LIBERTY: Liquid Biopsy to Diagnose and Monitor Central Nervous System (CNS) Involvement in High-risk B Cell Non-Hodgkin Lymphoma
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 入组人数
- 64
- 试验地点
- 22
- 主要终点
- Sensitivity
研究概览
简要总结
Prevention and treatment of CNS relapse remains a great unmet clinical need in the management of aggressive B-NHL. Hence, investigating novel diagnostic tests is of paramount importance to improve risk-stratification of lymphoma patients at diagnosis, as is the evaluation of novel therapeutic approaches that may prevent and / or treat CNS recurrence. Based on the highlighted evidence, the investigators hypothesize that ctDNA detected within the CSF could potentially improve the detection rate of CNS involvement and consequently improve patients' stratification and better discriminate those in need of consolidative CNS prophylaxis on a molecular basis. Similarly, the investigators postulate that CSF ctDNA could be used as a monitoring tool to assess treatment response and guide therapeutic management.
详细描述
Non-Hodgkin B-cell lymphoma (B-NHL) are cancers that arise from a subtype of white blood cells (lymphocyte) and typically involve the lymphatic system; they represent 4% of all cancers [SEER database, access 2022]. Despite booming novel antineoplastic agent development, a significant number of aggressive B-NHL patients continue to succumb to their disease, experiencing rapidly progressive disease or early relapse. Central nervous system or CNS (brain, spinal cord and cerebrospinal fluid (CSF)) involvement in aggressive B-NHL is a rare (2-5%) but it is a devastating event, with a life expectancy ranging between 2 and 5 months [PMID: 30125215]. Circulating tumor DNA (ctDNA) represents fragmented DNA that originates from tumors cells, carrying specific cancer-associated mutations that can be detected in the blood or other fluids subsumed under "liquid biopsies".
The role of ctDNA gained momentum with the advent of high throughput sequencing technologies, becoming increasingly relevant for clinical practice. In lymphoma, detecting and monitoring ctDNA has been shown to be feasible and of high prognostic relevance regarding response and relapse. As such, ctDNA is emerging as a promising biomarker that can provide valuable diagnostic and prognostic information [PMID: 30125215, PMID: 29449275]. Identification of patients suffering from aggressive B-NHL at high risk of CNS relapse remains extremely challenging and currently mainly relies on a clinical score (CNS-IPI) [PMID: 27382100]. The detection of asymptomatic CNS is limited to conventional techniques and is not standardized [PMID: 22927246]. In patients with biopsy-proven CNS lymphoma, ctDNA can be detected in CSF (CSF ctDNA) in approximately 95% of cases. Furthermore, CSF ctDNA is predictive of CNS relapse in a small series of neurologically asymptomatic patients with aggressive B-NHL [PMID: 36542815, PMID: 32079701, PMID: 34551072]. Prevention and treatment of CNS involvement remains a great unmet clinical need. The discovery of novel and robust biomarkers is of paramount importance for early detection and risk-adapted therapeutic strategies for CNS involvement. The investigators hypothesize that CSF ctDNA is superior to current standard diagnostic procedures (e.g., flowcytometry or cytology) to detect CNS involvement in high-risk patients.
Furthermore, in patients with positive CSF ctDNA, the investigators also postulate that the concept of monitoring minimal residual disease (MRD, small amount of ctDNA that persists in patients that have no signs of active disease on standard imaging techniques) will provide additional information on patient prognosis.
This is a multicenter prospective diagnostic study to compare the performance of experimental diagnostic test (ctDNA) versus conventional cytology (CC) and flow cytometry (FC). Each high-risk B-NHL participant will proceed through standard work-up to evaluate potential CNS involvement including a neurological physical examination, a brain MRI and a diagnostic lumbar puncture. Each participant's CSF will be assessed by the two diagnostic tests (CSF ctDNA and conventional test (CC/FC)); the gold standard being proven CNS lymphoma involvement.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Diagnostic
- 盲法
- None
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
- •Informed consent as documented by signature before registration and prior to any trial specific procedures, according to Swiss law and ICH E6 regulations Swiss law and ICH GCP E6(R2) regulations before registration.
- •Histologically and/or cytologically confirmed newly diagnosed lymphomas including the following:
- •Diffuse large B-cell lymphoma (DLBCL) with at least one of the following characteristics:
- •CNS IPI > 4
- •Non-GC/ABC subtype with IPI > 3
- •Testicular involvement
- •Breast involvement
- •Kidney involvement
- •Adrenal involvement
- •Paranasal sinus / orbit involvement
- •Involvement of ≥ 3 extranodal sites
- •HIV-positive
- •Radiological or histological CNS involvement
- •High-grade B-cell lymphoma with MYC translocation with BCL2 and / or BCL6 (HGBL)
- •Burkitt lymphoma
- •Mantle cell lymphoma (blastoid variant or Ki67 >30% or TP53 mutated)
- •Primary CNS lymphoma
- •Aggressive transformation from indolent lymphomas (pretreated or not) are allowed
- •Patients enrolled in other clinical trials may be included
- •Patients must be willing to undergo a lumbar puncture at screening
- •Age ≥ 18 years
排除标准
- •Subtypes of Non-Hodgkin lymphoma (NHL) not fulfilling above mentioned criteria (e.g., indolent lymphoma, T-cell lymphoma)
- •Relapsing B-NHL
- •Low/intermediate-risk DLBCL (CNS-IPI < 4) AND no CNS involvement on imaging
- •Any prior lymphoma-directed therapy before registration, with the exception of a maximum of 48 hours steroids prior to lumbar puncture procedure and therapies received for indolent lymphomas prior to transformation
- •Any active advanced or metastatic cancer
- •Any clinical contraindication to lumbar puncture procedure as per local guidelines
- •Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned diagnostic procedure.
结局指标
主要结局
Sensitivity
时间窗: at baseline
Sensitivity of liquid biopsy (ctDNA) measured within CSF in its performance to detect CNS involvement in newly diagnosed high-risk B-NHL in comparison to standard conventional diagnostic approaches (CC / FC). For the evaluation of the primary endpoint, only patients with confirmed CNS involvement at baseline (real positives) will be analyzed. CNS involvement at baseline is defined as having at least one of the following conditions: * Positive brain or spine MRI * Neurological symptoms of lymphoma manifestations (including ophthalmic symptoms) * Histologically confirmed CNS involvement
次要结局
- Time to lymphoma manifestation in the CNS(from the date of registration until the date of assessment of neurological symptoms or death due to lymphoma, assessed up to 1 year after registration)
- Time to minimal residual disease (MRD) negativity(from the date of first documented MRD positivity (CSF ctDNA detected positive) to the date of first documented MRD negativity, assessed up to 1 years after registration)
- Specificity(at baseline)
- Progression-free survival (PFS)(from the date of registration until the date of progression or relapse as per Lugano and / or IPCG criteria, or death whatever occurs first, assessed up to 1 year after registration)
- Overall response rate (ORR)(At the date of tumor assessment according to the Lugano criteria, assessed up to 1 year after registration)
- Event-free survival (EFS)(from the date of registration until the date of progression or relapse as per Lugano and / or IPCG criteria, treatment stop without achieving a complete response or death whatever occurs first, assessed up to 1 year after registration)
- Overall survival (OS)(from the date of registration until the date of death, assessed up to 1 year after registration)
- Duration of response (DOR)(from the date of first response CR until the date of lymphoma progression, relapse or death, whatever occurs first, assessed up to 1 years after registration)