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 1, 2 , Marie Laure Bonnet 2 , Nathalie Sorel 1, 2 , Ivan Sloma 3, 4, 5 , Annelise Bennaceur-Griscelli 3, 4, 5 , Delphine Rea 6, 7 , Laurence Legros 8 , Anne Marfaing-Koka 9 , Jean-Henri Bourhis 9, 10 , Shanti Ame 11 , Agnès Guerci-Bresler 12 , Philippe Rousselot 13, 14 , Ali G. Turhan 2, 3, 4, 5, 15 1 Laboratoire de Cancérologie Biologique, CHU de Poitiers, Poitiers, France 2 INSERM U935, Poitiers, France 3 Service d’Hématologie Biologique, Hôpital Paul Brousse, Villejuif, France 4 INSERM U935, Villejuif, France 5 Université Paris Sud, Le Kremlin-Bicêtre, France 6 Service d’Hématologie Adulte, Hôpital Saint Louis, Paris, France 7 INSERM UMRS-1160, IUH-Université Paris Diderot-Paris 7, Paris, France 8 Service d’Hématologie Clinique, Hôpital l’Archet, Nice, France 9 Service d’Hématologie Biologique, Hôpital Antoine Béclère, Clamart, France 10 Service d’Hématologie-Greffe de Moelle, Institut Gustave Roussy, Villejuif, France 11 Département d’Hématologie et Oncologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France 12 Service d'Hématologie Clinique, CHU Brabois, Vandoeuvre les Nancy, France 13 Service d’Hématologie et Oncologie, Centre Hospitalier de Versailles, Versailles, France 14 EA4340, Université Versailles-Saint Quentin en Yvelines, Université Paris-Saclay, France 15 Service 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.