An Integrated European Platform to Conduct Translational Studies in Myelodysplastic Syndromes Based on the EuroBloodNet Infrastructure
试验速览
- 阶段
- 不适用
- 发起方
- 入组人数
- 8,670
- 试验地点
- 4
- 主要终点
- DNA mutations in hematopoietic cells
研究概览
简要总结
Rationale Myelodysplastic syndromes (MDS) are rare cancers with unmet medical needs. Study of MDS has been rapidly transformed by genome characterization.
The investigators hypothesize that comprehensive analyses of large patient population will allow to correctly estimate the effect of each mutation on clinical outcomes, and that niche factors and immune dysfunctions may influence the development of MDS, clonal evolution and response to treatments
Aims
1- Investigate gene mutations, niche factors and immune dysfunctions influencing the development of MDS, and define biomarkers for early identification of individuals at risk; 2- Develop prognostic models for MDS patients through integration of comprehensive genomic/clinical information; 3- Define biomarkers to better stratify the individual probability of response to specific treatments
Methods EuroBloodNet, the European Reference Network in rare hematological diseases, will provide a basis for research activities. Study of genomic features of clonal dominance in elderly subjects enrolled in large population-based studies and description of the dynamics of clonal establishment and evolution; study of bone marrow microenvironment to identify immune dysfunctions influencing MDS development. Development of inclusive statistical models to accurately predict clinical outcome at individual level, based on large MDS populations with comprehensive genomic/clinical data. Finally, analysis of mutational screening and immune profiles from patients enrolled in prospective trials, to provide evidence on genetic/immunologic profiles associated with probability of response to specific compounds
Expected results To characterize how clonal hematopoiesis relates to the induction of MDS clinical phenotype, and to test the utility of gene sequencing to detect subjects at risk of developing MDS. To define effective prognostic systems and biomarkers to stratify the individual probability of response to treatment
详细描述
MDS typically occurs in elderly people and a portion of these subjects evolve into acute myeloid leukemia (AML). The natural history of MDS is highly heterogeneous, and therefore a risk-adapted treatment strategy is mandatory.
The presence of mutations in a given individual has only limited predictive power, as conversion to MDS is rare regardless of mutation status. In addition, in patients with overt MDS, genetic abnormalities explain only a proportion of the total hazard for survival, meaning that a large percentage is still associated with clinical and non-mutational factors. Comprehensive analyses of large patient populations are warranted to correctly estimate the independent effect of each mutation on clinical outcome and response to treatment.
Moreover, environmental factors influencing the development of MDS and the probability of response to specific treatments are to be characterized. They include alterations in the immune system. In this context, a significant association was found between autoimmune disorders and MDS, and activation of the inflammasome may contribute to MDS development
AIMS 1- Investigate gene mutations, niche factors and immune dysfunctions influencing the development of MDS, and define biomarkers for early identification of individuals at risk; 2- Develop prognostic models for MDS patients through integration of comprehensive genomic/clinical information; 3- Define biomarkers to better stratify the individual probability of response to specific treatments
EXPERIMENTAL DESIGN
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Other
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
- •Individuals aged 65 years or older from population-based studies (retrospective cohort)
排除标准
- •lack of biological samples availability
- •Inclusion Criteria:
- •adults patients (>18 years) with a diagnosis of MDS according to WHO criteria (retrospective cohort)
- •Exclusion Criteria:
- •lack of availability of information on clinical and DNA mutational screening data
- •Inclusion Criteria:
- •adults patients (>18 years) with a diagnosis of MDS according to WHO criteria and treated with HMAs
- •Exclusion Criteria:
- •lack of biological samples availability
结局指标
主要结局
DNA mutations in hematopoietic cells
时间窗: 0-24 months
The investigotors will study the prevalence and type of somatic mutations by a low-cost, high-throughput platform including 72 genes, relevant in myeloid neoplasms.
RNA expression on hematopoietic progenitors and mesenchymal stromal cells
时间窗: 6-24 months
The investigators will study the genes diffentially expressed between cell populations of interest and normal controls
Predictive biomarkers for survival and response to treatment
时间窗: 0-30 months
The investigators will define, by innovative bayesian and clustering models, independent clinical and molecular factors associated to the probability of survival and response to specific treatments.
Frequency and function of T lymphocytes, NK cells and ILC cells
时间窗: 6-30 motnhs
The investigators will analyse by flow-cytometry the frequency of T lymphocytes, NK cells and ILC cells during different disease stages and in response to therapy. Complementary immunoassays based on Luminex technology will be used to quantify secretory proteins (cytokines, chemokines, growth factors).
次要结局
未报告次要终点