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Frequent evolution of copy number alterations in CLL following first-line treatment with FC(R) is enriched with TP53 alterations: results from the CLL8 trial

Leukemia volume 31, pages 734–738 (2017)Cite this article

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Malignant populations constitute a mixture of multiple genetically distinct clones, which can often be dramatically altered with therapy.1 Clonal evolution was recently shown to be frequent in chronic lymphocytic leukemia (CLL) by sequential whole-exome sequencing of matched sequential samples taken at treatment initiation and first relapse following chemo(immuno)therapy from 59 individuals.2 This finding raises important questions: Is evolution occurring as frequently during the preceding ‘watch and wait’ period, or is it primarily driven by therapeutic intervention? Are there clinical features associated with higher rates of evolution? Do the genetic variations that emerge over the course of evolution alter the clinical outcome?

To address these questions, we analyzed serial samples from 103 individuals treated within the CLL8 trial, in which patients uniformly received fludarabine and cyclophosphamide as first-line treatment with/without additional rituximab (FC/FCR). Samples taken long before treatment initiation, at treatment initiation and at relapse/progressive disease were included. Genomic analysis was performed by single-nucleotide polymorphism arrays thereby focussing on the evolution of somatic copy number alterations (CNAs). Comparing sequential samples before therapy (N=27), CNA evolution occurred in 19% of cases. In contrast, when comparing treatment initiation and relapse genomic profiles (N=86), CNA evolution was seen twice as frequently. This suggested an association of FC(R) treatment with higher rate of CNA evolution. The only clinical feature significantly associated with CNA evolution was FCR therapy compared with FC (odds ratio =2.806, P=0.024). As this might be related to narrower evolutionary bottlenecks imposed by the more effective FCR therapy, which could execute more selection pressure, we examined matched minimal residual disease (MRD) data and found CNA evolution more frequently in cases with CLL cell numbers rapidly receding in early phases of treatment. Finally, we observed frequent rises of TP53 mutant/deficient clones with therapy (in N=19 cases, 22%) that were associated with decreased overall survival (P=0.016).

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Acknowledgements

We thank the patients who participated in the CLL8 trial; the investigators who treated patients and submitted samples; F Hoffmann-La Roche (Basel, Switzerland) for support; and Sabrina Kless, Christina Galler, Sabrina Rau, Karin Lanz and Andreas Streicher for excellent assistance and support. This work was supported by Deutsche Forschungsgemeinschaft (ED 256/1-1, SFB 1074/B2 and Z1), Else Kröner-Fresenius-Stiftung (2012_A146), Virtual Helmholtz Institute (VH-VI-404, TP2), BMBF (CancerEpiSys, PRECISE) and F Hoffmann-La Roche (genetic reference diagnostics of CLL8: CD19 enrichment, routine FISH analysis and IGHV-status). DAL is supported by the Burroughs Wellcome Fund Career Award for Medical Scientists, Stand Up to Cancer Innovative Research Grant, the Kimmel Scholar’s Award, the ASH Scholar Award, and and by the NIH Big Data to Knowledge initiative (BD2K, 1K01ES025431-01).

Author contributions

JE, ET, DAL, SB, CJW, HD and SS designed the research. JE, ET and DAL performed the experiments. JE, ET, DAL, SR, JBa, KF, A-MF, JBl, KH, SB, LW, MK, CJW, MH, HD and SS collected and analyzed the data. JE, ET, DAL, SR, JBa, KF, A-MF, JBl, KH, SB, LW, JGG, DSN, CJW, HD and SS interpreted the data. JE, DAL, SR, JBa, JBl, KH, SB, JGG, DSN, CJW, HD and SS contributed to write the manuscript.

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Authors and Affiliations

  1. Internal Medicine III, Ulm University, Ulm, Germany

    J Edelmann, E Tausch, J Bloehdorn, H Döhner & S Stilgenbauer

  2. Barts Cancer Institute, Queen Mary University of London, London, UK

    J Edelmann & J G Gribben

  3. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA

    D A Landau & C J Wu

  4. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA

    D A Landau

  5. Division of Hematology and Medical Oncology and The Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA

    D A Landau

  6. New York Genome Center, New York, NY, USA

    D A Landau

  7. Internal Medicine I, University of Cologne, Cologne, Germany

    S Robrecht, J Bahlo, K Fischer, A M Fink & M Hallek

  8. Center for Clinical Research, Genomics Core Facility, Ulm University, Ulm, Germany

    K Holzmann

  9. Second Department of Medicine, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany

    S Böttcher & M Kneba

  10. Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, USA

    L Werner & D S Neuberg

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  1. J Edelmann
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  2. E Tausch
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  3. D A Landau
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  11. L Werner
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Correspondence to J Edelmann.

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Edelmann, J., Tausch, E., Landau, D. et al. Frequent evolution of copy number alterations in CLL following first-line treatment with FC(R) is enriched with TP53 alterations: results from the CLL8 trial. Leukemia 31, 734–738 (2017). https://doi.org/10.1038/leu.2016.317

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