Abstract

Obinutuzumab (GA101) and ibrutinib show excellent efficacy for treatment of chronic lymphocytic leukemia (CLL). Preclinical investigations and a complementary safety profile were in support of testing their combined use. The exploratory CLL2-BIG-trial evaluated a sequential combination therapy following a recently proposed strategy. Two courses of bendamustine were used for debulking in patients with a high tumor load, followed by six courses of induction therapy with ibrutinib and GA101, followed by an MRD-triggered maintenance phase. The results of a pre-planned analysis at the end of the induction phase are presented. 61 patients were included, 30 previously untreated and 31 with relapsed/refractory CLL. 44 patients received bendamustine. During induction, neutropenia (14.8%) and thrombocytopenia (13.1%) were the most common CTC grade 3 and 4 events. One fatality (duodenitis) occurred. The overall response rate was 100%. 54.1% of patients achieved a partial remission, 41% a clinical complete remission (cCR) without confirmation by CT scan or bone marrow (BM) biopsy according to protocol and 4.9% a cCR with incomplete recovery of the BM. 29 patients (47.5%) had no detectable (<10−4) minimal residual disease assessed by flow cytometry in peripheral blood. In conclusion, the BIG regimen is a safe and highly effective therapy for CLL.

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Additional information

Statement of prior presentation: Presented in abstract form at the 57th annual meeting of the American Society of Hematology, Orlando, FL, 7 December 2015 [1], and the 58th annual meeting of the American Society of Hematology, San Diego, CA, 5 December 2016 [2].

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Acknowledgements

This study was initiated and organized by the German CLL Study Group as an academic trial with the University of Cologne being the sponsor, and financial support by F. Hoffmann La Roche and Janssen-Cilag. The authors wish to express their gratitude towards all patients participating in the trial and their families, as well as the physicians and trial staff at the sites. Furthermore, we thank all study team members involved; in particular, we acknowledge Johanna Wesselmann and Irene Stodden for their excellent contribution. Finally, we thank Dr. Birgit Fath and the monitors from the competence network malignant lymphoma (Kompetenznetz Maligne Lymphome) for facilitating the conduct of this trial.

Author information

Affiliations

  1. Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University of Cologne, Cologne, Germany

    • Julia von Tresckow
    • , Paula Cramer
    • , Jasmin Bahlo
    • , Sandra Robrecht
    • , Petra Langerbeins
    • , Anna-Maria Fink
    • , Othman Al-Sawaf
    • , Kirsten Fischer
    • , Clemens-Martin Wendtner
    • , Karl-Anton Kreuzer
    •  & Barbara F. Eichhorst
  2. BAG Freiberg-Richter, Jacobasch, Wolf, Illmer, Dresden, Germany

    • Thomas Illmer
  3. Hämatologische/ Onkologische Praxis Dr. Klaproth, Neunkirchen, Germany

    • Holger Klaproth
  4. Department of Internal Medicine III, Ulm University, Ulm, Germany

    • Sven Estenfelder
    •  & Stephan Stilgenbauer
  5. Department of Medicine II, University of Schleswig-Holstein, Kiel, Germany

    • Matthias Ritgen
  6. Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, Hospital Munich-Schwabing, Munich, Germany

    • Clemens-Martin Wendtner
  7. Department of Internal Medicine I, Saarland University, Homburg, Germany

    • Stephan Stilgenbauer
  8. Clinic for Internal Medicine III, Universityhospital Rostock, Rostock, Germany

    • Sebastian Böttcher
  9. Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, CECAD Cluster of Excellence at the University of Cologne, Clinical Research Unit (KFO) 286, German CLL Study Group, University of Cologne, Cologne, Germany

    • Michael Hallek

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Conflict of interest

JvT: Research funding (F. Hoffmann-LaRoche, Janssen-Cilag), honoraria and consultant or advisory board member (AbbVie, Janssen-Cilag and F. Hoffmann-LaRoche), travel grants (AbbVie, Celgene, F. Hoffmann-LaRoche and Janssen-Cilag). PC: Research funding (AbbVie, Gilead, GlaxoSmithKline/Novartis, F. Hoffmann-LaRoche, and Janssen-Cilag), honoraria (F. Hoffmann-LaRoche and Janssen-Cilag), consultant or advisory board member (AbbVie, AstraZeneca, Janssen-Cilag and Novartis) and travel grants (Astellas, F. Hoffmann LaRoche, Gilead, Janssen-Cilag and Mundipharma). JB: Honoraria and travel grants (F. Hoffmann-LaRoche). PL: Research funding (Janssen-Cilag), Honoraria (AbbVie, Janssen-Cilag and F. Hoffmann-LaRoche), travel grants (AbbVie, F. Hoffmann-LaRoche, Janssen-Cilag and Mundipharma) AF: Research funding (Celgene), honoraria (F. Hoffman-LaRoche) and travel grants (F. Hoffmann-LaRoche, Mundipharma, Abbvie and Celgene). OA: Honoraria and consultant or advisory board member (AbbVie, Gilead and F. Hoffmann-LaRoche), travel grants (AbbVie, Gilead, F. Hoffmann-LaRoche and Janssen-Cilag). TI: Travel grants (F. Hoffmann-LaRoche). MR: Research funding (AbbVie; F. Hoffmann-LaRoche), consultant or advisory board member (AbbVie, BMS, F. Hoffmann-LaRoche) and travel grants (F. Hoffmann-LaRoche). KF: Travels grants (F. Hoffmann-LaRoche). CMW: Honoraria, consultant or advisory board member, research funding and travel grants (AbbVie, Gilead, F. Hoffmann-LaRoche, Janssen-Cilag and Mundipharma). KK: Research funding, honoraria, consultant or advisory board member and speaker´s bureau (F. Hoffmann-LaRoche, Janssen-Cilag and Mundipharma). SS: Research support, honoraria, consultant or advisory board member, speaker´s bureau and travel support (AbbVie, Amgen, Astra-Zeneca, Celgene, F. Hoffmann-LaRoche, Gilead, GlaxoSmithKline, Janssen-Cilag and Novartis). SB: Reasearch funding (AbbVie, Celgene and F. Hoffmann-LaRoche), honoraria (AbbVie, Becton Dickinson, F. Hoffmann-LaRoche), consultant or advisory board member (F. Hoffmann-LaRoche), travel grants (Celgene, F. Hoffmann-LaRoche). BE: Research support, consultant or advisory board member and travel support (AbbVie, Celgene, F. Hoffmann-LaRoche, Gilead, GlaxoSmithKline, Janssen-Cilag, Mundipharma). MH: Research funding (AbbVie, Celgene, F. Hoffmann-LaRoche, Gilead, Janssen-Cilag, Mundipharma and Pharmacyclics), honoraria and speaker´s bureau (AbbVie, Boehringer-Ingelheim, Celgene, F. Hoffmann-LaRoche, Gilead, Janssen-Cilag, Mundipharma and Pharmacyclics) and consultant or advisory board member (AbbVie, F. Hoffmann-LaRoche, Gilead, Janssen-Cilag). The remaining authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Julia von Tresckow.

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DOI

https://doi.org/10.1038/s41375-018-0313-8