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Early, risk-adapted treatment with fludarabine in Binet stage A chronic lymphocytic leukemia patients: results of the CLL1 trial of the German CLL study group

Leukemia volume 31, pages 2833–2837 (2017)Cite this article

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Chronic lymphocytic leukemia (CLL) is one of the most common malignant lymphoid diseases in adults in the Western world. The American Cancer Society’s estimates for CLL in the United States for 2017 are about 20 110 new cases and about 4660 deaths.1 More than 80% of cases are diagnosed at early stage. Approximately 30–50% have an unfavorable outcome. Since immediate treatment with chlorambucil only deferred progression without survival benefit, management of early CLL means deferring treatment until the patient develops active disease.2 On the basis of these data and with respect to the high rate of treated patients who died from second primary malignancies, we designed the CLL1 protocol in 1997 and included a risk stratification that defined high-risk (HR) patients, who might progress and receive treatment within 2 years after diagnosis, by either diffuse bone marrow infiltration pattern or lymphocyte doubling time <12 months, in combination with either thymidine kinase >7.0 U/l or beta2-microglobulin (beta2-MG) >3.5 mg/l (Supplementary Figure 1).3, 4, 5 HR patients were centrally 1:1 randomized at the Institute of Medical Statistics and Epidemiology, Technical University Munich using a pre-defined randomization list between early fludarabine (high-risk fludarabine (HR-F): 25 mg/m2 i.v., days 1–5, q28 days × 6 cycles) versus watch and wait (HR-W&W). On the basis of the hypothesis that deeper remission would lead to improved progression-free survival (PFS) and overall survival (OS), fludarabine was considered as the most efficacious treatment in 1997.6, 7, 8

The CLL1 trial was conducted at 123 German and Austrian centers in adherence to good clinical practice guidelines and in consistence with the Declaration of Helsinki. The protocol was approved by the institutional review board of the University Munich, Germany. All the patients provided written informed consent. Eligibility criteria were based on the National Cancer Institute-sponsored Working Group guidelines 1996,9 excluding patients with monoclonal B-cell lymphocytosis. The upper age limit was 75 years and the eastern cooperative oncology group performance status had to be less or equal to 2. Beta2-MG, thymidine kinase, genetic characteristics and lymphocyte doubling time calculation were performed centrally at screening.

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Figure 1

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Acknowledgements

We thank Anne Westermann, Ute Elberskirch, Anna Fink, Thu-Trang Pham and Katrin Klein for their contribution to this work. The trial was supported by grants from Deutsche Krebshilfe (German Cancer Aid) (70–2434 and 106116), Wilhelm-Sander-Foundation (2001.004.1 and 2001.004.2), and BayerSchering Pharma AG.

Disclaimer

Study drug was provided by BayerSchering Pharma AG, which did not have a role in the design or conduct of the study, writing of the manuscript, or the decision to submit the manuscript for publication.

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Author notes

  1. H Döhner, M Hallek and S Stilgenbauer: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine I, Klinikum Schwabing, Munich, Germany

    M A Hoechstetter & C M Wendtner

  2. Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich, Germany

    R Busch

  3. Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany

    B Eichhorst, C M Wendtner, J Bahlo, K Fischer & M Hallek

  4. Department of Internal Medicine III, Ulm University, Ulm, Germany

    A Bühler, D Winkler, H Döhner & S Stilgenbauer

  5. Internal Medicine, Hematology and Oncology Private Practice, Erlangen, Germany

    M J Eckart

  6. Oncological Private Practice, Landshut, Germany

    U Vehling-Kaiser

  7. Internal Medicine, Hematology and Oncology Private Practice, Saarbrücken, Germany

    H Schimke

  8. Department of Internal Medicine I, Division of Hematology and Hemostaseology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

    U Jäger

  9. Internal Medicine, Hematology and Oncology Private Practice, Halle, Germany

    H J Hurtz

  10. Department of Internal Medicine I, Division of Bone Marrow Transplantation, Medical University of Vienna, Vienna, Austria

    G Hopfinger

  11. Department of Hematology and Oncology, Klinikum Lippe-Lemgo, Lemgo, Germany

    F Hartmann

  12. Department of Hematology, Oncology and Palliative Medicine, Klinikum Bad Saarow, Bad Saarow, Germany

    H Fuss

  13. Hematology and Oncology Private Practice, Munich, Germany

    W Abenhardt

  14. Hematology and Oncology Private Practice, Berlin, Germany

    I Blau

  15. Hematology and Oncology Private Practice, Hildesheim, Germany

    W Freier

  16. Hematology and Oncology Private Practice, Leer, Germany

    L Müller

  17. Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany

    M Goebeler

  18. Department of Internal Medicine III, Klinikum Karlsruhe, Karlsruhe, Germany

    M Bentz

  19. Interdisciplinary Oncology Center (IOZ) Private Practice, Munich, Germany

    B Emmerich

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  1. M A Hoechstetter
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Corresponding authors

Correspondence to M A Hoechstetter or M Hallek.

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The authors declare no conflict of interest.

Additional information

This paper was presented in part at the 49th annual meeting of the American Society of Hematology, Atlanta, GA, USA, 8 December 2007.

Supplementary Information accompanies this paper on the Leukemia website

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Hoechstetter, M., Busch, R., Eichhorst, B. et al. Early, risk-adapted treatment with fludarabine in Binet stage A chronic lymphocytic leukemia patients: results of the CLL1 trial of the German CLL study group. Leukemia 31, 2833–2837 (2017). https://doi.org/10.1038/leu.2017.246

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