title: Leukemic stem cell persistence in chronic myeloid leukemia patients in deep molecular response induced by tyrosine kinase inhibitors and the impact of therapy discontinuation.
abstract: During the last decade, the use of tyrosine kinase inhibitor (TKI) therapy has modified the natural history of chronic myeloid leukemia (CML) allowing an increase of the overall and disease-free survival, especially in patients in whom molecular residual disease becomes undetectable. However, it has been demonstrated that BCR-ABL1- expressing leukemic stem cells (LSCs) persist in patients in deep molecular response. It has also been shown that the discontinuation of Imatinib leads to a molecular relapse in the majority of cases. To determine a possible relationship between these two phenomena, we have evaluated by clonogenic and long-term culture initiating cell (LTC-IC) assays, the presence of BCR-ABL1-expressing LSCs in marrow samples from 21 patients in deep molecular response for three years after TKI therapy (mean duration seven years). LSCs were detected in 4/21 patients. Discontinuation of TKI therapy in 13/21 patients led to a rapid molecular relapse in five patients (4 without detectable LSCs and one with detectable LSCs). No relapse occurred in the eight patients still on TKI therapy, whether LSCs were detectable or not. Thus, this study demonstrates for the first time the in vivo efficiency of TKIs, both in the progenitor and the LSC compartments. It also confirms the persistence of leukemic stem cells in patients in deep molecular response, certainly at the origin of relapses. Finally, it emphasizes the difficulty of detecting residual LSCs due to their rarity and their low BCR-ABL1 mRNA expression.
authors.affiliation: Laboratoire de Cancérologie Biologique, CHU de Poitiers, Poitiers, France.|INSERM U935, Poitiers, France.
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Chomel
authors.affiliation: INSERM U935, Poitiers, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Bonnet
authors.affiliation: Laboratoire de Cancérologie Biologique, CHU de Poitiers, Poitiers, France.|INSERM U935, Poitiers, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sorel
authors.affiliation: Service d'Hématologie Biologique, Hôpital Paul Brousse, Villejuif, France.|INSERM U935, Villejuif, France.|Université Paris Sud, Le Kremlin-Bicêtre, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Sloma
authors.affiliation: Service d'Hématologie Biologique, Hôpital Paul Brousse, Villejuif, France.|INSERM U935, Villejuif, France.|Université Paris Sud, Le Kremlin-Bicêtre, France.
authors.forename: Annelise
authors.initials: A
authors.lastname: Bennaceur-Griscelli
authors.affiliation: Service d'Hématologie Adulte, Hôpital Saint Louis, Paris, France.|INSERM UMRS-1160, IUH-Université Paris Diderot-Paris 7, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Rea
authors.affiliation: Service d'Hématologie Clinique, Hôpital l'Archet, Nice, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Legros
authors.affiliation: Service d'Hématologie Biologique, Hôpital Antoine Béclère, Clamart, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Marfaing-Koka
authors.affiliation: Service d'Hématologie Biologique, Hôpital Antoine Béclère, Clamart, France.|Service d'Hématologie-Greffe de Moelle, Institut Gustave Roussy, Villejuif, France.
authors.forename: Jean-Henri
authors.initials: JH
authors.lastname: Bourhis
authors.affiliation: Département d'Hématologie et Oncologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Shanti
authors.initials: S
authors.lastname: Ame
authors.affiliation: Service d'Hématologie Clinique, CHU Brabois, Vandoeuvre les Nancy, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Guerci-Bresler
authors.affiliation: Service d'Hématologie et Oncologie, Centre Hospitalier de Versailles, Versailles, France.|EA4340, Université Versailles-Saint Quentin en Yvelines, Université Paris-Saclay, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rousselot
authors.affiliation: INSERM U935, Poitiers, France.|Service d'Hématologie Biologique, Hôpital Paul Brousse, Villejuif, France.|INSERM U935, Villejuif, France.|Université Paris Sud, Le Kremlin-Bicêtre, France.|Service d'Hématologie, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
authors.forename: Ali G
authors.initials: AG
authors.lastname: Turhan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000069439:Dasatinib / Q000627:therapeutic use; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology / Q000473:pathology*; D018365:Neoplasm, Residual; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D012074:Remission Induction
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D000069439:Dasatinib
keywords: chronic myeloid leukemia; leukemic stem cells; persistence; therapy discontinuation; tyrosine kinase inhibitors