Tumor Heterogeneity in Diffuse Large B-cell Lymphoma in Relation to CNS Involvement and Cell-free DNA
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 26
- 试验地点
- 1
- 主要终点
- Identify the pattern and variations of mutations in different lymphoma sites in individual patients
研究概览
简要总结
The aim of the project is to clarify whether DLBCL exhibits mutational diversity among different lymph node tumors in one and the same patient. It is desired to find out whether a possible difference between lymph node tumors / tumors can explain why patients who initially (at diagnosis) have the same prognosis, sometimes have a completely different course, eg with rapid recurrence of the disease after treatment.
A possible difference could also perhaps shed light on why disease in specific places spreads more frequently to the brain - and therefore have an impact on when one chooses to give preventive treatment against spread to the brain.
Monitoring of circulating cell-free DNA (ctDNA) is a new, potential, non-invasive tool for measuring the full spectrum of genetic variations / mutations and is to be investigated in our study as a possible non-invasive assessment of diversity / heterogeneity.
详细描述
Only about 60% of patients with diffuse large B-cell lymphoma (DLBCL) are cured with standard chemo- and immunotherapy, with R-CHOP(Rituximab, cyclophosphamide, doxorubicin hydrochloride, oncovin, prednisone).
Early and more accurate identification of patients with unfavorable prognosis after R-CHOP will enable the clinician to find patients who need other treatment strategies. New predictive biomarkers are needed to predict the effect of treatment at the individual level.
A proportion of patients have, or develop, lymphoma involvement of the central nervous system (CNS) and this group has a particularly dismal outcome. Identification of patients with primary subclinical or later manifest involvement of the CNS also requires new and improved diagnostic methods. Currently, a number of clinical parameters are included in a CNS-IPI risk score, that can be used to predict the risk of CNS disease. This score enables the clinicians to decide if patients should have prophylactic chemotherapy to prevent development of CNS disease. However, this risk model is far from accurate and the effect of prophylactic treatment is based on a low level of evidence.
DLBCL is a highly heterogeneous disease as evidenced by the 19 subtypes and variants of large B-cell lymphoma diagnoses found in the WHO classification of tumors of hematopoietic and lymphoid tissues. However, the cancer within each patient is also characterized by heterogeneity. The fact that different lymphoma cells may co-exist in the same tumor has been known for decades. One example of this is transformation of indolent lymphoma to a more aggressive lymphoma subtype, often DLBCL where the two types of lymphoma cells are found in the same lymph node. Differences between the cancer cells in the same tumor is termed intratumor heterogeneity. Such differences may be found within the same tumor as well as at spatially separate locations(inter-tumor heterogeneity). Intratumor heterogeneity may have an important impact on the clinical course and response to therapy. In clinical practice, the prognosis in patients with similar clinical stage and International Prognostic Index (IPI) score is often diverse. Such differences may be attributed to both intra and inter-tumor heterogeneity. Molecular profiling (mutations) in different nodal and extra nodal sites within the same patient have not before been studied in larger cohorts of DLBCL patients (Inter-tumor heterogeneity).
Monitoring circulating cell-free tumor DNA (ctDNA) has the potential to serve as a non-invasive tool for measuring the entire spectrum of genetic aberrations found in an individual patient as an alternative to more invasive diagnostic procedures.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
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
- •Diagnosed with DLBCL
- •Immunochemotherapy (rituximab and CHOP-like chemotherapy) planned and not yet initiated (pretreatment with prednisolone is allowed)
- •Age ≥ 18 years
- •More than 1 lymphoma site accessible for biopsy
- •Patient must consent to permit genetic analysis of their tumor biopsies
- •Patient must consent to additional biopsies and blood samples
- •Tumor biopsy and/or bone-marrow biopsy used for diagnosis available
- •Patient must consent to access of their medical records to monitor the clinical process
- •Written informed consent
- •Baseline 18FDG-PET/CT available
排除标准
- •History of previous or current malignancies
- •Other previous/current hematological malignancies or inflammatory disease
- •Concurrent diagnosis of follicular lymphoma or other indolent lymphomas (composite histology)
- •If the patient is deemed to have an acute treatment need, the patient cannot be included in the project.
- •Patients on blood thinners, which must be paused before an additional biopsy, causing too much delay in initiating treatment will be excluded
结局指标
主要结局
Identify the pattern and variations of mutations in different lymphoma sites in individual patients
时间窗: Through study completion, an average of 1. year
Differences in mutations will be analyzed with next generation sequencing
次要结局
- Identify inter-tumor heterogeneity between nodal and extra-nodal sites(1 year)
- Clonal evolution will be assessed between primary tumor site and tumor at relapse(1 year)
- Inter-patient heterogeneity identified with our local clinical lymphoma panel can be used to subdivide patients according to the Wright classification.(1 year)
- Number of patients, with detected heterogeneity, who develop CNS disease, assessed over time(1 year)
- Assess if ctDNA can be used as monitorering of inter-tumor heterogeneity(1 year)
- Identify heterogeneity between nodal sites and bone-marrow biopsy(1 year)
研究者
Lars Møller Pedersen
Senior Consultant
Herlev Hospital