title: Major molecular response achievement in CML Patients can be predicted by BCR-ABL1/ABL1 or BCR-ABL1/GUS ratio at an earlier time point of follow-up than currently recommended.
abstract: Recent studies demonstrate that early molecular response to tyrosine-kinase inhibitors is strongly predictive of outcome in chronic myeloid leukemia patients and that early response landmarks may identify patients at higher risk for transformation who would benefit from an early switch to second-line therapy. In this study, we evaluated the ability of the control gene GUS to identify relevant thresholds for known therapeutic decision levels (BCR-ABL1/ABL1IS  = 10% and 0.1%). We then defined the most relevant cut-offs for early molecular response markers (transcript level at 3 months, halving time and log reduction between diagnosis and 3 months of treatment) using GUS or ABL1. We demonstrated that, although both control genes could be used (in an equivalent way) to accurately assess early molecular response, the BCR-ABL1/GUS level at diagnosis is impacted by the higher GUS copy number over-expressed in CML cells, thus negatively impacting its ability to completely replace ABL1 at diagnosis. Furthermore, we pointed out, for the first time, that it would be helpful to monitor BCR-ABL1 levels at an earlier time point than that currently performed, in order to assess response to first-line tyrosine-kinase inhibitors and consider a potential switch of therapy as early as possible. We evaluated this optimal time point as being 19 days after the start of treatment in our cohort.
authors.affiliation: Laboratoire d'hématologie, Centre de Biologie Sud, Centre Hospitalier Lyon Sud, Pierre-Benite, France; Unité Mixte de Recherche 5239 Centre National de la Recherche Scientifique, Faculté de médecine Lyon Sud, Oullins, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Huet
authors.affiliation: Service clinique d'hématologie, Centre Hospitalier d'Annecy, Pringy, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Cony-Makhoul
authors.affiliation: Service clinique d'hématologie 1G, Centre Hospitalier Lyon Sud, Pierre-Benite, France.
authors.forename: Maël
authors.initials: M
authors.lastname: Heiblig
authors.affiliation: Laboratoire d'hématologie, Centre de Biologie Sud, Centre Hospitalier Lyon Sud, Pierre-Benite, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tigaud
authors.affiliation: Laboratoire d'hématologie, Centre de Biologie Sud, Centre Hospitalier Lyon Sud, Pierre-Benite, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Gazzo
authors.affiliation: Service clinique d'hématologie, Centre Régional de Lutte Contre le Cancer Léon Bérard, Lyon, France.
authors.forename: Amine
authors.initials: A
authors.lastname: Belhabri
authors.affiliation: Laboratoire d'hématologie, Centre de Biologie Sud, Centre Hospitalier Lyon Sud, Pierre-Benite, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Souche
authors.affiliation: Service clinique d'hématologie 1G, Centre Hospitalier Lyon Sud, Pierre-Benite, France.
authors.forename: Mauricette
authors.initials: M
authors.lastname: Michallet
authors.affiliation: Laboratoire d'hématologie, Centre de Biologie Sud, Centre Hospitalier Lyon Sud, Pierre-Benite, France; Unité Mixte de Recherche 5239 Centre National de la Recherche Scientifique, Faculté de médecine Lyon Sud, Oullins, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Magaud
authors.affiliation: Laboratoire d'hématologie, Centre de Biologie Sud, Centre Hospitalier Lyon Sud, Pierre-Benite, France; Unité Mixte de Recherche 5239 Centre National de la Recherche Scientifique, Faculté de médecine Lyon Sud, Oullins, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Hayette
authors.affiliation: Service clinique d'hématologie 1G, Centre Hospitalier Lyon Sud, Pierre-Benite, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Nicolini
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005966:Glucuronidase / Q000235:genetics*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D016044:Fusion Proteins, bcr-abl; D005966:Glucuronidase