title: Systematic review and meta-analysis of standard-dose imatinib vs. high-dose imatinib and second generation tyrosine kinase inhibitors for chronic myeloid leukemia.
abstract: OBJECTIVE
  Most randomized clinical trials evaluating second generation tyrosine kinase inhibitors (TKI) for the first-line treatment of Chronic Myeloid Leukemia used as comparator the 'standard' dose of 400 mg imatinib daily. Several studies showed higher rates of major molecular remission (MMR) at 12 months with 800 mg compared to 400 mg, suggesting that high-dose imatinib may be the appropriate comparator rather than 400 mg.
  
  
  METHODS
  We systematically reviewed randomized trials comparing the two dosages, calculated a common estimator and compared the result to a common estimator of trials evaluating a second generation TKI in comparison with 400 mg imatinib daily.
  
  
  RESULTS
  We identified three trials comparing 400-800 mg imatinib resulting in a common relative risk of 1.30 (1.13-1.49) and indicating a significantly higher rate of MMR in patients treated with 800 mg imatinib (p = 0.0003). We identified five trials comparing 400 mg imatinib daily to a second generation TKI. The common relative risk for MMR at 12 months was 1.69 (1.50-1.90, p < 0.0001). Differences in the prognostic profiles precluded a direct comparison of the common efficacy estimates.
  
  
  CONCLUSIONS
  We conclude that imatinib was probably not licensed at the optimal dose initially. We suggest that in the future, new TKIs are compared with a higher dose of imatinib. In addition, high-dose imatinib should be considered more often for routine clinical decisions based on the characteristics of the individual patient.
authors.affiliation: Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universität, Marchioninistraße 15, 81377, Munich, Germany. verena.s.hoffmann@lrz.uni-muenchen.de.|Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany. verena.s.hoffmann@lrz.uni-muenchen.de.
authors.forename: Verena S
authors.initials: VS
authors.lastname: Hoffmann
authors.affiliation: Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universität, Marchioninistraße 15, 81377, Munich, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Hasford
authors.affiliation: University of Utah Huntsman Cancer Institute, Salt Lake City, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Deininger
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.affiliation: Department of Hematology and Oncology L. and A. Seragnoli, University of Bologna, Bologna, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.affiliation: Medizinische Fakultaet Mannheim, Universität Heidelberg, Heidelberg, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Hehlmann
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases
keywords: Dosage; Imatinib; Meta-analysis; Systematic review; TKI