الفهرس 
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Abstract
Chronic myeloid leukemia (CML) is a hematological malignancy characterized by the presence of the BCR-ABL1 oncokinase resulting from the reciprocal translocation t(9;22) in myeloid stem cells of the bone marrow (BM) which profoundly affects proliferation, apoptosis, and cell adhesion signaling pathways. The current mainstays of Treatment in CML are tyrosine kinase inhibitors (TKIs) of which imatinib, nilotinib, dasatinib, and bosutinib can be used as first-line treatments. The development of TKIs has profoundly improved prognosis of chronic-phase CML patients, with treatment aiming to achieve a deep molecular response (DMR; MR4; BCRABL1mRNA ≤0.01%) to prevent disease progression. TKIs monotherapies are unable to completely eliminate Philadelphia chromosome-positive hematopoietic stem cells led to the recommendation that patients remain on TKI treatment indefinitely. CML is characterized by a period of immune dysfunction present in patients at diagnosis, prior to the commencement of TKI therapy. This facilitates tumor progression and self-preservation, by preventing host development of antileukemia immune responses. Myeloid derived suppressor cells (MDSCs), immature myeloid cells able to induce immune-escape, angiogenesis, and tumor progression in CML patients. Myeloid-derived suppressor cells (MDSCs) block both innate and adaptive arms of anti-tumour immunity, mostly through inhibition of T cell activation and expansion. Human Mo-MDSCs are mostly identified as CD14+ cells with negative or low expression of HLADR. Mo-MDSCs express also high levels of CD11b and CD33 antigens. Human Gr-MDSCs are usually defined as CD33+ CD11b+ CD14- HLADR- cells. In this study, we investigated the effect of the Tyrosine Kinase Inhibitors (TKIs) (Imatinib and nilotinib) on the level of myeloid derived suppressor cells MDSCs and the role of MDSCs as a prognostic factor in CML patients. One hundred and three newly diagnosed CML patients from January 2018 to December 2020 attending outpatient clinic of the Clinical Hematology unit of Internal Medicine Department at Assiut University Hospital were enrolled in the study after they met the requirements for inclusion criteria and after written informed conset. Mean age of those patients was 51.97 ± 12.66 years and (51.5%) of the patients was males. Two groups of patients were included in this study: group one: newly diagnosed CML patients treated with Imatinib (Gleevec) (n=58) 400mg/ day orally as a first line treatment. group two: newly diagnosed CML patients treated with Nilotinib (tasigna) (n=45) 600 mg/ day as a first line treatment. All patients were assessed clinically, and laboratory parameters (CBC, bone marrow aspirate and biopsy, BCR-ABL by quantative PCR, liver function test, kidney function test, serum Na, K, Mg, uric acid and (HbA1C) were obtained. Follow up clinical response and laboratory investigations were done at monthly and 3 months interval. MDSCs were analyzed by flowcytometry in peripheral blood of CML patients at diagnosis and during TKIs treatment (patients treated with Imatinib and patients treated with Nilotinib) after patient reached MMR (major molecular response) and after 6 months even if patients did not reach MMR. Granulocytic MDSCs (G-MDSCs) were identified as CD11b+CD33+CD14-HLADR- cells. Monocytic MDSCs (M-MDSCs) asCD11b+CD33+ CD14+HLADR-Twenty six (25.2%) patients were heavy smokers. Also, 63 (61.2%) patients had, low sokal score. Left hypochondrial pain was the most frequent presentation (56.3%). Only two patients presented with priapism. Both studied groups showed no significant differences as regard baseline data. There was significant increase in baseline level of G-MDSCs and M-MDSCs in both groups. The frequency of baseline M‐MDSC and G-MDSCs significantly correlated with baseline BCR/ABL transcript levels (r= 0.24, p= 0.01 vs. r= 0.25, p= 0.01). The percentages of G‐MDSC and M‐MDSC didnot correlate neither with age, nor with leukocytosis or Sokal risk. To detect the effect of TKIs treatment, there was significant reduction in the level of G-MDSCs and M-MDSCs during follow up in both groups of patients for imatinib group (73.91±20.59 vs.59.28 ± 20.11, p< 0.001) vs (75.25 ± 15.48 vs 63.28 ± 20.11, p < 0.001) for nilotinib group (19.28 ± 11.65vs7.25 ± 7.19, p < 0.001) vs (16.09 ± 10.19 vs7.14 ± 6.42, p< 0.001). It was found that percentage of reduction in G-MDSCs (-21.81 ± 5.26 vs. -17.47 ± 8.53 (%); p= 0.33) and M-MDSCs (-58.30 ± 23.45 vs. -54.45 ± 30.91(%); p= 0.63) was higher among Imatinib group but with no significant difference. Achieving MMR is extremely important in the course of CML to avoid relapse, we investigated the correlation of MDSCs with clinical response to TKI therapy. Patients who didn’t achieved MMR had significantly higher baseline M-MDSCs in comparison to those with MMR (19.70 ± 11.51 vs. 7.03 ± 2.33; p= 0.04). Patients with relapse had significantly higher M-MDSCs at baseline in comparison to those without relapse (19.73 ± 11.6 vs. 9.34 ± 3.02; p= 0.03). We found that, the only predictors for major molecular response among those patients is baseline M-MDSCs (odd’s ratio= 0.78, 95%CI=0.66-0.93, p< 0.001) with cutoff point < 8.9% where it had 89.2% accuracy with area under curve was 0.90The only predictors for relapse among those patients is baseline M-MDSCs (odd’s ratio= 2.17, 95%CI=1.22-3.87, p< 0.001). with cutoff point > 8.5, where it had 89.5% accuracy with area under curve was 0.92. MDSC, especially monocytic subset, could be able to favour the growth of CML cells in vivo through impairment of immunosurveillance against LSC. Therefore, these myeloid cells could be candidate as predictive markers of relapse and response. Furthermore, it remains to be elucidated whether MDSC might be candidate predictive markers of relapse risk following TKI discontinuation. The emerging landscape of immune dysfunction and immunosurveillance in CML highlights the critical importance of the immune system in optimizing treatment responses in CML. It is therefore reasonable to hypothesize that targeting of MDSCs in CML may restore the T-cell mediated leukemia surveillance and improve further patients’ long-term outcome.