Real-world outcomes following venetoclax therapy in patients with chronic lymphocytic leukemia or Richter syndrome: a FILO study of the French compassionate use cohort


The BCL2 inhibitor venetoclax is transforming the management of patients with chronic lymphocytic leukemia (CLL), given its high efficacy in relapsed/refractory CLL as observed in both early-phase and randomized clinical trials. The present study aimed to determine whether venetoclax is effective and well tolerated in patients with CLL or Richter’s syndrome (RS) in a real-world setting and to highlight factors impacting survival. Data from a venetoclax French compassionate use program were collected for 67 patients (60 with CLL and 7 with RS). Most patients presented adverse genetic features, such as TP53 disruption (74%) or complex karyotype (58%). Tumor lysis syndrome was observed in 14 (22%) patients, and 16 (24%) patients were hospitalized for grade III/IV infection. In the CLL cohort, ORR was 75 %, 1-year PFS was 61% (95% CI = 47–72%) and 1-year OS 70% (95% CI = 56–80%). No impact of TP53 disruption was noted while complex karyotype was identified as a predictor of both inferior PFS (HR = 3.46; 95% CI = 1–12; log-rank p = 0.03) and OS (HR = 3.2; 95% CI = 0.9–11.4, log-rank p = 0.047). Among the seven patients with RS, two achieved an objective response to venetoclax; however, the median OS was only 1.1 month. The well-balanced safety/efficacy profile of venetoclax is confirmed in this real-world setting. Complex karyotype should be evaluated as a predictive factor of survival for patients treated by venetoclax.

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  1. 1.

    Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, Grant B, Sharman JP, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Sukbuntherng J, Chang BY, Clow F, Hedrick E, Buggy JJ, James DF, O'Brien S (2013) Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 369(1):32–42

    CAS  Article  Google Scholar 

  2. 2.

    Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O'Brien SM (2014) Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370(11):997–1007

    CAS  Article  Google Scholar 

  3. 3.

    Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF (2016) Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 374(4):311–322

    CAS  Article  Google Scholar 

  4. 4.

    Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, Puvvada SD, Wendtner CM, Roberts AW, Jurczak W, Mulligan SP, Böttcher S, Mobasher M, Zhu M, Desai M, Chyla B, Verdugo M, Enschede SH, Cerri E, Humerickhouse R, Gordon G, Hallek M, Wierda WG (2016) Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol 17(6):768–778

    CAS  Article  Google Scholar 

  5. 5.

    Guièze R, Wu CJ (2015) Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia. Blood. 126(4):445–453

    Article  Google Scholar 

  6. 6.

    Guièze R, Liu VM, Rosebrock D, et al. Mitochondrial reprogramming underlies resistance to BCL-2 inhibition in lymphoid malignancies. Cancer Cell. 2019;36(4):369-384.e13.

  7. 7.

    Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D’Rozario J, Assouline S, Owen C, Gerecitano J, Robak T, de la Serna J, Jaeger U, Cartron G, Montillo M, Humerickhouse R, Punnoose EA, Li Y, Boyer M, Humphrey K, Mobasher M, Kater AP (2018) Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 378(12):1107–1120

    CAS  Article  Google Scholar 

  8. 8.

    Fischer K, Al-Sawaf O, Bahlo J et al (2019) Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 380(23):2225–2236

    CAS  Article  Google Scholar 

  9. 9.

    Roeker LE, Fox CP, Eyre TA et al (2019) Tumor lysis, adverse events, and dose adjustments in 297 venetoclax-treated CLL patients in routine clinical practice. Clin Cancer Res Off J Am Assoc Cancer Res 25(14):4264–4270

    CAS  Article  Google Scholar 

  10. 10.

    Mato AR, Thompson M, Allan JN, et al. Real world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States. Haematologica. 2018;

  11. 11.

    Eyre TA, Kirkwood AA, Gohill S, Follows G, Walewska R, Walter H, Cross M, Forconi F, Shah N, Chasty R, Hart A, Broom A, Marr H, Patten PEM, Dann A, Arumainathan A, Munir T, Shankara P, Bloor A, Johnston R, Orchard K, Schuh AH, Fox CP, the UK CLL Forum (2019) Efficacy of venetoclax monotherapy in patients with relapsed chronic lymphocytic leukaemia in the post-BCR inhibitor setting: a UK wide analysis. Br J Haematol 185(4):656–669

    CAS  Article  Google Scholar 

  12. 12.

    Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating M, Montserrat E, Chiorazzi N, Stilgenbauer S, Rai KR, Byrd JC, Eichhorst B, O’Brien S, Robak T, Seymour JF, Kipps TJ (2018) Guidelines for diagnosis, indications for treatment, response assessment and supportive management of chronic lymphocytic leukemia. Blood. 131:2745–2760

    CAS  Article  Google Scholar 

  13. 13.

    Howard SC, Jones DP, Pui C-H (2011) The tumor lysis syndrome. N Engl J Med 364(19):1844–1854

    CAS  Article  Google Scholar 

  14. 14.

    Roberts AW, Ma S, Kipps TJ, Coutre SE, Davids MS, Eichhorst B, Hallek M, Byrd JC, Humphrey K, Zhou L, Chyla B, Nielsen J, Potluri J, Kim SY, Verdugo M, Stilgenbauer S, Wierda WG, Seymour JF (2019) Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables. Blood. 134(2):111–122

    CAS  Article  Google Scholar 

  15. 15.

    Davids MS, Roberts AW, Seymour JF, Pagel JM, Kahl BS, Wierda WG, Puvvada S, Kipps TJ, Anderson MA, Salem AH, Dunbar M, Zhu M, Peale F, Ross JA, Gressick L, Desai M, Kim SY, Verdugo M, Humerickhouse RA, Gordon GB, Gerecitano JF (2017) Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol Off J Am Soc Clin Oncol 35(8):826–833

    CAS  Article  Google Scholar 

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The authors would thank all participating physicians who treated the patients as part of the venetoclax French compassionate program and for providing the clinical data required. Editorial assistance, in the form of language editing and correction, was provided by XpertScientific Editing and Consulting Services.


The study was supported by AbbVie.

Author information




F.B. and R.G. designed the study, analyzed the data, and wrote the manuscript. B.P. performed statistical analyses. F.B. collected clinical data. L.V. helped to interpret cytogenetic data. A.C., M-S.D., S.A., F.C., C.H., S.D.G., D.R-W, B.H., T.A., J.D., A.B., E.T., K.L., N.D., P.M., A-S.M., C.D., F.N-K., A.D., P.F., and L.Y. included patients and collected clinical and biological data. All authors approved the final manuscript.

Corresponding author

Correspondence to Romain Guièze.

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Conflict of interest

Bouclet Florian: AbbVie, Amgen

Herbaux Charles: research funding: Takeda, AbbVie; honoraria and non-financial support: Roche, Janssen-Cilag, AbbVie, Takeda

de Guibert Sophie: honoraria: AbbVie, Janssen, Gilead

Hivert Bénedicte: participation boards scientifiques: Sanofi, Janssen

Aurran Thérèse: honoraria: Janssen, AbbVie

Dupuis Jehan: Celgene and AbbVie

Laribi Kamel: scientific partnership: Novartis, Takeda, Janssen, Sandoz, AbbVie, Amgen, Roche

Michallet Anne-Sophie: scientific partnership: Janssen AbbVie

Dartigeas Caroline: honoraria and travels support: AbbVie, Roche. Travel support: Janssen

Tournilhac Olivier: Roche Gilead Amgen AbbVie Takeda Sandoz

Delmer Alain: advisory board: Janssen, Astra Zeneca, Roche, AbbVie. Travel support: Janssen, AbbVie, Roche, Gilead

Feugier Pierre: Janssen, Roche, Gilead, Amgen, AstraZeneca, AbbVie

Ysebaert Loic: advisory boards: AbbVie, Astra Zeneca, Gilead, Janssen, Roche

Guieze Romain: advisory board: Astra Zeneca, Janssen, AbbVie. Travel support: Roche, AbbVie, Gilead, Jansen

There is no conflict of interest to disclose for the remaining authors.

Ethics approval

The study was approved by the board of the FILO and was conducted according to the Declaration of Helsinki.

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All the authors approved the final manuscript.

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Bouclet, F., Calleja, A., Dilhuydy, MS. et al. Real-world outcomes following venetoclax therapy in patients with chronic lymphocytic leukemia or Richter syndrome: a FILO study of the French compassionate use cohort. Ann Hematol (2021).

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  • Chronic lymphocytic leukemia
  • Richter syndrome
  • B cell
  • Targeted therapy
  • Bcl-2 inhibitor
  • Venetoclax