title: 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.
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/m(2) 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).
authors.affiliation: Department of Hematology, VU University Medical Center, De Boelelaan 1117, Amsterdam, the Netherlands. n.thielen@vumc.nl
authors.forename: Noortje
authors.initials: N
authors.lastname: Thielen
authors.forename: Bronno
authors.initials: B
authors.lastname: van der Holt
authors.forename: Gregor E G
authors.initials: GE
authors.lastname: Verhoef
authors.forename: Rianne A H M
authors.initials: RA
authors.lastname: Ammerlaan
authors.forename: Pieter
authors.initials: P
authors.lastname: Sonneveld
authors.forename: Jeroen J W M
authors.initials: JJ
authors.lastname: Janssen
authors.forename: Wendy
authors.initials: W
authors.lastname: Deenik
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
authors.forename: Marie José
authors.initials: MJ
authors.lastname: Kersten
authors.forename: Harm A M
authors.initials: HA
authors.lastname: Sinnige
authors.forename: Martin
authors.initials: M
authors.lastname: Schipperus
authors.forename: Anton
authors.initials: A
authors.lastname: Schattenberg
authors.forename: Rien
authors.initials: R
authors.lastname: van Marwijk Kooy
authors.forename: Willem M
authors.initials: WM
authors.lastname: Smit
authors.forename: Isabel W T
authors.initials: IW
authors.lastname: Chu
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Cornelissen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D057239:Early Termination of Clinical Trials; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D000068877:Imatinib Mesylate; D007239:Infections / Q000209:etiology; D053208:Kaplan-Meier Estimate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000139:chemically induced; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018401:Sample Size; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D003561:Cytarabine; D000068877:Imatinib Mesylate