Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Lymphoma

Lymphoma, B-Cell

Lymphoma, Non-Hodgkin

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

B-cell Lymphoma

Lumbar punction at diagnosis. CSF and blood samples will be assessed by the two diagnostic tests (CSF ctDNA and conventional test (CC/FC))

ctDNA detection

Sabrina Chiquet

Noémie Lang, MD

Marc Heizmann, MD

Benjamin Kasenda, MD

Maria Pirosa, MD

Urban Novak, MD

Ulrich Mey, Prof

Gaëlle Rhyner Agocs, MD

Amandine Segot, MD

Michèle Voegeli, MD

Grégoire Berthod, MD

Felicitas Hitz, MD

Christoph Renner, Prof

Adrian Schmidt, MD

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.

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.

This is a multicenter prospective diagnostic study to compare the performance of experimental diagnostic test (ctDNA) versus conventional cytology (CC) and flow cytometry (FC).

LIBERTY: Liquid Biopsy to Diagnose and Monitor CNS Involvement in High-risk B Cell Non-Hodgkin Lymphoma

LIBERTY: Liquid Biopsy to Diagnose and Monitor Central Nervous System (CNS) Involvement in High-risk B Cell Non-Hodgkin Lymphoma

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

Specificity 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 specificity, only patients without CNS involvement at baseline (real negatives) will be analyzed. Absence of CNS involvement at baseline is defined as having none of the following conditions:

* Positive brain or spine MRI
* Neurological symptoms of lymphoma manifestations (including ophthalmic symptoms)
* Histologically confirmed CNS involvement

Time to lymphoma manifestation in the CNS, defined as time from diagnosis to one of the following events, whatever occurs first:

* Clinical neurological symptoms likely related to lymphoma manifestations
* Brain or spine MRI changes compatible with lymphoma involvement
* Histologically confirmed CNS involvement
* Confirmed involvement of the eye (positive CC / FC)
* Death due to lymphoma Patients without lymphoma manifestation in the CNS will be censored at their last tumor assessment by CNS imaging showing non-progression

PFS is defined as the time from diagnosis to lymphoma progression or relapse as per Lugano and / or IPCG criteria, or death whatever occurs first. Patients not having an event at the time of the analysis will be censored at the date of their last tumor assessment showing non-progression.

EFS is defined as the time from diagnosis to lymphoma progression or relapse as per Lugano and / or IPCG criteria, treatment stop without achieving a complete response or death whatever occurs first. Patients not having an event at the time of analysis will be censored at the date of their last tumor assessment showing non-progression. This endpoint will be calculated separately for each treatment line.

OS will be calculated from diagnosis until death from any cause. Patients not experiencing an event will be censored at the last date they were known to be alive.

Overall response rate (ORR) is defined as either PR or CR according to the Lugano criteria. Patients with no tumor assessment will be considered:

* non-ORR, if they have no following tumor assessment within the trial (patient died, refused or was lost to follow-up) or if they have non-ORR at the following tumor assessment after the end of therapy.
* ORR, if they have ORR at the following tumor assessment after end of therapy. This endpoint will be calculated separately for each treatment line.

DOR is evaluated in all patients who achieved a CR after the end of the intended treatment. DOR is defined as time from first complete response until lymphoma progression, relapse or death, whatever occurs first. Response and progression are evaluated according to Lugano criteria. Patients not having an event at the time of analysis will be censored at the date of their last tumor assessment showing non-progression.

Time from first documented MRD positivity (CSF ctDNA detected positive) to first documented MRD negativity. Patients not reaching MRD negativity will be censored at the last time they were known to be MRD positive. Evaluated only in patients with documented MRD positivity at any time.

Spots Global Cancer Trial Database for experimental diagnostic test