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

Delphine Rea (1) , Guylaine Henry (2) , Zena Khaznadar (1, 3) , Gabriel Etienne (4) , François Guilhot (5) , Franck Nicolini (6) , Joëlle Guilhot (5) , Philippe Rousselot , Françoise Huguet (7) , Laurence Legros (8) , Martine Gardembas (9) , Viviane Dubruille (10) , Agnès Guerci-Bresler (11) , Aude Charbonnier (12) , Frédéric Maloisel (13) , Jean-Christophe Ianotto (14) , Bruno Villemagne (15) , François-Xavier Mahon (16) , Hélène Moins-Teisserenc (17) , Nicolas Dulphy (18) , Antoine Toubert (18)

1 EMily (UMR_S_1160 / U1160) - Ecotaxie, microenvironnement et développement lymphocytaire
2 Hôpital Saint-Louis
3 IUH - Institut Universitaire d'Hématologie
4 Institut Bergonié [Bordeaux]
5 INSERM - CHU de Poitiers - INSERM CIC 0802
6 Service d'hématologie [Hôpital Edouard Herriot - HCL]
7 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
8 Hôpital l'Archet
9 Service des maladies du sang [CHU Angers]
10 Service d'Hématologie Clinique [Hôpital Hôtel Dieu, Nantes]
11 Service d'Hématologie Clinique [CHRU Nancy]
12 IPC - Institut Paoli-Calmettes
13 Service d'hématologie clinique
14 Institut de cancérologie et d'hématologie
15 Hématologie clinique [CH La Roche-sur-Yon]
16 Biothérapies des maladies génétiques et cancers
17 Hématologie -Immunologie -Cibles thérapeutiques
18 A2T - Alloimmunité-Autoimmunité-Transplantation

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.

Domaines: Cancer; Hématologie; Immunité innée

Delphine Rea, Guylaine Henry, Zena Khaznadar, Gabriel Etienne, François Guilhot, et al.. Natural killer-cell counts are associated with molecular relapse-free survival after imatinib discontinuation in chronic myeloid leukemia: the IMMUNOSTIM study. Haematologica, 2017, 102 (8), pp.1368-1377. ⟨10.3324/haematol.2017.165001⟩. ⟨hal-02043232⟩