Original Article

Annals of Hematology

, Volume 92, Issue 8, pp 1049-1056

First online:

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

  • Noortje ThielenAffiliated withDepartment of Hematology, VU University Medical Center Email author 
  • , Bronno van der HoltAffiliated withHOVON Data Center, Erasmus University Medical Center-Daniel den Hoed
  • , Gregor E. G. VerhoefAffiliated withDepartment of Hematology, University Hospital Gasthuisberg
  • , Rianne A. H. M. AmmerlaanAffiliated withHOVON Data Center, Erasmus University Medical Center-Daniel den Hoed
  • , Pieter SonneveldAffiliated withDepartment of Hematology, Erasmus University Medical Center
  • , Jeroen J. W. M. JanssenAffiliated withDepartment of Hematology, VU University Medical Center
  • , Wendy DeenikAffiliated withDepartment of Internal Medicine, Tergooiziekenhuizen
  • , J. H. Frederik FalkenburgAffiliated withDepartment of Hematology, Leiden University Medical Center
  • , Marie José KerstenAffiliated withDepartment of Hematology, Academic Medical Center
    • , Harm A. M. SinnigeAffiliated withDepartment of Hematology, Jeroen Bosch Hospital
    • , Martin SchipperusAffiliated withDepartment of Hematology, Haga Hospital
    • , Anton SchattenbergAffiliated withDepartment of Hematology, Radboud University Nijmegen Medical Center
    • , Rien van Marwijk KooyAffiliated withDepartment of Internal Medicine, Isala Klinieken
    • , Willem M. SmitAffiliated withDepartment of Internal Medicine, Medisch Spectrum Twente
    • , Isabel W. T. ChuAffiliated withDepartment of Hematology, Erasmus University Medical Center
    • , Peter J. M. ValkAffiliated withDepartment of Hematology, Erasmus University Medical Center
    • , Gert J. OssenkoppeleAffiliated withDepartment of Hematology, VU University Medical Center
    • , Jan J. CornelissenAffiliated withDepartment of Hematology, Erasmus University Medical Center

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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).

Keywords

Chronic myeloid leukemia Imatinib Cytarabine Major molecular response