PS1169 CYTOKINE AND ARGINASE‐1 EXPRESSION DYNAMICS IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA REVEALS EARLY MOLECULAR RESPONSE TO IMATINIB

Background: Imatinib remains as the preferred tyrosine kinase inhibitor (TKI) to treat chronic myeloid leukaemia (CML) patients. Besides its direct action targeting BCR‐ABL1, TKI therapy may also influence the anti‐tumour response. A broadly compromised immune system has been described at time of diagnosis supporting for a suppression of anti‐CML immune responses. These abnormalities include an expansion of the suppressive immune cell populations, myeloid derived suppressor cells (MDSCs) and regulatory T cells (Treg), and dysfunctional effector NK‐ and T‐immune responses. On TKI treatments, CML patients seem to re‐activate their immune system restoring the effector‐mediated immune surveillance. Aims: To describe TNF , IFNG , IL6 , IL10, TGBF1 , and ARG1 gene expression dynamic regarding molecular response to imatinib, since previous studies were designed by different approaches, criteria for timing and 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 3 months (n = 41), 6 months (n = 42) classified according to the molecular response. An aliquot of the stored sample used to monitor BCR‐ABL1 level was retro‐transcribed to cDNA and TNF , IFNG , IL6 , IL10 , TGFB1 and 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 with healthy 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 ARG1 expression 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 an early 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 ARG1 expression decreased to control levels. At 6 months, the enhancement of TNF and IL6 was observed in either responders ( BCR‐ABL1 <1%) or non‐responders (≥1%), whereas the decrease of ARG1 expression was similar to control levels just in responders. At both 3 and 6 months of treatment, TNF correlated with IL6 expression only in responders (Spearman: r = 0.48, p   =   0.0222 ; and r = 0.57, p   =   0.0168 , respectively). Furthermore, the longitudinal analysis between diagnosis and 3 months on therapy, those patients who achieve an EMR showed a statistically significant increase of 3 and 13 folds of TNF and IL6, respectively, and a significant 22‐fold decrease of ARG1 (Wilcoxon test: p   =   0.0444 , p   =   0.0038 and p   =   0.0094 , respectively). Summary/Conclusion: Our results are in agreement with a significant immune suppression in CML patients at diagnosis, mediated by MDSCs and their influence on Tregs; also with a stimulatory effect on the immune system after imatinib initiation, especially in those who responded at 3 months. The dynamic of cytokines and, principally, ARG1 may play a role as an immune biomarker to monitor the response to TKI allowing the differentiation of optimal responders.