Myeloid Derived Suppressor Cells and Chronic Myeloid Leukemia

Study Overview
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Brief Summary
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The suppression of the immune system creates a permissive environment for development and progression of cancer. One population of immunosuppressive cells that have become the focus of intense study is myeloid derived suppressor cells , immature myeloid cells able to induce immune-escape, angiogenesis, and tumor progression. Two different subpopulations have been identified and studied: granulocytic and monocytic myeloid derived suppressor cells with a different immunophenotype and immunosuppressive properties

Detailed Description
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Myeloid-derived suppressor cells utilize different mechanisms to block both innate and adaptive arms of anti-tumour immunity, mostly through inhibition of T cell activation and expansion . Human monocytic myeloid derived suppressor cells are mostly identified as CD14+ cells with negative or low expression of HLADR. And also express high levels of CD11b and CD33 antigen . Human granulocytic myeloid derived suppressor cells are usually defined as CD66b+ CD11b+ CD15+ HLADR- cells and display an intermediate expression of CD33 and a variable expression of CD11b, depending on their maturation stage . Chronic myeloid leukemia (CML) is a hematological cancer, characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 [t(9;22)], producing the Bcr-Abl oncogene. Tyrosine kinase inhibitors represent the standard of care for CML patients and exert a dual mode of action: direct oncokinase inhibition and restoration of effector-mediated immune surveillance, which is rendered dysfunctional in CML patients at diagnosis, prior to TKI therapy. TKIs such as imatinib, and more potent second-generation nilotinib and dasatinib induce a high rate of deep molecular response (DMR, BCR-ABL1 ≤ 0.01%) in CML patients. As a result, the more recent goal of therapy in CML treatment is to induce a durable deep molecular response as a prelude to successful treatment-free remission . Accumulation of both Gr-MDSCs and Mo-MDSCs cells has been found in the peripheral blood of chronic myeloid leukemia (CML) patients. They are part of the tumor clone showing BCR/ABL expression. BCR-ABL tyrosine kinase inhibitors (TKI) are able to induce remission in CML patients but not to eliminate leukemia stem cells , which can regenerate leukemia on drug discontinuation . Unfortunately, molecular relapse is observed after cessation of tyrosine kinase inhibitors in 61-66% of CML patients, previously in complete molecular response (presumably due to the reactivation of dormant CML LSCs that are resistant to TKI-induced leukemic cell ablation. Thus, current research efforts aim to develop additional therapies to target these TKI-refractory CML LSCs . With the aim of increasing cure rates and make it possible for patients to discontinue treatment, TKI therapies are currently evaluated in combination with immune modulators .

Official Title
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Effect of Tyrosine Kinase Inhibitors on Myeloid Derived Suppressor Cells in Chronic Myeloid Leukemia Patients

Conditions
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Chronic Myeloid Leukemia Patients

Intervention / Treatment
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* Diagnostic Test: Measurement level of myeloid derived suppressor cells in CML patients treated with imatinibe 400 mg/day
* Diagnostic Test: Measurement level of myeloid derived suppressor cells in CML patients treated with nilotinib 600 mg/day


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All newly diagnosed chronic phase CML patients during one year in Assiut university hospital. Exclusion Criteria: Preivously diagnosed CML patients . Other myeloproliferative disorders .

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CML patients treated with imatinib 400 mg/day<br>Measurement of the level of myeloid derived suppressor cells (MDSCs) by flowctytometry for each newly diagnosed chronic phase chronic myeloid leukemia (CML) patients treated with imatinib 400 mg/day before starting treatment and every 3 months till one year and correlate between it and level of BCR-ABL gene level and the sokal score of the patients and deep molecular response of the patients after one year . | Diagnostic Test: Measurement level of myeloid derived suppressor cells in CML patients treated with imatinibe 400 mg/day<br>* For each patient these investigation will be done: - Complete blood count,bone marrow aspirate and bone marrow biopsy Measure BCR-ABL GENE Level by FISH at diagnosis and every 3 months till one year . Measurement Level of myeloid derived suppressor cells both granulocytic and monocytic cells by flowcytometry .<br>|
| Active Comparator: CML patients treated with nilotinib 600 mg/day<br>Measurement of the level of myeloid derived suppressor cells (MDSCs) for each newly diagnosed chronic phase chronic myeloid leukemia ( CML) patients treated with nilotinib 600 mg/day before starting treatment and every 3 months till one year and correlate between it and level of BCR-ABL gene, the sokal score and deep molecular response of the patients after one year . | Diagnostic Test: Measurement level of myeloid derived suppressor cells in CML patients treated with nilotinib 600 mg/day<br>* For each patient these investigation will be done: - Complete blood count,bone marrow aspirate and bone marrow biopsy Measure BCR-ABL GENE Level by FISH at diagnosis and every 3 months till one year . Measurement Level of myeloid derived suppressor cells both granulocytic and monocytic cells by flowcytometry .<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect of the different types of tyrosine kinase inhibitors (TKI) ( imatinib and nilotinib) therapy on MDSC and possible correlation with clinical response. | measuring response rate of patients on TKIs whether imatinib 400mg/ day or nilotinib 600 mg / day by assessment of level of BCR-ABL gene level measured by FISH in %every 3 months till one year. and correlate between this level and between level of MDSCs measured in % ,.Granulocytic MDSCs (G-MDSCs) were identified as CD11b+CD33+CD14-HLADR- cells, while the monocytic MDSCs (M-MDSCs) as CD14+HLADR by cytofluorimetric analysis also measured every 3 months till one year,and detect if there is decline in level of MDSCs after one year of TKIs therapy. | one years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relation between the level of (MDSC) and clinical feature and sokal score of CML patients .. | correlate between MDSCs and clinical features of CML patients as spleen size measured in centimeters, haemoglobin level measured in gram/dl, sokal score of the patients exp (0.0116 x (age [years] - 43.4)) + (0.0345 x (spleen size [cm] - 7.51) + (0.188 x ((platelets [109/L]/700)^2 - 0.563)) + (0.0887 x (blasts [%] - 2.10)). low-risk (Sokal score < 0.8), intermediate-risk (Sokal score 0.8 - 1.2) and high-risk (> 1.2 ) . | one year |