CSF DNA testing to improve diagnosis and monitoring in primary CNS lymphoma

Mutational Analysis in the Cerebrospinal Fluid to Improve Diagnostic Sensitivity, Response Definition and Precision Treatment in Primary Central Nervous System Lymphoma

This project will test whether sequencing DNA from spinal fluid can help diagnose and monitor people with suspected or confirmed primary CNS lymphoma.

Quick facts

• Phase: Not applicable
• Study type: Interventional
• Enrollment: 70 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: IRCCS San Raffaele (Academic / other)
• Drugs / interventions: immunotherapy
• Locations: 1 site (Milan, Italy/Lombardy)
• Trial ID: NCT05036564 on ClinicalTrials.gov

What this trial studies

This is a prospective, low-intervention effort to create a core panel of genetic alterations by sequencing cell-free DNA in cerebrospinal fluid (CSF) from patients with confirmed or suspected primary CNS lymphoma (PCNSL). Participants will undergo lumbar puncture for CSF collection and have available histopathology and imaging data; sequencing results will be compared to standard diagnostic and response measures. Enrolled patients will receive standard-of-care treatments and the molecular data will not change treatment choices. The goal is to improve diagnostic sensitivity, track objective responses, and detect early CNS relapse in routine practice.

Who should consider this trial

Good fit: Adults aged 18 or older with newly diagnosed or suspected PCNSL who can provide CSF and biopsy material and tolerate lumbar puncture and brain biopsy are ideal candidates.

Not a fit: Patients with simultaneous systemic lymphoma at presentation, non-DLBCL CNS lymphoma subtypes, pregnant or breastfeeding patients, or those with serious comorbidities or contraindications to lumbar puncture or biopsy are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could allow earlier and more accurate diagnosis and faster detection of relapse using a minimally invasive lumbar puncture.

How similar studies have performed: Similar uses of CSF circulating tumor DNA (ctDNA) have shown promising results in small series but are still emerging and not yet widely validated for routine use.

Eligibility criteria

Inclusion Criteria for study population:

1. Age ≥18 years
2. Newly diagnosed PCNSL with available clinical and radiological data, CSF and histopathological brain biopsy material fresh and/or formalin fixed and paraffin embedded;
3. No contraindications to stereotactic or open brain biopsy and lumbar puncture;
4. No formal contraindications to intravenous chemo-immunotherapy or whole-brain irradiation;
5. Given written informed consent prior to any study specific procedures, with the understanding that the patient has the right to withdraw from the study at any time, without any prejudice.

Exclusion Criteria for study population:

1. Patients with concomitant CNS and systemic involvement at presentation (potentially eligible as "control"; see below)
2. Patients with CNS lymphoma other than DLBCL subtype
3. Any other serious medical condition which could impair the ability of the patient to participate in the trial
4. Pregnant and lactating female patients. Sexually active patients of childbearing potential must implement adequate contraceptive measures during study participation.
5. Previous or concurrent malignancies at other sites diagnosed or relapsed within the last 3 years before PCNSL diagnosis. Patients with surgically cured in situ carcinomas and basal cell carcinoma of the skin are allowed.
6. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Inclusion criteria for controls:

1. Age ≥18 years
2. Newly diagnosed DLBCL with a high risk for relapse/progression in the CNS or High-grade B-cell (HGBC) lymphoma with available clinical and radiological data, CSF and diagnostic histopathological specimen. 3. Newly diagnosed and/or relapsed SCNSL with available clinical and radiological data, CSF and diagnostic histopathological specimen. 4. Newly diagnosed lymphoma confined to CNS other than DLBC subtype 5. Neoplastic and non-neoplastic neurological disorders (neurodegenerative and neuroinflammatory disorders, toxic or infective encephalitis, primary CNS tumors other than lymphomas (mainly gliomas)) with available clinical and radiological data, CSF samples and, where possible, histo-pathological brain biopsy material formalin fixed and paraffin embedded.

6\. No contraindications to stereotactic or open brain biopsy and lumbar puncture; 7. Given written informed consent prior to any study specific procedures, with the understanding that the patient has the right to withdraw from the study at any time, without any prejudice.

Exclusion criteria for controls:

1. Patients with extra-CNS lymphoma other than DLBC or HGBC subtypes, and not classified as high risk of CNS relapse;
2. Any other serious medical condition which could impair the ability of the patient to participate in the trial;
3. Pregnant and lactating female patients. Sexually active patients of childbearing potential must implement adequate contraceptive measures during study participation;
4. Previous or concurrent malignancies at other sites diagnosed or relapsed within the last 3 years of follow-up. Patients with surgically cured in situ carcinomas and basal cell carcinoma of the skin are allowed;
5. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Where this trial is running

Milan, Italy/Lombardy

• IRCCS Ospedale San Raffaele — Milan, Italy/Lombardy, Italy (Recruiting)

Study contacts

• Principal investigator: Andrés J.M. Ferreri, MD — IRCCS Ospedale San Raffaele
• Study coordinator: Andrés J.M. Ferreri, MD

Conditions Primary CNS Lymphoma; PCNSL; ctDNA; CSF