The Use of Biomarkers to Predict CNS Involvement in Diffuse Large B-Cell Lymphoma: a Danish Nationwide Registry Study
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 2,969
- 主要终点
- Bio-CNS-IPI
研究概览
简要总结
Diffuse Large B-cell Lymphoma (DLBCL) is a malignant, aggressive lymphoid cancer. The incidence in Denmark is approximately 450 cases per year. In 2/3 of the cases, complete remission is achieved with immunochemotherapy. The remaining 30% will experience relapse and in 5 % of the patients, this will occur in the central nervous system (CNS). CNS relapse has a very poor prognosis with an overall survival of 3-6 months.
In order to identify patients at risk of CNS relapse, the CNS-IPI score is used to stratify the patients into three risk groups according to number of risk factors (low 0-1, middle 2-3 and high risk 4-6 which corresponds to 2-year CNS relapse rates of 0,6%, 3,4% and 10,2% respectively).
DLBCL can be subdivided by gene expression analysis into three different types based on the cell of origin (ie the stage of the equivalent normal cell development from which the disease arises): the germinal center B-cell (GCB)-like subtype, the activated B-cell (ABC)-like subtype and unclassifiable. The subdivision is of prognostic importance as patients with GCB-like subtype have a 5-year OS of 76% vs 34% in the non-GCB group. Furthermore, studies have found a higher risk of CNS relapse in the ABC-like subtype compared to the GCB subtype0. Other gene rearrangements of potential importance to the risk of CNS relapse is "double hit" (DHL) (5-10% of newly diagnosed DLBCL patients) and MYC/BCL2 co-expressors (double expressors, DEL).
Chemotherapeutic CNS prophylaxis is recommended based on the CNS-IPI stratification for the high-risk group (CNS-IPI 4-5) due to an estimated risk of CNS relapse of 10,2%. However, a relapse risk with a specificity of 10,2% results in almost 90% of the patients potentially receiving 'unnecessary' prophylactic chemotherapy with toxic side effects. One study published on data from the GOYA-trial have integrated COO into the CNS-IPI and found an increased sensitivity with a two year relapse risk of 15,2% in the high risk group.
In this study we aim to validate the CNS-IPI and evaluate whether the addition of biomarkers for cell of origin (COO) and double hit (DH) DLBCL improves the prediction of later CNS relapse. This will be done through analysis of patientdata from the Danish nationwide lymphoma database, LYFO, on all patients with DLBCL diagnosed from 1.1.2014 to 1.1.2021 combined with pathology reports from the Danish Pathology registry.
详细描述
Background Diffuse Large B-cell Lymphoma (DLBCL) is a malignant, aggressive lymphoid cancer. The incidence in Denmark is approximately 450 cases per year. In 2/3 of the cases, complete remission is achieved with immunochemotherapy. The remaining 30% will experience relapse and in 5 % of the patients, this will occur in the central nervous system (CNS). CNS relapse has a very poor prognosis with an overall survival of 3-6 months1.
In order to identify patients at risk of CNS relapse, the IPI score has been further elaborated and validated using real life data2 to the CNS-IPI score including the five IPI criteria (age greater than 60 years, stage III or IV disease, elevated serum LDH, ECOG performance status >1, more than 1 extranodal site) with the addition of disease localized to the adrenal glands or the kidneys. The CNS-IPI stratifies the patients into three risk groups according to number of risk factors (low 0-1, middle 2-3 and high risk 4-6 which corresponds to 2-year CNS relapse rates of 0,6%, 3,4% and 10,2% respectively).
CNS prophylaxis can be administered by two different approaches; either injected intrathecally (IT) or intravenously (termed high dose, (HD)) with drugs with a well established ability to penetrate the blood-brain-barrier. Recent studies have raised concerns regarding the efficacy of CNS prophylaxis, and current evidence is problematic in relation to:
In general the studies are small and limited by the low event rate of CNS relapses3 4
- Patient selection (ie. patients, who receive prophylaxis per se have a higher risk of CNS relapse than the background population) which result in a higher rate of CNS relapse in the patients receiving prophylaxis
- Prophylaxis given by clinician's choice5
- Some register based studies cannot distinguish between the timing or type of prophylaxis administered1 However recent prospective studies with focus on HD prophylaxis have shown a lower than expected number of CNS events67. Furthermore the question has been raised as to whether the timing of the administration matters based on the fact that most relapses occur within the first 6 months after treatment and thus may imply occult CNS-involvement at the time of diagnosis6.
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
- •Patients with DLBCL
- •Received first line R-CHOP like immunochemotherapy from 2014-2020
排除标准
- •Patients with lymphoma in the central nervous system at time of diagnosis
- •Patients with transformed indolent lymphomas
结局指标
主要结局
Bio-CNS-IPI
时间窗: 1.1.14-1.1.21
To validate the CNS-IPI and evaluate whether the addition of biomarkers for cell of origin (COO) and double hit (DH) DLBCL improves the prediction of later CNS relapse
次要结局
- CNS-IPI 3(1.1.14-1.1.21)
- CNS-IPI 4(1.1.14-1.1.21)
- CNS-IPI 6(1.1.14-1.1.21)
- CNS-IPI 1(1.1.14-1.1.21)
- CNS-IPI 5(1.1.14-1.1.21)
- CNS-IPI 2(1.1.14-1.1.21)
- CNS-IPI 7(1.1.14-1.1.21)
研究者
Lars Møller Pedersen
Senior Consultant
Herlev Hospital