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Annals of Hematology

, Volume 95, Issue 2, pp 191–199 | Cite as

Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group

  • Michael Lübbert
  • Stefan Suciu
  • Anne Hagemeijer
  • Björn Rüter
  • Uwe Platzbecker
  • Aristoteles Giagounidis
  • Dominik Selleslag
  • Boris Labar
  • Ulrich Germing
  • Helmut R. Salih
  • Petra Muus
  • Karl-Heinz Pflüger
  • Hans-Eckart Schaefer
  • Lioudmila Bogatyreva
  • Carlo Aul
  • Theo de Witte
  • Arnold Ganser
  • Heiko Becker
  • Gerwin Huls
  • Lieke van der Helm
  • Edo Vellenga
  • Frédéric Baron
  • Jean-Pierre Marie
  • Pierre W. Wijermans
  • on behalf of the EORTC Leukemia Group and the German MDS Study Group
Original Article

Abstract

In a study of elderly AML patients treated with the hypomethylating agent decitabine (DAC), we noted a surprisingly favorable outcome in the (usually very unfavorable) subgroup with two or more autosomal monosomies (MK2+) within a complex karyotype (Lübbert et al., Haematologica 97:393-401, 2012). We now analyzed 206 myelodysplastic syndrome (MDS) patients (88 % of 233 patients randomized in the EORTC/GMDSSG phase III trial 06011, 61 of them with RAEBt, i.e. AML by WHO) with cytogenetics informative for MK status.. Endpoints are the following: complete/partial (CR/PR) and overall response rate (ORR) and progression-free (PFS) and overall survival (OS). Cytogenetic subgroups are the following: 63 cytogenetically normal (CN) patients, 143 with cytogenetic abnormalities, 73 of them MK-negative (MK−), and 70 MK-positive (MK+). These MK+ patients could be divided into 17 with a single autosomal monosomy (MK1) and 53 with at least two monosomies (MK2+). ORR with DAC in CN patients: 36.1 %, in MK− patients: 16.7 %, in MK+ patients: 43.6 % (MK1: 44.4 %, MK2+ 43.3 %). PFS was prolonged by DAC compared to best supportive care (BSC) in the CN (hazard ratio (HR) 0.55, 99 % confidence interval (CI), 0.26; 1.15, p = 0.03) and MK2+ (HR 0.50; 99 % CI, 0.23; 1.06, p = 0.016) but not in the MK−, MK+, and MK1 subgroups. OS was not improved by DAC in any subgroup. In conclusion, we demonstrate for the first time in a randomized phase III trial that high-risk MDS patients with complex karyotypes harboring two or more autosomal monosomies attain encouraging responses and have improved PFS with DAC treatment compared to BSC.

Keywords

Monosomal karyotype Adverse cytogenetics Hypomethylating agents Azacytidine Epigenetic therapy Elderly patients 

Notes

Acknowledgments

The authors thank Philipp Sander and Margit Sauer for the editorial assistance and Claudia Schmoor for the helpful discussions. This publication was supported by the EORTC Charitable Trust; the 06011 trial was supported by an educational grant from MGI Pharma and Janssen Research and Development. Survival data of the PCH phase II studies were kindly provided by Janssen Research and Development. M.L. is supported by DFG (SFB 992/Medep).

Authors’ contributions

M.L., S. S., A. H., B. R., P. M., L. B., G. H., T. de W., and P. W. W. contributed to the conception and design. M. L., B. R., U. P., A. G., D. S., U. G., B. L, K.-H. P., H.-E. Sch., H. R. S., P. M., G. H., L. van der H., E. V., F. B., J.-P. M., A. G., C. A., T. de W., and P. W. W. contributed to the provision of study materials or patients. M.L., S. S., A. H., L. van der H., and G. H. contributed to the collection and assembly of data. M.L., S. S., and L. B. contributed to the data analyses and interpretation. M.L., S.S., and L. B. contributed to the manuscript writing. All authors have read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial conflict of interests except for the following authors (U, no compensation was received; C, compensation was received): Consultant or Advisory Role: Uwe Platzbecker, Celgene (C), Amgen (C), and Novartis (C); Aristoteles Giagounidis, Celgene (C); Dominik Selleslag, Celgene (C), Novartis (C), and Amgen (C); Arnold Ganser, Celgene (C) and Novartis (C); and Michael Lübbert, Johnson & Johnson (C); and Petra Muus, Alexion (U). Honoraria: Uwe Platzbecker, Celgene, Novartis, and Amgen; Aristoteles Giagounidis, Celgene; Dominik Selleslag, Celgene, Novartis, and Amgen; Ulrich Germing, Johnson & Johnson; and Arnold Ganser, Genzyme. Research Funding: Michael Lübbert, Johnson & Johnson; Uwe Platzbecker, Celgene and Novartis; and Ulrich Germing, MDS Registry Düsseldorf.

Supplementary material

277_2015_2547_MOESM1_ESM.doc (136 kb)
ESM 1 (DOC 136 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Michael Lübbert
    • 1
  • Stefan Suciu
    • 2
  • Anne Hagemeijer
    • 3
  • Björn Rüter
    • 1
  • Uwe Platzbecker
    • 4
  • Aristoteles Giagounidis
    • 5
  • Dominik Selleslag
    • 6
  • Boris Labar
    • 7
  • Ulrich Germing
    • 8
  • Helmut R. Salih
    • 9
  • Petra Muus
    • 10
  • Karl-Heinz Pflüger
    • 11
  • Hans-Eckart Schaefer
    • 12
  • Lioudmila Bogatyreva
    • 1
    • 13
  • Carlo Aul
    • 14
  • Theo de Witte
    • 15
  • Arnold Ganser
    • 16
  • Heiko Becker
    • 1
  • Gerwin Huls
    • 10
    • 17
  • Lieke van der Helm
    • 17
  • Edo Vellenga
    • 17
  • Frédéric Baron
    • 18
  • Jean-Pierre Marie
    • 19
  • Pierre W. Wijermans
    • 20
  • on behalf of the EORTC Leukemia Group and the German MDS Study Group
  1. 1.Division of Hematology, Oncology and Stem Cell TransplantationUniversity of Freiburg Medical CenterFreiburgGermany
  2. 2.European Organisation for Research and Treatment of Cancer HeadquartersBrusselsBelgium
  3. 3.Department of Human Genetics, University HospitalUniversity of LeuvenLeuvenBelgium
  4. 4.Department of Hematology and OncologyUniversity of DresdenDresdenGermany
  5. 5.Department of Hematology and OncologyMarienhospitalDüsseldorfGermany
  6. 6.Department of HematologyAZ Sint-Jan Brugge-OostendeBruggeBelgium
  7. 7.University Hospital Center RebroZagrebCroatia
  8. 8.Department of Hematology, Oncology and Clinical ImmunologyHeinrich-Heine-UniversityDüsseldorfGermany
  9. 9.Department of Hematology/OncologyEberhard Karls UniversityTübingenGermany
  10. 10.Department of HematologyRadboud University Nijmegen Medical CentreNijmegenThe Netherlands
  11. 11.Department of Medicine IIDIAKO BremenBremenGermany
  12. 12.Institute of PathologyUniversity of FreiburgFreiburgGermany
  13. 13.Institute for Medical Biometry and Medical InformaticsUniversity of FreiburgFreiburgGermany
  14. 14.Hematology, Oncology, and Clinical ImmunologySt Johannes HospitalDuisburgGermany
  15. 15.Department of Tumor ImmunologyRadboud University Nijmegen Medical CentreNijmegenThe Netherlands
  16. 16.Department of Hematology, Hemostasis, Oncology, and Stem Cell TransplantationHannover Medical SchoolHannoverGermany
  17. 17.Department of HematologyUniversity Medical Center GroningenGroningenThe Netherlands
  18. 18.C.H.U. Sart-TilmanLiègeBelgium
  19. 19.UPMC, UMRS 872 and Saint-Antoine Hospital, AP-HPParisFrance
  20. 20.Department of HematologyHaga HospitalThe HagueThe Netherlands

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