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Annals of Hematology

, Volume 97, Issue 10, pp 1757–1765 | Cite as

Digital droplet PCR-based absolute quantification of pre-transplant NPM1 mutation burden predicts relapse in acute myeloid leukemia patients

  • Marius Bill
  • Juliane Grimm
  • Madlen Jentzsch
  • Laura Kloss
  • Karoline Goldmann
  • Julia Schulz
  • Stefanie Beinicke
  • Janine Häntschel
  • Michael Cross
  • Vladan Vucinic
  • Wolfram Pönisch
  • Gerhard Behre
  • Georg-Nikolaus Franke
  • Thoralf Lange
  • Dietger Niederwieser
  • Sebastian Schwind
Original Article

Abstract

Allogeneic hematopoietic stem cell transplantation is an established consolidation therapy for patients with acute myeloid leukemia. However, relapse after transplantation remains a major clinical problem resulting in poor prognosis. Thus, detection of measurable (“minimal”) residual disease to identify patients at high risk of relapse is essential. A feasible method to determine measurable residual disease may be digital droplet PCR (ddPCR) that allows absolute quantification with high sensitivity and specificity without the necessity of standard curves. Using ddPCR, we analyzed pre-transplant peripheral blood and bone marrow of 51 NPM1-mutated acute myeloid leukemia patients transplanted in complete remission or complete remission with incomplete recovery. Mutated NPM1 measurable residual disease-positive patients had higher cumulative incidence of relapse (P < 0.001) and shorter overall survival (P = 0.014). Restricting the analyses to patients receiving non-myeloablative conditioning, mutated NPM1 measurable residual disease positivity is associated with higher cumulative incidence of relapse (P < 0.001) and shorter overall survival (P = 0.006). Positive mutated NPM1 measurable residual disease status determined by ddPCR before allogeneic stem cell transplantation is associated with worse prognosis independent of other known prognostic markers—also for those receiving non-myeloablative conditioning. In the future, mutated NPM1 measurable residual disease status determined by ddPCR might guide treatment and improve patients’ outcomes.

Keywords

Acute myeloid leukemia Measurable residual disease Digital droplet PCR Allogeneic hematopoietic stem cell transplantation 

Notes

Acknowledgements

The authors thank Ines Kovacs, Kathrin Wildenberger, Scarlett Schwabe, Christine Günther, Daniela Bretschneider, Evelin Hennig, and Christel Müller for their assistance.

Authors’ contributions

M.B., J.G., and S.S. designed, performed experiments, analyzed, and interpreted data. L.K., K.G., J.S., S.B., and J.H. performed experiments. M.J. analyzed data. T.L., M.C., G.B., V.V., W.P., and GN.F. provided administrative and technical support. M.B., J.G., and S.S. wrote and all authors reviewed and approved the manuscript. D.N. and S.S. supervised the study.

Funding information

This work was supported by the Deutsche José-Carreras-Stiftung (#04R/2016 and #PS15/05 J.G.), Verein zusammen gegen den Krebs e.V., Ein Herz für Kinder e.V., and the Medical Faculty of the University of Leipzig (#990101-089).

Compliance with ethical standards

Written informed consent for participation in studies was obtained in accordance with the Declaration of Helsinki.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

277_2018_3373_MOESM1_ESM.docx (148 kb)
ESM 1 (DOCX 147 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Marius Bill
    • 1
  • Juliane Grimm
    • 1
  • Madlen Jentzsch
    • 1
  • Laura Kloss
    • 1
  • Karoline Goldmann
    • 1
  • Julia Schulz
    • 1
  • Stefanie Beinicke
    • 1
  • Janine Häntschel
    • 1
  • Michael Cross
    • 1
  • Vladan Vucinic
    • 1
  • Wolfram Pönisch
    • 1
  • Gerhard Behre
    • 1
  • Georg-Nikolaus Franke
    • 1
  • Thoralf Lange
    • 1
  • Dietger Niederwieser
    • 1
  • Sebastian Schwind
    • 1
  1. 1.Department of Hematology and OncologyUniversity Hospital Leipzig, University of LeipzigLeipzigGermany

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