Utilizing Real-World Evidence (RWE) to Improve Care in Chronic Lymphocytic Leukemia: Challenges and Opportunities


Purpose of Review

This review discusses important findings from real-world evidence (RWE) studies impacting the field of chronic lymphocytic leukemia (CLL), from prognostication to long-term management and sequencing of novel agents.

Recent Findings

RWE data, which represents a heterogeneous cohort of patients treated at non-academic centers and off-clinical trial, demonstrate several key differences between findings in randomized controlled trials (RCT) of novel agents in CLL. While toxicity and discontinuation rates are higher, survival outcomes are encouraging in clinical practice, with often equivalent outcomes from reduced-dose or time-limited therapy of drug. Though sequencing of novel agents lacks robust RCT data, RWE data provide important guidance for selection and sequencing of novel agents.


RWE has critically informed our practice by providing diverse patient data and real-time analysis for important clinical questions outpacing the rapidly growing field of CLL.

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


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

  1. 1.

    da Cunha-Bang C, Geisler CH, Enggaard L, Poulsen CB, de Nully BP, Frederiksen H, et al. The Danish National Chronic Lymphocytic Leukemia Registry. Clin Epidemiol. 2016;8:561–5.

    Article  Google Scholar 

  2. 2.

    Winqvist M, Andersson PO, Asklid A, Karlsson K, Karlsson C, Lauri B, et al. Long-term real-world results of ibrutinib therapy in patients with relapsed or refractory chronic lymphocytic leukemia: 30-month follow up of the Swedish compassionate use cohort. Haematologica. 2019;104(5):e208–e10.

    CAS  Article  Google Scholar 

  3. 3.

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

    Article  Google Scholar 

  4. 4.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.

    Article  Google Scholar 

  5. 5.

    Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745–60.

    CAS  Article  Google Scholar 

  6. 6.

    Mato A, Nabhan C, Kay NE, Lamanna N, Kipps TJ, Grinblatt DL, et al. Prognostic testing patterns and outcomes of chronic lymphocytic leukemia patients stratified by fluorescence in situ hybridization/Cytogenetics: a real-world clinical experience in the Connect CLL registry. Clin Lymphoma Myeloma Leuk. 2018;18(2):114–24 e2.

    Article  Google Scholar 

  7. 7.

    Mato A, Barrientos, JC., Brander, DM. Prognostic testing and treatment approaches in patients with chronic lymphocytic leukemia: clinical experience from an interim analysis of the informCLLTM real-world registry. American Society of Hematology; November 29 2018; San Diego, CA: Blood; 2018.

  8. 8.

    Jones J, Mato A, Coutre S, Byrd JC, Furman RR, Hillmen P, et al. Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials. Br J Haematol. 2018;182(4):504–12.

    CAS  Article  Google Scholar 

  9. 9.

    International CLLIPI. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17(6):779–90.

    Article  Google Scholar 

  10. 10.

    Stilgenbauer S, Eichhorst B, Schetelig J, Hillmen P, Seymour JF, Coutre S, 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(19):1973–80.

    CAS  Article  Google Scholar 

  11. 11.

    Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768–78.

    CAS  Article  Google Scholar 

  12. 12.

    Brander D, Rhodes, J., Pagel, JM., et al. Applicability of the chronic lymphocytic leukemia (CLL)-IPI on patients treated with front-line Ibrutinib in the real world: the case for new prognostic models. American Society of Hematology; December 7 2017; Washington, D.C.: Blood; 2017.

  13. 13.

    Anderson MA, Tam C, Lew TE, Juneja S, Juneja M, Westerman D, et al. Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax. Blood. 2017;129(25):3362–70.

    CAS  Article  Google Scholar 

  14. 14.

    • Mato AR, Roeker LE, Allan JN, Pagel JM, Brander DM, Hill BT, et al. Outcomes of front-line ibrutinib treated CLL patients excluded from landmark clinical trial. Am J Hematol. 2018;93(11):1394–401 Provides comprehensive safety, toxicity, treatment course and outcomes information for patient populations excluded from RESONATE-2.

    CAS  Article  Google Scholar 

  15. 15.

    •• Mato AR, Nabhan C, Thompson MC, Lamanna N, Brander DM, Hill B, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103(5):874–9 One of the largest RWE cohort of ibrutinib treated CLL reported, provides comprehensive information on ibrutinib safety, toxicity, and treatment course in the real-world.

    CAS  Article  Google Scholar 

  16. 16.

    Roeker LE, Fox CP, Eyre TA, Brander DM, Allan JN, Schuster SJ, et al. Tumor Lysis, adverse events, and dose adjustments in 297 venetoclax-treated CLL patients in routine clinical practice. Clin Cancer Res. 2019;25(14):4264–70.

    Article  Google Scholar 

  17. 17.

    Ahn IE, Farooqui MZH, Tian X, Valdez J, Sun C, Soto S, et al. Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study. Blood. 2018;131(21):2357–66.

    CAS  Article  Google Scholar 

  18. 18.

    Burger JA, Barr PM, Robak T, Owen C, Ghia P, Tedeschi A, 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. 2019;34:787–98.

  19. 19.

