title: BCR-ABL transcript dynamics support the hypothesis that leukemic stem cells are reduced during imatinib treatment.
abstract: OBJECTIVE
  Imatinib induces a durable response in most patients with Philadelphia chromosome-positive chronic myeloid leukemia, but it is currently unclear whether imatinib reduces the leukemic stem cell (LSC) burden, which may be an important step toward enabling safe discontinuation of therapy. In this article, we use mathematical models of BCR-ABL levels to make inferences on the dynamics of LSCs.
  
  
  METHODS
  Patients with at least 1 BCR-ABL transcript measurement on imatinib were included (N = 477). Maximum likelihood methods were used to test 3 potential hypotheses of the dynamics of BCR-ABL transcripts on imatinib therapy: (i) monoexponential, in which there is little, if any, decline in BCR-ABL transcripts; (ii) biexponential, in which patients have a rapid initial decrease in BCR-ABL transcripts followed by a more gradual response; and (iii) triexponential, in which patients first exhibit a biphasic decline but then have a third phase when BCR-ABL transcripts increase rapidly.
  
  
  RESULTS
  We found that most patients treated with imatinib exhibit a biphasic decrease in BCR-ABL transcript levels, with a rapid decrease during the first few months of treatment, followed by a more gradual decrease that often continues over many years.
  
  
  CONCLUSIONS
  We show that the only hypothesis consistent with current data on progenitor cell turnover and with the long-term, gradual decrease in the BCR-ABL levels seen in most patients is that these patients exhibit a continual, gradual reduction of the LSCs. This observation may explain the ability to discontinue imatinib therapy without relapse in some cases.
authors: Oncology, Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts 02139, USA. andrew.stein@novartis.com
authors: Andrew M
authors: AM
authors: Stein
authors: Dean
authors: D
authors: Bottino
authors: Vijay
authors: V
authors: Modur
authors: Susan
authors: S
authors: Branford
authors: Jaspal
authors: J
authors: Kaeda
authors: John M
authors: JM
authors: Goldman
authors: Timothy P
authors: TP
authors: Hughes
authors: Jerald P
authors: JP
authors: Radich
authors: Andreas
authors: A
authors: Hochhaus
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis / Q000235:genetics*; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl