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Peripheral blood cytogenetics allows treatment monitoring and early identification of treatment failure to lenalidomide in MDS patients: results of the LE-MON-5 trial

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Abstract

Transfusion-dependent patients with low- or intermediate-1-risk myelodysplastic syndrome, <5% bone marrow (BM) blasts and isolated 5q-deletion received lenalidomide within the German MDS study group phase-II clinical trial LE-MON-5 (EudraCT:2008-001866-10) of the University of Duesseldorf, Germany. Cytogenetic monitoring was performed by chromosome banding analyses (CBA) of BM cells and fluorescence in situ hybridization (FISH) analyses of peripheral blood (PB) mononuclear CD34+ cells using extended probe panels. Out of 144 patients screened for study enrollment, 24% failed to meet inclusion criteria due to cytogenetic findings. Eighty-seven patients were followed with a median observation time of 30 months. Cytogenetic response detected by FISH and CBA in 74 and 66% of patients, respectively, was predictive for hematologic response as well as of high prognostic relevance. After 2 years, AML rate was 8% for all patients. Karyotype evolution was detected in 21 (FISH)–34% (CBA) of patients associated with significantly shorter AML-free survival. Disease progression was first detectable on the cytogenetic level on average 5–6 months before recurrence of transfusion dependence. Our data show for the first time in a prospective setting that a cytogenetic monitoring from the PB helps to early identify treatment failure and progressive disease in lenalidomide-treated patients to improve clinical management. Trial registration: EudraCT:2008-001866-10

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Acknowledgments

The trial was supported by Celgene, providing the compound, supporting data monitoring, and technical processing of bone marrow biopsies. FB, UG, ES, UP, FN, WKH, A Giagounidis, KG, ML, RFS, JS, UB, A Ganser, AL, PS, GB, THB, RH, LT, and DH included patients, analyzed the data, wrote the paper, and approved the final manuscript. AG performed centralized cytology. GB performed centralized pathology. DH, FB, JS, UB, and KS performed central cytogenetic banding and molecular-cytogenetic analyses. XS performed the statistical analyses, wrote the paper, and gave the final approval. UG designed the clinical trial, contributed essential data, analyzed the data, and approved the final version.

Author information

Authors and Affiliations

  1. Department of Hematology and Medical Oncology, University Medicine of Goettingen, Robert-Koch-Str. 40, 37075, Goettingen, Germany

    Friederike Braulke, Julie Schanz, Ulrike Bacher, Lorenz Trümper, Katayoon Shirneshan & Detlef Haase

  2. Department of Medical Statistics, University Medicine of Goettingen, Goettingen, Germany

    Xenia Schulz

  3. Department of Hematology and Oncology, University of Duesseldorf, Duesseldorf, Germany

    Ulrich Germing, Esther Schuler & Rainer Haas

  4. Department of Hematology and Oncology, University of Dresden, Dresden, Germany

    Uwe Platzbecker

  5. Department of Hematology and Oncology, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany

    Florian Nolte & Wolf-Karsten Hofmann

  6. Department of Hematology and Oncology, Marienhospital, Duesseldorf, Germany

    Aristoteles Giagounidis

  7. Department of Hematology and Oncology, Technical University of Munich, Munich, Germany

    Katharina Götze

  8. Department of Hematology and Oncology, University of Freiburg Medical Center, Freiburg, Germany

    Michael Lübbert

  9. Department of Hematology and Oncology, University of Ulm, Germany, now National Center of Tumor Diseases, Heidelberg, Germany

    Richard F. Schlenk

  10. Department of Hematology, Hemostaseology and Stem Cell Transplantation, Hannover Medical School (MHH), Hannover, Germany

    Arnold Ganser

  11. Institute of Pathology, Hannover Medical School (MHH), Hannover, Germany

    Guntram Büsche

  12. Departement of Hematology and Oncology, Charite University Medical Center Berlin, Berlin, Germany

    Anne Letsch

  13. Department of Oncology, Hematology, BMT with section Pneumology, Hubertus Wald Cancer Center, Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Philippe Schafhausen

  14. Department of Internal Medicine II, Hematology and Oncology, Johann Wolfgang Goethe University of Frankfurt, Frankfurt, Germany

    Gesine Bug

  15. Department of Hematology and Oncology, Hemostaseology and SCT, University Hospital RWTH Aachen, Aachen, Germany

    Tim H. Brümmendorf

Authors
  1. Friederike Braulke
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  2. Xenia Schulz
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  3. Ulrich Germing
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  4. Esther Schuler
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  5. Uwe Platzbecker
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  6. Florian Nolte
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  7. Wolf-Karsten Hofmann
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  8. Aristoteles Giagounidis
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  9. Katharina Götze
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  10. Michael Lübbert
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  11. Richard F. Schlenk
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  12. Julie Schanz
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  13. Ulrike Bacher
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  14. Arnold Ganser
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  15. Guntram Büsche
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  16. Anne Letsch
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  17. Philippe Schafhausen
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  18. Gesine Bug
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  19. Tim H. Brümmendorf
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  20. Rainer Haas
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  21. Lorenz Trümper
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  22. Katayoon Shirneshan
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  23. Detlef Haase
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Corresponding author

Correspondence to Friederike Braulke.

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Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Conflict of interest

This trial was supported by Celgene. DH, FB, JS, and UB received speakers honoraria and research support by Celgene and Novartis. UG, UP, and FN obtained speakers honoraria and research support from Celgene. ES and KS received travel grants by Celgene. AG obtained honoraria from Celgene. KG obtained honoraria from Celgene. RFS obtained research support from Celgene. AL obtained research funding from Celgene. GB received research support, honoraria, and travel grants by Celgene. THB is a member of the Data Safety Monitoring Committee (DSMC) of this trial. PS obtained educational grants from Celgene. The remaining authors had no competing interests concerning this project.

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Braulke, F., Schulz, X., Germing, U. et al. Peripheral blood cytogenetics allows treatment monitoring and early identification of treatment failure to lenalidomide in MDS patients: results of the LE-MON-5 trial. Ann Hematol 96, 887–894 (2017). https://doi.org/10.1007/s00277-017-2983-0

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  • DOI: https://doi.org/10.1007/s00277-017-2983-0

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