Search for an Association Between the Innate CD8+ T Cell Population and the Evolution of TKI (Tyrosine Kinase Inhibitor) Resistance Mutations in Phi+ Hematological Malignancies.
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 30
- 试验地点
- 2
- 主要终点
- Association between innate CD8+ T cell population levels and the rate of progression of TKI resistance mutations in Chronic Myeloid Leukemia: mutated BcrAbl1
研究概览
简要总结
The aim of this project is to test whether low levels of BcrAbl1, despite the presence of resistance mutations, are related to high levels of innate CD8+ T cells, in the hypothesis that these cells have an anti-tumor role. This research aims to investigate:
- An association between the rate of innate CD8+ T cells and the evolution of Phi+ pathologies (Chronic Myeloid Leukemia and Philadelphia chromosome-positive Acute lymphocytic leukemia (Phi+ ALL) carrying a resistance mutation, according to the ELN 2013 and Phi LMC recommendations.
- An association between the level of innate CD8+ T cells and the expansion of TKI resistance clones, assessed as the number of BcrAbl1 copies carrying the mutation relative to the number of Abl1 copies.
详细描述
Before the advent of the first targeted therapies with imatinib in 2000, chronic myeloid leukemia (CML) was the most feared myeloproliferative syndrome (MPS, Philadelphia+), with a median survival of 3 years. Apart from a small percentage of patients who do not respond or respond poorly to tyrosine kinase inhibitors (TKIs), the probability of survival is now very close to that of the general population when patients are on lifelong TKI therapy (leukemic stem cells have low sensitivity to TKIs). Some patients with good response to treatment are likely to consider stopping treatment but just over 50% of them will have to resume it. So many patients will have to take TKIs for life, which poses several problems:
- - intolerance to the various molecules depending on the toxicity of each one,
- - development of resistance to TKIs, characterized by a rise in the percentage of BcrAbl1 fusion RNA, despite treatment or increased dosages.
There are many causes of these resistances including those known for any molecule:
- pharmacokinetic causes which can be evaluated by the plasma dosage of the molecules;
- Leukemic cell-related causes: passage into the cell depending on antagonism between influx pump (hOct1) and efflux pumps (MDR1) and failure to bind to the BcrAbl1 target (pharmacodynamics), mainly by mutation of the tyrosine kinase domain of Abl1, exceptionally by amplification of the Abl1 gene.
These apply to the consolidation phase of Phi+ acute lymphoblastic leukemia (Phi+ALL).
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Retrospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Chronic Myeloid Leukemia or Phi+ ALL patients with TKI resistance mutations being monitored by the Clinical Cytology and Cytogenetics Laboratory at Nîmes University Hospital.
- •Pathology resulting from a BcrAbl1 fusion gene (CML or Phi+ ALL) and presence of a TKI resistance mutation.
- •Patients affiliated to or beneficiaries of a health insurance scheme.
- •Adult patients over18 years of age.
排除标准
- •Blast crisis stage pathology (according to WHO 2017 criteria (Table2.01, p33, WHO classification of tumours of haematopoietic and lymphoid tissues, IARC 2017).
- •Patients Under 18 years of age
研究组 & 干预措施
Chronic Myeloid Leukemia
There will be approximately 10 patients with Chronic Myeloid Leukemia in this group
干预措施: Phenotyping of total and innate CD8+T cells by flow cytometry (Genetic)
Philadelphia+ Acute Lymphoblastic Leukemia
There will be approximately 20 patients with Philadelphia chromosome-positive Acute lymphocytic leukemia in this group
干预措施: Phenotyping of total and innate CD8+T cells by flow cytometry (Genetic)
结局指标
主要结局
Association between innate CD8+ T cell population levels and the rate of progression of TKI resistance mutations in Chronic Myeloid Leukemia: mutated BcrAbl1
时间窗: 1-6 months after collecting last sample
The number of copies of mutated BcrAbl1 / 1000 copies of Abl1 will be measured.
Association between innate CD8+ T cell population levels and the rate of progression of TKI resistance mutations in Philadelphia+ Acute Lymphoblastic Leukemia:% of BcrAbl1
时间窗: 1-6 months after collecting last sample
The percentage of BcrAbl1 will be measured against total Abl1
Association between innate CD8+ T cell population levels and the rate of progression of TKI resistance mutations in Chronic Myeloid Leukemia: % of innate CD8+ T cells
时间窗: 1-6 months after collecting last sample
The percentage of innate CD8+ T cells will be measured against total CD8+ T cells.
Association between innate CD8+ T cell population levels and the rate of progression of TKI resistance mutations in Philadelphia+ Acute Lymphoblastic Leukemia:% of innate CD8+ T cells
时间窗: 1-6 months after collecting last sample
The percentage of innate CD8+ T cells will be measured against total CD8+ T cells
Association between innate CD8+ T cell population levels and the rate of progression of TKI resistance mutations in Philadelphia+ Acute Lymphoblastic Leukemia:mutated BcrAbl1
时间窗: 1-6 months after collecting last sample
The number of copies of mutated BcrAbl1 / 1000 copies of Abl1 will be measured.
Association between innate CD8+ T cell population levels and the rate of progression of TKI resistance mutations in Chronic Myeloid Leukemia: % of BcrAbl1
时间窗: 1-6 months after collecting last sample
The percentage of BcrAbl1 will be measured against total Abl1
次要结局
- Association between the rate of innate CD8+ T cells and the molecular response during Chronic myeloid Leukemia.(1-6 months after collecting last sample)
- Association between the rate of innate CD8+ T cells and the molecular response during Philadelphia + Acute Lymphoblastic Leukemia(1-6 months after collecting last sample)