Oncotarget

Research Papers:

Leukemic stem cell persistence in chronic myeloid leukemia patients in deep molecular response induced by tyrosine kinase inhibitors and the impact of therapy discontinuation

Jean Claude Chomel, Marie Laure Bonnet, Nathalie Sorel, Ivan Sloma, Annelise Bennaceur-Griscelli, Delphine Rea, Laurence Legros, Anne Marfaing-Koka, Jean-Henri Bourhis, Shanti Ame, Agnès Guerci-Bresler, Philippe Rousselot and Ali G. Turhan _

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Oncotarget. 2016; 7:35293-35301. https://doi.org/10.18632/oncotarget.9182

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Abstract

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

Correspondence to:

Ali G. Turhan, email: turviv33@gmail.com

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

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.


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