title: Selection pressure exerted by imatinib therapy leads to disparate outcomes of imatinib discontinuation trials.
abstract: BACKGROUND
  Chronic myeloid leukemia is successfully managed by imatinib therapy, but the question remains whether treatment must be administered indefinitely. Imatinib discontinuation trials have led to two distinct outcomes: about 60% of patients experienced disease relapse within 6 months of treatment cessation, while the remaining 40% remained disease-free throughout the duration of follow-up. We aimed to investigate the mechanisms underlying these disparate clinical outcomes.
  
  
  METHODS
  We utilized molecular data from the "Stop Imatinib" trial together with a mathematical framework of chronic myeloid leukemia, based on a four-compartment model that can explain the kinetics of the molecular response to imatinib. This approach was complemented by statistical analyses to estimate system parameters and investigate whether chronic myeloid leukemia can be cured by imatinib therapy alone.
  
  
  RESULTS
  We found that there are insufficient follow-up data from the "Stop Imatinib" trial in order to conclude whether the absence of a relapse signifies cure of the disease. We determined that selection of less aggressive leukemic phenotypes by imatinib therapy recapitulates the trial outcomes. This postulated mechanism agrees with the observation that most patients who have a complete molecular response after discontinuation of imatinib continue to harbor minimal residual disease, and might work in concert with other factors suppressing leukemic cell expansion when the tumor burden remains low.
  
  
  CONCLUSIONS
  Our analysis provides evidence for a mechanistic model of chronic myeloid leukemia selection by imatinib treatment and suggests that it may not be safe to discontinue therapy outside a clinical trial.
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Tang
authors.forename: Jasmine
authors.initials: J
authors.lastname: Foo
authors.forename: Mithat
authors.initials: M
authors.lastname: Gönen
authors.forename: Joëlle
authors.initials: J
authors.lastname: Guilhot
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Mahon
authors.forename: Franziska
authors.initials: F
authors.lastname: Michor
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000401:mortality; D008962:Models, Theoretical; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate