CYTOKINE AND ARGINASE-1 EXPRESSION DYNAMICS IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA REVEALS EARLY MOLECULAR RESPONSE TO IMATINIB

TOLOZA, M. J.; BELLI, C.; ENRICO MATTOS, A.; BESTACH, Y.; LARRIPA, I.

Amsterdam

Congreso; 24th EHA Congress; 2019

European Hematology Association

Background: Imatinib remains as the preferred tyrosine kinase inhibitor (TKI) to treat chronic myeloid leukaemia (CML) patients. Besidesits direct action targeting BCR-ABL1, TKI therapy may also influencethe anti-tumour response. A broadly compromised immune system hasbeen described at time of diagnosis supporting for a suppression of anti-CML immune responses. These abnormalities include an expansionof the suppressive immune cell populations, myeloid derived suppressorcells (MDSCs) and regulatory T cells (Treg), and dysfunctional effectorNK- and T-immune responses. On TKI treatments, CML patients seemto re-activate their immune system restoring the effector-mediated immune surveillance.Aims: To describe TNF, IFNG, IL6, IL10, TGBF1, and ARG1 geneexpression dynamic regarding molecular response to imatinib, since previous studies were designed by different approaches, criteria for timingand longitudinally studies are scare or missing.Methods: We analysed 106 peripheral blood samples of 64 CML patients,with multiple samples of 34 serially followed, and 26 of healthy donors.Were included patients at diagnosis (n = 23) and on imatinib 400 mg at 3months (n = 41), 6 months (n = 42) classified according to the molecularresponse. An aliquot of the stored sample used to monitor BCR-ABL1level was retro-transcribed to cDNA and TNF, IFNG, IL6, IL10, TGFB1and ARG1 gene expression was quantified by PCR real time.Results: For patients at diagnosis, the expression of TNF, IFNG, IL6,IL10 and TGFB1 was significantly decreased when compared withhealthy controls (Mann-Whitney test p = 0.0336, p < 0.0001, p =0.0007, p < 0.0001 and p = 0.0001, respectively); while ARG1 was significantly increased (Mann-Whitney test p < 0.0001). The level of ARG1expression correlated with the level of IL10 and TGFB1 expressions(Spearman r = 0.54, p = 0.0368 and r = 0.74, p = 0.0057, respectively),and IL10 with TGFB1 expression (Spearman: r = 0.65, p = 0.0087).Once imatinib therapy was initiated, those patients who achieved anearly molecular response (EMR, BCR-ABL1 ≤10% at 3 months) significantly increased the expression of the pro-inflammatory cytokines TNF and IL6 when compared with healthy controls, and the ARG1expression decreased to control levels. At 6 months, the enhancementof TNF and IL6 was observed in either responders (BCR-ABL1