The Evolution of Targeted Therapies in Chronic Lymphocytic Leukaemia. Curr Hematol Malig Rep 15, 343–349 (2020). https://doi.org/10.1007/s11899-020-00586-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-020-00586-1

Keywords

Search

Navigation