The purpose of this study is to find out how many people with B-cell lymphoma who are at high risk for central nervous system/CNS relapse test positive for cerebral spinal fluid/CSF ctDNA but test negative for CNS involvement using standard tests. The study will also look at how often CNS relapse happens in people with and without detected CSF ctDNA.

Inclusion Criteria:

• Signed Informed Consent.

• Ability and willingness to comply with the requirements of the study protocol.

• Age ≥ 18 years old.

• Diagnosis of the following histologies according to the 2016 WHO Classification for Mature Lymphoid Neoplasms81 along with a specific high-risk criteria for CNS relapse if indicated as certain diagnoses in of themselves are high-risk alone:

  1. Diffuse Large B-cell Lymphoma (DLBCL) with CNS IPI score ≥ 4.
  2. Stage III/IV High Grade B-cell lymphoma (HGBCL) with MYC, BCL2, and/or BCL6 translocations
  3. Primary DLBCL of Breast
  4. Primary DLBCL of Testis
  5. Primary Cutaneous DLBCL, Leg Type
  6. Intravascular Large B-cell Lymphoma
  7. Stage III/IV HIV-associated DLBCL
  8. Double expressor DLBCL (co-expression of MYC ≥ 40% and BCL2 ≥ 50% without translocations) with a CNS IPI score ≥ 3
  9. DLBCL with the following extranodal involvement AND CNS IPI score ≥ 3:

  i. Adrenal ii. Breast iii. Bone Marrow with pathological overt morphological involvement iv. Epidural/Paraspinal v. Nasal/parasinus with local invasion such as bone destruction vi. Renal viii. Uterine ix. Testis xi. Skull involvement without direct invasion into CNS/brain parenchyma

• Transformed DLBCL from any indolent B-cell lymphoma is permitted (as long as there is no prior history of CNS involvement).

• Planned to receive standard chemoimmunotherapy.

• Patient is able to undergo lumbar puncture without any contraindications which include but are not limited to altered mental status, increased intracranial pressure due to any CNS lesion (mass, abscess), overlying skin infection at the site of LP, inability to safely access CSF due to lymphomatous involvement (i.e. epidural mass), or inability to hold antiplatelet or anticoagulation safely for the procedure to be performed.

• No systemic therapy prior to study enrollment for an aggressive B-cell lymphoma is permitted. Treatment for a history of indolent lymphoma is permitted. Systemic corticosteroids are permitted (must be ≤7 days and tapered down to prednisone ≤ 20 mg oral/day or steroid equivalent by first day of anthracycline treatment). Clinical exceptions in regards to steroid management can be made after discussion with PI.

• ECOG performance status of 0 to 2.

Exclusion Criteria:

• Active systemic therapy for another malignancy (other than indolent B-cell lymphoma) within 2 years; local/regional therapy with curative intent such as surgical resection or localized radiation within 2 years of treatment is permitted.
• Active concurrent malignancy with the exception of basal cell or localized squamous cell skin carcinoma, localized prostate cancer, or other localized carcinomas such as carcinoma in situ of cervix, breast, or bladder.
• Any uncontrolled illness that in the opinion of the investigator would preclude administration of curative intent chemoimmunotherapy (e.g. significant active infections, hypertension, angina, arrhythmias, pulmonary disease, or autoimmune dysfunction).
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization within 2 weeks prior to Cycle 1, Day 1.
• Psychiatric illness or social situations that would limit the patient's ability to tolerate and/or comply with study requirements.

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.