    •• Coutre SE, Byrd JC, Hillmen P, Barrientos JC, Barr PM, Devereux S, 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 Provides consolidated long-term safety data from pivotal clinical trials of ibrutinib in CLL.

    CAS  Article  Google Scholar 

  20. 20.

    Mato AR, Islam P, Daniel C, Strelec L, Kaye AH, Brooks S, et al. Ibrutinib-induced pneumonitis in patients with chronic lymphocytic leukemia. Blood. 2016;127(8):1064–7.

    CAS  Article  Google Scholar 

  21. 21.

    • Davids MS, Hallek M, Wierda W, Roberts AW, Stilgenbauer S, Jones JA, et al. Comprehensive safety analysis of venetoclax monotherapy for patients with relapsed/refractory chronic lymphocytic leukemia. Clin Cancer Res. 2018;24(18):4371–9 Provides comprehensive safety analysis from integrated data on three pivotal phase I/II venetoclax clinical trials.

    CAS  Article  Google Scholar 

  22. 22.

    •• Mato AR, Thompson M, Allan JN, Brander DM, Pagel JM, Ujjani CS, et al. Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States. Haematologica. 2018;103(9):1511–7 Proviedes RWE analysis of venetoclax safety, toxicity, treatment course and outcomes in patient populations excluded from clinical trials.

    CAS  Article  Google Scholar 

  23. 23.

    Seymour JF, Mobasher M, Kater AP. Venetoclax-rituximab in chronic lymphocytic leukemia. N Engl J Med. 2018;378(22):2143–4.

    PubMed  Google Scholar 

  24. 24.

    Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011;364(19):1844–54.

    CAS  Article  Google Scholar 

  25. 25.

    Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225–36.

    CAS  Article  Google Scholar 

  26. 26.

    O'Brien SM, Byrd JC, Hillmen P, Coutre S, Brown JR, Barr PM, et al. Outcomes with ibrutinib by line of therapy and post-ibrutinib discontinuation in patients with chronic lymphocytic leukemia: phase 3 analysis. Am J Hematol. 2019;94(5):554–62.

    CAS  Article  Google Scholar 

  27. 27.

    Akhtar OS, Attwood K, Lund I, Hare R, Hernandez-Ilizaliturri FJ, Torka P. Dose reductions in ibrutinib therapy are not associated with inferior outcomes in patients with chronic lymphocytic leukemia (CLL). Leuk Lymphoma. 2019;60(7):1650–5.

    CAS  Article  Google Scholar 

  28. 28.

    Mato AR, Roeker LE, Eyre TA, Nabhan C, Lamanna N, Hill BT, et al. A retrospective comparison of venetoclax alone or in combination with an anti-CD20 monoclonal antibody in R/R CLL. Blood Adv. 2019;3(10):1568–73.

    CAS  Article  Google Scholar 

  29. 29.

    Mato AR, Timlin C, Ujjani C, Skarbnik A, Howlett C, Banerjee R, et al. Comparable outcomes in chronic lymphocytic leukaemia (CLL) patients treated with reduced-dose ibrutinib: results from a multi-Centre study. Br J Haematol. 2018;181(2):259–61.

    Article  Google Scholar 

  30. 30.

    Jones JA, Mato AR, Wierda WG, Davids MS, Choi M, Cheson BD, 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.

    CAS  Article  Google Scholar 

  31. 31.

    • Mato AR, Roeker LE, Jacobs R, et al. Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK inhibition as an Effective Strategy. Clin Cancer Res. 2020. Provides important guidance on optimal choice of treatment following venetoclax.

  32. 32.

    •• Mato AR, Hill BT, Lamanna N, Barr PM, Ujjani CS, Brander DM, 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 Compares sequencing outcomes among three classes of novel agents, BTK inhibitors, PI3K inhibitors and BCL-2 inhibitors, and gives important insights to their optimal sequencing.

    CAS  Article  Google Scholar 

  33. 33.

    Ghia PPA, Wach M, et al. ASCEND phase 3 study of Acalabrutinib vs Investigator's choice of rituximab plus Idelalisib (IdR) or bendamustine (BR) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). EHA 2019.

Download references

Author information



Corresponding author

Correspondence to Prioty Islam.

Ethics declarations

Conflict of Interest

P.I. declares no conflicts of interest.

A.R.M. holds a consultancy role for TG Therapeutics (in addition DSMB), Abbvie, Pharmacyclics, Johnson & Johnson, Regeneron, Astra Zeneca, Genentech, LOXO, Celgene (including DSMB), Sunesis, and Adaptive and has received research funding from TG Therapeutics, Abbvie, Pharmacyclics, Johnson & Johnson, Regeneron, Genentech, LOXO, Portola, DTRM, Adaptive, and Acerta.

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 Healthcare Economics

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Islam, P., Mato, A.R. Utilizing Real-World Evidence (RWE) to Improve Care in Chronic Lymphocytic Leukemia: Challenges and Opportunities. Curr Hematol Malig Rep 15, 254–260 (2020). https://doi.org/10.1007/s11899-020-00584-3

Download citation


  • Real-world evidence
  • Chronic lymphocytic leukemia
  • Small-molecule inhibitor
  • Bruton’s tyrosine kinase inhibitor
  • PI3K inhibitor
  • BCL-2 inhibitor
  • Novel agents