Natural killer-cell counts are associated with molecular relapse-free survival after imatinib discontinuation in chronic myeloid leukemia: the IMMUNOSTIM study

Autor: Antoine Toubert, Agnès Guerci-Bresler, Hélène Moins-Teisserenc, Gabriel Etienne, Delphine Rea, Françoise Huguet, Laurence Legros, François Guilhot, Frédéric Maloisel, Zena Khaznadar, Joelle Guilhot, Martine Gardembas, Philippe Rousselot, Francois-Xavier Mahon, Bruno Villemagne, Jean-Christophe Ianotto, Franck E. Nicolini, Nicolas Dulphy, Viviane Dubruille, Aude Charbonnier, Guylaine Henry
Přispěvatelé: Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Saint-Louis, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Institut Bergonié [Bordeaux], UNICANCER, INSERM CIC 0802 (INSERM - CHU de Poitiers), Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital l'Archet - CHU de Nice, Service des maladies du sang [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service d'Hématologie Clinique [Hôpital Hôtel Dieu, Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Hôtel Dieu, Service d'Hématologie Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'hématologie clinique, Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de cancérologie et d'hématologie, Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hématologie clinique [CH La Roche-sur-Yon], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématologie -Immunologie -Cibles thérapeutiques, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alloimmunité-Autoimmunité-Transplantation (A2T), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
medicine.drug_class
Receptor expression
Chronic Myeloid Leukemia
Cell Count
[SDV.CAN]Life Sciences [q-bio]/Cancer
[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity
Tyrosine-kinase inhibitor
Article
Disease-Free Survival
Natural killer cell
03 medical and health sciences
Interferon-gamma
0302 clinical medicine
Recurrence
Leukemia
Myelogenous
Chronic
BCR-ABL Positive
hemic and lymphatic diseases
medicine
Cytotoxic T cell
Humans
Protein Kinase Inhibitors
business.industry
Degranulation
Myeloid leukemia
Imatinib
[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology
Hematology
medicine.disease
3. Good health
Killer Cells
Natural
Leukemia
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Immunology
Imatinib Mesylate
Receptors
Natural Killer Cell
business
medicine.drug
Zdroj: Haematologica
Haematologica, Ferrata Storti Foundation, 2017, 102 (8), pp.1368-1377. ⟨10.3324/haematol.2017.165001⟩
ISSN: 0390-6078
1592-8721
DOI: 10.3324/haematol.2017.165001⟩
Popis: Despite persistence of leukemic stem cells, patients with chronic myeloid leukemia who achieve and maintain deep molecular responses may successfully stop the tyrosine kinase inhibitor imatinib. However, questions remain unanswered regarding the biological basis of molecular relapse after imatinib cessation. In IMMUNOSTIM, we monitored 51 patients from the French Stop IMatinib trial for peripheral blood T cells and natural killer cells. Molecular relapse-free survival at 24 months was 45.1% (95% CI: 31.44%-58.75%). At the time of imatinib discontinuation, non-relapsing patients had significantly higher numbers of natural killer cells of the cytotoxic CD56dim subset than had relapsing patients, while CD56bright natural killer cells, T cells and their subsets did not differ significantly. Furthermore, the CD56dim natural killer-cell count was an independent prognostic factor of molecular-relapse free survival in a multivariate analysis. However, expression of natural killer-cell activating receptors, BCR-ABL1+ leukemia cell line K562-specific degranulation and cytokine-induced interferon-gamma secretion were decreased in non-relapsing and relapsing patients as compared with healthy individuals. After imatinib cessation, the natural killer-cell count increased significantly and stayed higher in non-relapsing patients than in relapsing patients, while receptor expression and functional properties remained unchanged. Altogether, our results suggest that natural killer cells may play a role in controlling leukemia-initiating cells at the origin of relapse after imatinib cessation, provided that these cells are numerous enough to compensate for their functional defects. Further research will decipher mechanisms underlying functional differences between natural killer cells from patients and healthy individuals and evaluate the potential interest of immunostimulatory approaches in tyrosine kinase inhibitor discontinuation strategies. (ClinicalTrial.gov Identifier NCT00478985).
Databáze: OpenAIRE
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