1. Sensitivity (Time Frame - 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
Secondary outcome:
1. Specificity (Time Frame - at baseline): 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
2. Time to lymphoma manifestation in the CNS (Time Frame - 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 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
3. Progression-free survival (PFS) (Time Frame - 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): 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.
4. Event-free survival (EFS) (Time Frame - 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): 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.
5. Overall survival (OS) (Time Frame - from the date of registration until the date of death, assessed up to 1 year after registration): 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.
6. Overall response rate (ORR) (Time Frame - At the date of tumor assessment according to the Lugano criteria, assessed up to 1 year after registration): 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.
7. Duration of response (DOR) (Time Frame - 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): 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.
8. Time to minimal residual disease (MRD) negativity (Time Frame - 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): 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.
