Diagnosis; Objective RespOnse; THErApy (DOROTHEA)

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

Thi is a prospective and low-intervention clinical trial. We propose to design a panel of "core" genetic alterations by sequencing Cerebral Spinal Fluid (CSF) DNA in patients with confirmed or suspicious Primary Central Neurvous System Lymphoma (PCNSL) with the aim to improve diagnostic sensitivity, response assessment and monitoring early CNS relapse in routine practice.

Enrolled patients will receive conventional treatments according to well-established international guidelines, DNA assessments will not influence the treatment choices.

Study Overview

• Status: Recruiting
• Conditions: Primary CNS Lymphoma
• Intervention / Treatment: Procedure: Lumbar puncture

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Andrés J.M. Ferreri, MD; Phone Number: 02 2643 7649; Email: ferreri.andres@hsr.it
• Study Contact Backup: Name: Teresa Calimeri, MD/PhD; Phone Number: 02 2643 7612; Email: calimeri.teresa@hsr.it

Study Locations

• Italy
  • Italy/Lombardy
    • Milan, Italy/Lombardy, Italy, 20132
      • Recruiting
      • Irccs Ospedale San Raffaele
      • Contact: Andrés J.M. Ferreri, MD; Phone Number: 02 2643 7649; Email: ferreri.andres@hsr.it
      • Contact: Teresa Calimeri, MD/PhD; Phone Number: 02 2643 7612; Email: calimeri.teresa@hsr.it
      • Principal Investigator: Andrés J.M. Ferreri, MD
      • Sub-Investigator: Teresa Calimeri, MD/PhD
      • Sub-Investigator: Sara Steffanoni, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Study population - PCNSL; Patients (pts) with clinical and radiological suspicion of PCNSL or with confirmed diagnosis of PCNSL will be enrolled to the protocol. They will represent the "Study population"	Procedure: Lumbar puncture; A lumbar puncture (spinal tap) is performed in patient lower back, in the lumbar region. During a lumbar puncture, a needle is inserted between two lumbar bones (vertebrae) to remove a sample of cerebrospinal fluid (CSF). This is the fluid that surrounds brain and spinal cord to protect them from injury. This procedure is usually performed at the time of diagnosis for disease staging and/or repeated in the course of the disease history, only if positive or for clinical reasons (i.e. suspicious of relapse progression). In this study sequential CSF and peripheral blood samples of study population will be collected also at different time points, with the aim to improve diagnostics sensitivity, response assessment and monitoring early CNS relapse.
Other: Control; Pts with suspicion of secondary CNS lymphoma, that includes subjects with DLBCL and involvement of the CNS at presentation in association with systemic disease, or subjects with systemic DLBCL and CNS relapse during or after primary therapy.; Pts with histological diagnosis of systemic DLBCL at high risk of CNS relapse according to Institutional guidelines and patients with histological diagnosis of systemic high grade B cell lymphoma, according to 2017 WHO classification;; pts affected by neurological disorders that are usually differential diagnosis of PCNSL (i.e. neurodegenerative and neuroinflammatory disorders, toxic or infective encephalitis, other primary CNS tumors).	Procedure: Lumbar puncture; A lumbar puncture (spinal tap) is performed in patient lower back, in the lumbar region. During a lumbar puncture, a needle is inserted between two lumbar bones (vertebrae) to remove a sample of cerebrospinal fluid (CSF). This is the fluid that surrounds brain and spinal cord to protect them from injury. This procedure is usually performed at the time of diagnosis for disease staging and/or repeated in the course of the disease history, only if positive or for clinical reasons (i.e. suspicious of relapse progression). In this study sequential CSF and peripheral blood samples of study population will be collected also at different time points, with the aim to improve diagnostics sensitivity, response assessment and monitoring early CNS relapse.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association between recurrent genetic alterations and PCNSL diagnosis or relapse	Frequency of various genetic mutations among enrolled patients at diagnosis or relapse	3 years and 6 months
Association between recurrent genetic alterations and residual enhanced and not-enhanced images at the MRI	Frequency of various genetic mutations among enrolled patients during treatment	3 years and 6 months

Collaborators and Investigators

• Sponsor: IRCCS San Raffaele
• Collaborators: Teresa Calimeri; Sara Steffanoni
• Investigators: Principal Investigator: Andrés J.M. Ferreri, MD, Irccs Ospedale San Raffaele

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2020
• Primary Completion (Estimated): July 31, 2026
• Study Completion (Estimated): April 30, 2027

Study Registration Dates

• First Submitted: May 7, 2021
• First Submitted That Met QC Criteria: August 31, 2021
• First Posted (Actual): September 5, 2021

Study Record Updates

• Last Update Posted (Actual): May 31, 2025
• Last Update Submitted That Met QC Criteria: May 27, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: ctDNA; CSF; PCNSL
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma
• Other Study ID Numbers: DOROTHEA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No