Leukemic stem cell persistence in chronic myeloid leukemia patients in deep molecular response induced by tyrosine kinase inhibitors and the impact of therapy discontinuation
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Jean Claude Chomel1,2, Marie Laure Bonnet2, Nathalie Sorel1,2, Ivan Sloma3,4,5, Annelise Bennaceur-Griscelli3,4,5, Delphine Rea6,7, Laurence Legros8, Anne Marfaing-Koka9, Jean-Henri Bourhis9,10, Shanti Ame11, Agnès Guerci-Bresler12, Philippe Rousselot13,14, Ali G. Turhan2,3,4,5,15
1Laboratoire de Cancérologie Biologique, CHU de Poitiers, Poitiers, France
2INSERM U935, Poitiers, France
3Service d’Hématologie Biologique, Hôpital Paul Brousse, Villejuif, France
4INSERM U935, Villejuif, France
5Université Paris Sud, Le Kremlin-Bicêtre, France
6Service d’Hématologie Adulte, Hôpital Saint Louis, Paris, France
7INSERM UMRS-1160, IUH-Université Paris Diderot-Paris 7, Paris, France
8Service d’Hématologie Clinique, Hôpital l’Archet, Nice, France
9Service d’Hématologie Biologique, Hôpital Antoine Béclère, Clamart, France
10Service d’Hématologie-Greffe de Moelle, Institut Gustave Roussy, Villejuif, France
11Département d’Hématologie et Oncologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
12Service d'Hématologie Clinique, CHU Brabois, Vandoeuvre les Nancy, France
13Service d’Hématologie et Oncologie, Centre Hospitalier de Versailles, Versailles, France
14EA4340, Université Versailles-Saint Quentin en Yvelines, Université Paris-Saclay, France
15Service d’Hématologie, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
Ali G. Turhan, email: firstname.lastname@example.org
Keywords: chronic myeloid leukemia, leukemic stem cells, persistence, tyrosine kinase inhibitors, therapy discontinuation
Received: February 17, 2016 Accepted: April 10, 2016 Published: May 5, 2016
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.
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