The study is a prospective clinical study which investigates the use of new diagnostic methods to localize aggressive lymphoma involving the central nervous system(CNS). By measuring cell-free tumor DNA and metabolomics in cerebrospinal fluid and blood in patients with systemic Diffuse Large B-cell Lymphoma the investigators aim to improve the diagnostic certainty of an impending relapse of lymphoma in CNS.

Diffuse Large B-cell Lymphoma is a malignant, aggressive cancer representing 40% of Non-Hodgkin Lymphomas globally. The risk of relapse after primary treatment is approximately 30% of which up to 10 % occurs in the central nervous system (CNS). The prognosis after CNS relapse is severely discouraging with an overall survival of 3-6 months. Currently CNS relapse is diagnosed by either flow cytometry performed on cerebrospinal fluid or a stereotactic biopsy based on tumor localization by an MRI scan. Both diagnostic methods however require a certain tumor mass in order avoid false negative test results.

The purpose of this study is to learn whether tumor-derived cell-free circulating DNA (cfDNA) and/or metabolite profiles from diffuse large B-cell lymphoma (DLBCL) cells can be identified in the cerebrospinal fluid (CSF), before the malignant cells themselves are detectable in CSF. Thus the investigators aim to investigate the diagnostic potential of cfDNA and/or metabolites measured in blood and cerebrospinal fluid. The study is based on the following four hypotheses:

Hypothesis 1: Measurement of cfDNA and/or metabolites in CSF are more sensitive methods of detecting DLBCL involvement in CNS compared to conventional diagnostics.

Hypothesis 2: Quantitative cfDNA/metabolomics in CSF has independent prognostic value in DLBCL.

Hypothesis 3: cfDNA and/or metabolite profile in CSF detected at primary diagnosis predicts relapse of DLBCL in the CNS also when CNS-IPI is taken into account.

Hypothesis 4: Particular aberrations of cfDNA and/or metabolite profiles detected in blood (plasma) may, in some cases, be associated with CNS involvement in DLBCL patients and/or predict CNS relapse.

The study is composed of a pilot study including 5 patients with verified either primary or secondary CNS lymphoma followed by two studies: One including 40 patients with de novo DLBCL and one including 30 patients in a relapse setting. The patients will have to consent to having a lumbar puncture performed and blood samples taken before treatment initiation. After treatment a second set of lumbar puncture and blood samples will be requested.

Pilot Study:

Inclusion criteria:

1. Verified or suspected primary CNS lymphoma or verified or suspected DLBCL relapsed in the CNS
2. Treatment of the relapse not initiated (except pretreatment with corticosteroids)
3. Age ≥ 18 years
4. Patient must consent to genetic and metabolomic analysis of their cancer
5. Written informed consent

Exclusion criteria:

1. Evidence of a CNS mass creating mass-effect or midline shift such that lumbar puncture is contraindicated
2. Other contraindications to lumbar puncture according to local guidelines
3. Other previous or current hematological malignancy
4. Prior treatment for CNS disease (except CNS prophylaxis in first line lymphoma treatment)
5. Known CNS autoimmune or inflammatory disease
6. Known HIV infection
7. Patient is currently receiving treatment for DLBCL

Study 1

Inclusion criteria:

1. Previously diagnosed histologically documented DLBCL
2. Verified relapsed DLBCL
3. ≥ 1 prior DLBCL treatments
4. Treatment of the relapse not initiated (except pretreatment with corticosteroids)
5. Being able to undergo standard assessment ( eg, Fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG-PET), MRI of the neuroaxis and bone marrow biopsy)
6. Tumor biopsy and/or bone-marrow biopsy used for diagnosis available
7. Age ≥ 18 years
8. ECOG performance status of 0, 1 or 2
9. Life expectancy ≥ 12 weeks
10. Patient must consent to permit genetic and metabolomic analysis of their cancer
11. Patient must consent to permit access to records in order to ascertain progression or relapse of their cancer
12. Written informed consent

Exclusion criteria:

1. Evidence of a CNS mass creating mass-effect or midline shift such that lumbar puncture is contraindicated
2. Other contraindications to lumbar puncture according to local guidelines
3. Other previous or current hematological malignancy
4. Previous or current primary CNS malignancy including know DLBCL relapse to the CNS
5. Prior treatment for CNS disease (except CNS prophylaxis in first line lymphoma treatment)
6. Known CNS autoimmune or inflammatory disease
7. Known HIV infection
8. Patient is currently receiving treatment for DLBCL (except pretreatment with corticosteroids)

Study 2

Inclusion criteria:

1. A newly diagnosed and histologically verified DLBCL
2. No prior DLBCL treatments
3. Anti-lymphoma treatment not initiated (except pretreatment with corticosteroids)
4. CNS-IPI >/= 3
5. Being able to undergo standard assessment ( eg, Fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG-PET), MRI of the neuroaxis and bone marrow biopsy)
6. Tumor biopsy and/or bone-marrow biopsy used for diagnosis available
7. Age ≥ 18 years
8. ECOG performance status of 0, 1 or 2
9. Life expectancy >/= 12 weeks
10. Patient must consent to permit genetic analysis of their cancer
11. Patient must consent to permit access to records in order to ascertain progression or relapse of their cancer
12. Written informed consent

Exclusion criteria:

1. Evidence of a CNS mass creating mass-effect or midline shift such that lumbar puncture is contraindicated
2. Other contraindications to lumbar puncture according to local guidelines
3. Other previous or current hematological malignancy
4. Previous or current primary CNS malignancy including primary CNS lymphoma
5. Prior treatment for CNS disease
6. Known CNS autoimmune or inflammatory disease
7. Known HIV infection
8. Patient is currently receiving treatment for DLBCL (except pretreatment with corticosteroids)

See above