Abstract

Current risk algorithms are primarily based on pre-treatment factors and imperfectly predict outcome in acute myeloid leukemia (AML). We introduce and validate a post-treatment approach of leukemic stem cell (LSC) assessment for prediction of outcome. LSC containing CD34+CD38− fractions were measured using flow cytometry in an add-on study of the HOVON102/SAKK trial. Predefined cut-off levels were prospectively evaluated to assess CD34+CD38−LSC levels at diagnosis (n = 594), and, to identify LSClow/LSChigh (n = 302) and MRDlow/MRDhigh patients (n = 305) in bone marrow in morphological complete remission (CR). In 242 CR patients combined MRD and LSC results were available. At diagnosis the CD34+CD38 LSC frequency independently predicts overall survival (OS). After achieving CR, combining LSC and MRD showed reduced survival in MRDhigh/LSChigh patients (hazard ratio [HR] 3.62 for OS and 5.89 for cumulative incidence of relapse [CIR]) compared to MRDlow/LSChigh, MRDhigh/LSClow, and especially MRDlow/LSClow patients. Moreover, in the NPM1mutant positive sub-group, prognostic value of golden standard NPM1-MRD by qPCR can be improved by addition of flow cytometric approaches. This is the first prospective study demonstrating that LSC strongly improves prognostic impact of MRD detection, identifying a patient subgroup with an almost 100% treatment failure probability, warranting consideration of LSC measurement incorporation in future AML risk schemes.

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Acknowledgements

We thank all participating HOVON/SAKK study centers, and the patients herein.

Author information

Author notes

  1. These authors contributed equally: Tim Grob, Rosa Meijer, Diana Hanekamp

  2. These authors contributed equally: Peter J. M. Valk, Mojca Jongen-Lavrencic

  3. These authors contributed equally: Gert J. Ossenkoppele, Gerrit J. Schuurhuis

Affiliations

  1. Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands

    • Wendelien Zeijlemaker
    • , Diana Hanekamp
    • , Angèle Kelder
    • , Jannemieke C. Carbaat-Ham
    • , Yvonne J. M. Oussoren-Brockhoff
    • , Alexander N. Snel
    • , Dennis Veldhuizen
    • , Willemijn J. Scholten
    • , Jacqueline Cloos
    • , Arjan A. van de Loosdrecht
    • , Gert J. Ossenkoppele
    •  & Gerrit J. Schuurhuis
  2. Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands

    • Tim Grob
    • , Bob Löwenberg
    • , Peter J. M. Valk
    •  & Mojca Jongen-Lavrencic
  3. Clinical trial Center- HOVON data center, Erasmus University Medical Center, Rotterdam, The Netherlands

    • Rosa Meijer
  4. Department of Hematology, University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium

    • Johan Maertens
  5. Department of Hematology, Ziekenhuis Netwerk Antwerpen, Antwerp, Belgium

    • Dimitri A. Breems
  6. Department of Hematology, Inselspital, Bern University Hospital, Bern, Switzerland

    • Thomas Pabst
  7. Department of Hematology, University and University Hospital Zürich, Zürich, Switzerland

    • Markus G. Manz
  8. Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    • Vincent H. J. van der Velden
  9. Department of Clinical Chemistry, Medisch Spectrum Twente/Medlon, Enschede, The Netherlands

    • Jennichjen Slomp
  10. Department of Laboratory Medicine – Laboratory for Hematology, Radboud University Nijmegen Medical Center, RUNMC, Nijmegen, The Netherlands

    • Frank Preijers
  11. Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands

    • Jacqueline Cloos

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Gerrit J. Schuurhuis.

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DOI

https://doi.org/10.1038/s41375-018-0326-3

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