title: Therapy of chronic myeloid leukaemia can benefit from the activation of stem cells: simulation studies of different treatment combinations.
abstract: BACKGROUND
  Newly diagnosed patients with chronic myeloid leukaemia (CML) are currently treated with tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib or dasatinib. However, incomplete eradication of residual disease is a general problem of long-term TKI therapy. Activation of mouse haematopoietic stem cells by interferon-α (IFNα) stimulated the discussion of whether a combination treatment leads to accelerated eradication of the CML clone.
  
  
  METHODS
  We base our simulation approach on a mathematical model describing human CML as a competition phenomenon between normal and malignant cells. We amend this model to incorporate the description of IFNα activity and simulate different scenarios for potential treatment combinations.
  
  
  RESULTS
  We demonstrate that the overall sensitivity of CML stem cells to IFNα activation is a crucial determinant for the benefit of a potential combination therapy. We furthermore show that pulsed IFNα together with continuous TKI administration is the most promising strategy for a combination treatment in which the therapeutic benefit prevails adverse side effects.
  
  
  CONCLUSIONS
  Our modelling approach is a highly beneficial tool to quantitatively address the competition between normal and leukaemic haematopoiesis in treated CML patients. We derive testable predictions for different experimental settings that are suggested before the clinical implementation of the combination treatment.
authors.affiliation: Institute for Medical Informatics and Biometry (IMB), Faculty of Medicine Carl Gustav Carus, Dresden University of Technology, Fetscherstr. 74, D-01307 Dresden, Germany. ingmar.glauche@tu-dresden.de
authors.forename: I
authors.initials: I
authors.lastname: Glauche
authors.forename: K
authors.initials: K
authors.lastname: Horn
authors.forename: M
authors.initials: M
authors.lastname: Horn
authors.forename: L
authors.initials: L
authors.lastname: Thielecke
authors.forename: M A G
authors.initials: MA
authors.lastname: Essers
authors.forename: A
authors.initials: A
authors.lastname: Trumpp
authors.forename: I
authors.initials: I
authors.lastname: Roeder
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage; D016898:Interferon-alpha / Q000008:administration & dosage; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D051379:Mice; D008962:Models, Theoretical; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage
chemical_list: D007155:Immunologic Factors; D016898:Interferon-alpha; D047428:Protein Kinase Inhibitors