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High-dose imatinib versus high-dose imatinib in combination with intermediate-dose cytarabine in patients with first chronic phase myeloid leukemia: a randomized phase III trial of the Dutch-Belgian HOVON study group

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Abstract

Despite the revolutionary change in the prognosis of chronic myeloid leukemia (CML) patients with the introduction of imatinib, patients with resistant disease still pose a considerable problem. In this multicenter, randomized phase III trial, we investigate whether the combination of high-dose imatinib and intermediate-dose cytarabine compared to high-dose imatinib alone, improves the rate of major molecular response (MMR) in newly diagnosed CML patients. This study was closed prematurely because of declining inclusion due to the introduction of second generation tyrosine kinase inhibitors and only one third of the initially required patients were accrued. One hundred nine patients aged 18–65 years were randomly assigned to either imatinib 800 mg (n = 55) or to imatinib 800 mg in combination with two successive cycles of cytarabine 200 mg/m2 for 7 days (n = 54). After a median follow-up of 41 months, 67 % of patients were still on protocol treatment. The MMR rate at 12 months was 56 % in the imatinib arm and 48 % in the combination arm (p = 0.39). Progression-free survival was 96 % after 1 year and 89 % after 4 years. Four-year overall survival was 97 %. Adverse events grades 3 and 4 were more common in the combination arm. The addition of intermediate-dose of cytarabine to imatinib did not improve the MMR rate at 12 months. However, the underpowering of the study precludes any definitive conclusions. This trial is registered at www.trialregister.nl (NTR674).

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Acknowledgments

The authors would like to thank Sonia Cunha at the HOVON Data Center for her work in data management in this study. This work was supported by a grant from the Dutch Cancer Society Queen Wilhelmina Foundation (project 2005–4163).

Conflict of interest

JJWMJ and GJO received honoraria from Novartis. The remaining authors report no potential conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Hematology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands

    Noortje Thielen, Jeroen J. W. M. Janssen & Gert J. Ossenkoppele

  2. HOVON Data Center, Erasmus University Medical Center-Daniel den Hoed, Rotterdam, the Netherlands

    Bronno van der Holt & Rianne A. H. M. Ammerlaan

  3. Department of Hematology, University Hospital Gasthuisberg, Leuven, Belgium

    Gregor E. G. Verhoef

  4. Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands

    Pieter Sonneveld, Isabel W. T. Chu, Peter J. M. Valk & Jan J. Cornelissen

  5. Department of Internal Medicine, Tergooiziekenhuizen, Hilversum, the Netherlands

    Wendy Deenik

  6. Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands

    J. H. Frederik Falkenburg

  7. Department of Hematology, Academic Medical Center, Amsterdam, the Netherlands

    Marie José Kersten

  8. Department of Hematology, Jeroen Bosch Hospital, ‘s-Hertogenbosch, the Netherlands

    Harm A. M. Sinnige

  9. Department of Hematology, Haga Hospital, the Hague, the Netherlands

    Martin Schipperus

  10. Department of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands

    Anton Schattenberg

  11. Department of Internal Medicine, Isala Klinieken, Zwolle, the Netherlands

    Rien van Marwijk Kooy

  12. Department of Internal Medicine, Medisch Spectrum Twente, Enschede, the Netherlands

    Willem M. Smit

Authors
  1. Noortje Thielen
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  2. Bronno van der Holt
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  3. Gregor E. G. Verhoef
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  4. Rianne A. H. M. Ammerlaan
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  6. Jeroen J. W. M. Janssen
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  7. Wendy Deenik
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  8. J. H. Frederik Falkenburg
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  9. Marie José Kersten
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  11. Martin Schipperus
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  14. Willem M. Smit
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  15. Isabel W. T. Chu
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Corresponding author

Correspondence to Noortje Thielen.

Additional information

This study has been presented as a poster presentation at the 2011 Annual Meeting of the American Society of Hematology, San Diego, December 11, 2011 and as an oral presentation at the Dutch Hematology Congress, Papendal, January 25, 2012

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Appendix

Appendix

The following institutes and investigators of the Dutch-Belgian Cooperative Trial group for Hemato-Oncology (HOVON) participated in the study:

Belgium: Antwerp, Hospital Network Antwerp, Campus Stuivenberg, D.A. Breems; Leuven, University Hospital Gasthuisberg, G.E.G. Verhoef

The Netherlands: Amersfoort, Meander Medisch Centrum, S. Wittebol; Amsterdam, VU University Medical Center, G.J. Ossenkoppele; Amsterdam, Academic Medical Center, M.J. Kersten; Blaricum, Tergooi Ziekenhuizen, W.Deenik; Breda, Amphia Ziekenhuis, J.W.J. Esser; Den Haag, Haga Ziekenhuis, M.R. Schipperus, P.W. Weijermans; Dordrecht, Albert Schweitzer Ziekenhuis, M.D. Levin; Enschede, Medisch Spectrum Twente, W.M. Smit; Groningen, University Medical Center Groningen, J.C. Kluin-Nelemans; ’s-Hertogenbosch, Jeroen Bosch Ziekenhuis, H.A.M. Sinnige; Hoofddorp, Spaarne Ziekenhuis, A. Beeker; Leiden, Leiden University Medical Center, J.H.F. Falkenburg, R. Willemze; Maastricht, Maastricht University Medical Center, G.M.J. Bos; Nieuwegein, Antonius Ziekenhuis, O. de Weerdt; Nijmegen, Radboud University Nijmegen Medical Center, A. Schattenberg; Rotterdam, Erasmus University Medical Center, J.J. Cornelissen, P. Sonneveld; Utrecht, University Medical Center Utrecht, E.J. Petersen, L.F. Verdonck; Zwolle, Isala Klinieken, R. van Marwijk Kooy

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Thielen, N., van der Holt, B., Verhoef, G.E.G. et al. High-dose imatinib versus high-dose imatinib in combination with intermediate-dose cytarabine in patients with first chronic phase myeloid leukemia: a randomized phase III trial of the Dutch-Belgian HOVON study group. Ann Hematol 92, 1049–1056 (2013). https://doi.org/10.1007/s00277-013-1730-4

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