Skip to main content

Advertisement

Log in

Management of Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma in the Era of Targeted Therapies

  • Chronic Lymphocytic Leukemias (N Jain, Section Editor)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The treatment landscape for relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has changed substantially over the past decade and continues to evolve. Despite the emergence of targeted therapies that are well tolerated and prolong survival, the disease remains incurable and relapse is common particularly in individuals with high-risk features. Herein, we review the key literature about the current options for relapsed disease and explore the emerging role of cellular therapies.

Recent Findings

Clinical trials have established the role of Bruton tyrosine kinase inhibitors, selective BCL-2 inhibition, and anti-CD20 monoclonal antibodies as treatment options for CLL/SLL. The role of chimeric antigen receptor T cells has shown promise in individuals with CLL/SLL in early phase clinical trials.

Summary

Novel therapeutic approaches with targeted therapies have redefined the management of CLL/SLL in both the front-line and relapsed/refractory settings. Optimal management in terms of sequencing or combining therapies, especially in individuals with high-risk features, remains a challenge. The emerging role of cellular therapies has the potential to build upon and further improve the current treatment paradigm.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30.

    Article  Google Scholar 

  2. Teras LR, et al. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin. 2016;66(6):443–59.

    Article  Google Scholar 

  3. Santos FP, O’Brien S. Small lymphocytic lymphoma and chronic lymphocytic leukemia: are they the same disease? Cancer J. 2012;18(5):396–403.

    Article  CAS  Google Scholar 

  4. Hallek M, Pflug N. State of the art treatment of chronic lymphocytic leukaemia. Blood Rev. 2011;25(1):1–9.

    Article  CAS  Google Scholar 

  5. Fischer K, 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.

    Article  CAS  Google Scholar 

  6. Burger JA. Treatment of chronic lymphocytic leukemia. N Engl J Med. 2020;383(5):460–73.

    Article  CAS  Google Scholar 

  7. Burger JA, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425–37.

    Article  CAS  Google Scholar 

  8. Network NCC. Chronic lymphocytic leukemia/small lymphocytic lymphoma (version 2.2021). [December 16, 2020]; Available from: https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf.

  9. Hallek M, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446–56.

    Article  CAS  Google Scholar 

  10. Byrd JC, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213–23.

    Article  Google Scholar 

  11. O’Brien S, et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016;17(10):1409–18.

    Article  CAS  Google Scholar 

  12. Byrd JC, et al. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019;133(19):2031–42.

    Article  CAS  Google Scholar 

  13. Munir T, 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.

    Article  CAS  Google Scholar 

  14. Byrd JC, et al. Ibrutinib treatment for first-line and relapsed/refractory chronic lymphocytic leukemia: final analysis of the pivotal phase Ib/II PCYC-1102 Study. Clin Cancer Res. 2020;26(15):3918–27.

    Article  CAS  Google Scholar 

  15. Ghia P, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849–61.

    Article  CAS  Google Scholar 

  16. Tam C, 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. Blood. 2019;134.

  17. Seymour JF, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107–20.

    Article  CAS  Google Scholar 

  18. Flinn IW, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018;132(23):2446–55.

    Article  CAS  Google Scholar 

  19. Sharman JP, et al. Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol. 2019;37(16):1391–402.

    Article  CAS  Google Scholar 

  20. Gribben JG, Jurczak W, Jacobs R, et al. 543 Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 Unity-CLL Study, in ASH. 2020.

  21. Mato AR, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103(5):874–9.

    Article  CAS  Google Scholar 

  22. Ganatra S, et al. Ibrutinib-associated atrial fibrillation. JACC Clin Electrophysiol. 2018;4(12):1491–500.

    Article  Google Scholar 

  23. Chai KL, et al. Practical recommendations for the choice of anticoagulants in the management of patients with atrial fibrillation on ibrutinib. Leuk Lymphoma. 2017;58(12):2811–4.

    Article  CAS  Google Scholar 

  24. de Weerdt I, et al. Incidence and management of toxicity associated with ibrutinib and idelalisib: a practical approach. Haematologica. 2017;102(10):1629–39.

    Article  Google Scholar 

  25. Thompson PA, et al. Atrial fibrillation in CLL patients treated with ibrutinib. An international retrospective study. Br J Haematol. 2016;175(3):462–466.

  26. Woyach JA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517–28.

    Article  CAS  Google Scholar 

  27. Shanafelt TD, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432–43.

    Article  CAS  Google Scholar 

  28. Moreno C, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(1):43–56.

    Article  CAS  Google Scholar 

  29. Sharman JP, et al. Ublituximab (TG-1101), a novel glycoengineered anti-CD20 antibody, in combination with ibrutinib is safe and highly active in patients with relapsed and/or refractory chronic lymphocytic leukaemia: results of a phase 2 trial. Br J Haematol. 2017;176(3):412–20.

    Article  CAS  Google Scholar 

  30. Burger JA, et al. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019;133(10):1011–9.

    Article  CAS  Google Scholar 

  31. Greil R, et al. Efficacy and safety of ibrutinib (IBR) after venetoclax (VEN) treatment in IBR-naïve patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): follow-up of patients from the MURANO Study. Blood. 2018;132(Supplement 1):5548–5548.

    Article  Google Scholar 

  32. Sharman JP, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278–91.

    Article  CAS  Google Scholar 

  33. Byrd JC, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323–32.

    Article  CAS  Google Scholar 

  34. Xu W, et al. Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with the BTK inhibitor zanubrutinib: phase 2, single-arm, multicenter study. J Hematol Oncol. 2020;13(1):48.

    Article  Google Scholar 

  35. Al-Sawaf O, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188–200.

    Article  CAS  Google Scholar 

  36. Roberts AW, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–22.

    Article  CAS  Google Scholar 

  37. Kater AP, 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  Google Scholar 

  38. Jones JA, 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(1):65–75.

    Article  CAS  Google Scholar 

  39. Coutre S, et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018;131(15):1704–11.

    Article  CAS  Google Scholar 

  40. Flinn IW, et al. Duvelisib, a novel oral dual inhibitor of PI3K-delta, gamma, is clinically active in advanced hematologic malignancies. Blood. 2018;131(8):877–87.

    Article  CAS  Google Scholar 

  41. Gopal AK, et al. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008–18.

    Article  CAS  Google Scholar 

  42. Kalos M, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011; 3(95):95ra73.

  43. Melenhorst JJ. Abstract 358, in ASGCT annual meeting. 2019.

  44. Porter DL, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7(303):303ra139.

  45. Turtle CJ, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J Clin Oncol. 2017;35(26):3010–20.

    Article  CAS  Google Scholar 

  46. Gauthier J, et al. Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure. Blood. 2020;135(19):1650–60.

    Article  Google Scholar 

  47. Siddiqi T, et al. Blood. 2021. https://doi.org/10.1182/blood.2021011895.

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tanya Siddiqi.

Ethics declarations

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.

Conflict of Interest

The authors declare no competing interests.

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 Chronic Lymphocytic Leukemias

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rainone, M., Siddiqi, T. Management of Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma in the Era of Targeted Therapies. Curr Hematol Malig Rep 17, 39–45 (2022). https://doi.org/10.1007/s11899-021-00652-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-021-00652-2

Keywords

Navigation