Selection pressure exerted by imatinib therapy leads to disparate outcomes of imatinib discontinuation trials

Min Tang, Jasmine Foo, Mithat Gönen, Joëlle Guilhot, François Xavier Mahon, Franziska Michor

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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. Design and 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.

Original languageEnglish (US)
Pages (from-to)1553-1561
Number of pages9
JournalHaematologica
Volume97
Issue number10
DOIs
StatePublished - Oct 1 2012

Keywords

  • Biostatistics
  • Chronic myeloid leukemia
  • Mathematical modeling
  • Minimal residual disease
  • Targeted therapy

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