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Annals of Hematology

, Volume 97, Issue 10, pp 1785–1795 | Cite as

Cytogenetic clonal heterogeneity is not an independent prognosis factor in 15–60-year-old AML patients: results on 1291 patients included in the EORTC/GIMEMA AML-10 and AML-12 trials

  • Frédéric Baron
  • Marian Stevens-Kroef
  • Michal Kicinski
  • Giovanna Meloni
  • Petra Muus
  • Jean-Pierre Marie
  • Constantijn J. M. Halkes
  • Xavier Thomas
  • Radovan Vrhovac
  • Giorgina Specchia
  • Francois LefrereSr
  • Simona Sica
  • Marco Mancini
  • Adriano Venditti
  • Anne Hagemeijer
  • Heiko Becker
  • Joop H. Jansen
  • Sergio Amadori
  • Theo de Witte
  • Roelof Willemze
  • Stefan Suciu
Original Article

Abstract

The presence of cytogenetic clonal heterogeneity has been associated with poor prognosis in patients with acute myeloid leukemia (AML). Here, we reassessed this association. The study cohort consisted of all patients with an abnormal karyotype randomized in the EORTC/GIMEMA AML-10 and AML-12 trials. Abnormal karyotypes were classified as no subclones present (cytogenetic abnormality in a single clone), defined subclones present (presence of one to three subclones), and composite karyotypes (CP) (clonal heterogeneity not allowing enumeration of individual subclones). The main endpoints were overall survival (OS) and disease-free survival (DFS). Among 1291 patients with an abnormal karyotype, 1026 had no subclones, 226 at least 1 subclone, and 39 a CP. Patients with defined subclones had an OS similar to those with no subclones (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.88–1.26), but CP patients had a shorter OS (HR = 1.58, 95% CI 1.11–2.26). However, in a multivariate Cox model stratified by protocol and adjusted for age, cytogenetic risk group, secondary versus primary AML, and performance status, clonal heterogeneity lost its prognostic importance (HR = 1.10, 95% CI 0.91–1.32 for defined subclones versus no subclones; HR = 0.96, 95% CI 0.67–1.38 for CP versus no subclones). Also, the impact of having a donor on DFS was similar in the three clonal subgroups. In summary, in patients with cytogenetic abnormality, presence of subclones had no impact on OS. The dismal outcome in patients with a CP was explained by the known predictors of poor prognosis. Trial registration: AML-10: ClinicalTrials.gov identifier: NCT00002549, retrospectively registered July 19, 2004; AML12: ClinicalTrials.gov identifier: NCT00004128, registered January 27, 2003.

Keywords

AML Cytogenetic Clonal heterogeneity Clonal evolution Transplantation 

Abbreviations

Allo-HSCT

Allogeneic stem cell transplantation

AML

Acute myeloid leukemia

CR

Complete response

CRi

CR with incomplete counts recovery

CP

Composite karyotypes

DFS

Disease-free survival

IDA

Idarubicin

DNR

Daunorubicin

HiDAC

High-dose cytarabine

HR

Hazard ratio

MDS

Myelodysplastic syndrome

MRC

UK Medical Research Council

MK

Monosomal karyotype

MTZ

Mitoxantrone

OS

Overall survival

PR

Partial response

SAL

Study Alliance Leukemia group

SDAC

Standard-dose cytarabine

tAML

Therapy-related AML

WBC

White blood cell

Notes

Acknowledgements

FB is senior research associate of the Fund for Scientific Research (FRS-FNRS), Belgium.

Authors’ contributions

Conception and design: All authors.

Provision of study materials or patients: Frédéric Baron, Giovanna Meloni, Petra Muus, Jean-Pierre Marie, Constantijn J.M. Halkes, Xavier Thomas, Radovan Vrhovac, Giorgina Specchia, Francois Lefrere Sr., Simona Sica, Marco Mancini, Adriano Venditti, Anne Hagemeijer, Sergio Amadori, Theo de Witte, and Roelof Willemze.

Collection and assembly of data: All authors.

Data analysis and interpretation: All authors.

Manuscript writing: Frédéric Baron, Marian Stevens-Kroef, Michal Kicinski, Stefan Suciu.

Manuscript editing: Giovanna Meloni, Petra Muus, Jean-Pierre Marie, Constantijn J.M. Halkes, Xavier Thomas, Radovan Vrhovac, Giorgina Specchia, Francois Lefrere Sr., Simona Sica, Marco Mancini, Adriano Venditti, Anne Hagemeijer, Heiko Becker, Joop H. Jansen, Sergio Amadori, Theo de Witte, and Roelof Willemze.

Final approval of manuscript: All authors.

Funding

This publication was supported by a donation from the “Fondation contre le cancer” from “Belgium” through the EORTC Cancer Research Fund.

Compliance with ethical standards

Ethics approval and consent to participate

The current retrospective analysis includes only data from patients included in phase III multicenter prospective trials (either the EORTC/GIMEMA AML-10 or the EORTC/GIMEMA AML-12). Both prospective phase III trials were approved by the internal review boards of EORTC and GIMEMA and the ethical committee of each participating institution, and were conducted in accordance with the Declaration of Helsinki. All patients signed the respective informed consent form.

Consent for publication

Not applicable.

Competing interests

Petra Muus has consulting or advisory role for Alexion, Opsona, Akari, and Ra Pharma and has a speaker’s bureau at Alexion. Xavier Thomas has consulting or advisory role for Celgene, Pfizer, Amgen, and Sunesis. Adriano Venditti has consulting or advisory role for Sandoz, Novartis, Janssen, and Jazz Pharmaceuticals and has received research grant from Sandoz. Heiko Becker has received honoraria from Bristol-Myers Squibb. Sergio Amadori has consulting or advisory role for Novartis, Celgene, and Abbvie. The other authors have nothing to disclose with respect to this manuscript.

Supplementary material

277_2018_3396_MOESM1_ESM.docx (44 kb)
ESM 1 (DOCX 43 kb)

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Copyright information

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

Authors and Affiliations

  • Frédéric Baron
    • 1
  • Marian Stevens-Kroef
    • 2
  • Michal Kicinski
    • 3
  • Giovanna Meloni
    • 4
  • Petra Muus
    • 2
  • Jean-Pierre Marie
    • 5
  • Constantijn J. M. Halkes
    • 6
  • Xavier Thomas
    • 7
  • Radovan Vrhovac
    • 8
  • Giorgina Specchia
    • 9
  • Francois LefrereSr
    • 10
  • Simona Sica
    • 11
  • Marco Mancini
    • 4
  • Adriano Venditti
    • 12
  • Anne Hagemeijer
    • 13
  • Heiko Becker
    • 14
  • Joop H. Jansen
    • 2
  • Sergio Amadori
    • 12
  • Theo de Witte
    • 2
  • Roelof Willemze
    • 6
  • Stefan Suciu
    • 3
  1. 1.Department of Hematology, GIGA-I3 and CHUUniversity of LiègeLiègeBelgium
  2. 2.Radboud University Medical CenterNijmegenNetherlands
  3. 3.EORTC HeadquartersBrusselsBelgium
  4. 4.Sapienza UniversityRomeItaly
  5. 5.Saint Antoine HospitalParisFrance
  6. 6.Leiden University Medical CenterLeidenNetherlands
  7. 7.CHU of LyonLyonFrance
  8. 8.University Hospital Centre ZagrebZagrebCroatia
  9. 9.University of BariBariItaly
  10. 10.Necker HospitalParisFrance
  11. 11.Universita Cattolica Sacro CuoreRomeItaly
  12. 12.University Tor VergataRomeItaly
  13. 13.University of LeuvenLeuvenBelgium
  14. 14.Medical Center – University of Freiburg, Faculty of MedicineUniversity of FreiburgFreiburgGermany

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