The purpose of this additional part of the study is to test whether the study drug, nivolumab, is a safe treatment that will prevent participants' primary central nervous system lymphoma (PCNSL) from growing again (recurrence). Participants will be people with PCNSL who continue to have cell free tumor DNA (cfDNA) in their CSF despite completion of their first treatment (first-line treatment).

Inclusion Criteria:

Biospecimen and Data Collection:

• Histologically documented PCNSL with the ability to submit up to 20 unstained formalinfixed, paraffin embedded (FFPE) slides from the initial tissue diagnosis prior to study registration or histologically confirmed lymphomatous involvement of the CSF and/or eye/vitreous
• Patients must be able to tolerate MRI/CT scans with [18F FDG]
• Patients must be able to tolerate lumbar punctures and/or Ommaya taps

Additional Criteria for Nivolumab Maintenance Arm:

All criteria in the above "Biospecimen and Data Collection" section must be satisfied as well as:

• Persistent cfDNA in the CSF

• Participants must be able to understand and be willing to sign a written informed consent document

• Women and men who are at least 18 years of age on the day of consenting to the study

• KPS ≥60

• Life expectancy of > 3 months (in the opinion of the investigator)

• Participants must have adequate bone marrow and organ function shown by:

  • Absolute neutrophil count (ANC) ≥ 0.75 x 10^9/L
  • Platelets ≥ 75 x 10^9/L and no platelet transfusion within the past 21 days prior to study registration
  • Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past 21 days prior to study registration
  • International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper limit of normal. Patients on anticoagulants should be managed according to MSK SOPs as outlined in: 'Therapeutic Anticoagulation Guidelines in Adults' regarding management of anticoagulants prior to each CSF collection. Please discuss any complicated patient with the PI for consideration.
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal
  • Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3 times the upper limit of normal with direct bilirubin within the normal range in patients with well documented Gilbert Syndrome
  • Serum creatinine ≤ 2 times the upper limit of normal

• Women of reproductive potential must agree to use highly effective methods of birth control during the period of therapy and for 5 months after the last dose of the study drug. Men who are sexually active must agree to use highly effective contraception during the period of therapy and for 7 months after the last dose

• Women of childbearing potential must have a negative plasma pregnancy test upon study entry. See section on Pregnancy and Reproduction

Exclusion Criteria:

Biospecimen and Data Collection:

• Patients with recurrent/refractory PCNSL. Patients with stable disease as their best response to first-line chemotherapy will also come off study.
• Patient with systemic, non-CNS lymphoma metastatic to the CNS
• Patient is known to have human immunodeficiency virus (HIV) infection
• Patient is known to have a history of active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) as determined by serologic tests
• Patient's who are planned to undergo consolidation with autologous HSCT

Additional Criteria for Nivolumab Maintenance Arm:

None of the criteria in the above "Biospecimen and Data Collection" section can be present. The following criteria must also not be present:

• Patient has undergone prior allogenic stem cell transplant
• Patient's who are planned to undergo consolidation with autologous HSCT
• Any chemotherapy, external beam radiation therapy, or anticancer antibodies within 14 days of the first dose of study drug
• Patient is allergic to components of the study drug
• Patient is concurrently using other approved or investigational antineoplastic agents
• Previous or current treatment with an anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PDL2 agent
• Patient has an active concurrent malignancy requiring active therapy
• Patient is requiring escalating or chronic supraphysiologic doses of corticosteroids (> 8 mg dexamethasone daily) for control of disease at the time of registration
• Patient is using systemic immunosuppressant therapy including: cyclosporine A, tacrolimus, sirolimus, and other such medications, or chronic administration of > 5 mg/day of prednisone or the equivalent. Participants must be off immunosuppressant therapy for at least 28 days prior to the first dose of the study drug
• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Known history of, or any evidence of active, non-infectious pneumonitis
• Patient has significant abnormalities on screening electrocardiogram (EKG) and active and significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, uncontrolled congestive heart failure, uncontrolled hypertension, valvular disease, pericarditis, or myocardial infarction within 6 months of screening
• Peptic ulcer, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within past 6 months
• Patient is known to have an uncontrolled active systemic infection
• Patient has a life-threatening illness, medical condition, or organ system dysfunction that, in the opinion of the investigator, could compromise the subject's safety or put the study outcomes at undue risk
• Women who are pregnant or nursing (lactating), where pregnancy is defined as a state of a female after conception until the termination of gestation, confirmed by a positive plasma hCG laboratory test of > 5 mIU/mL (See section on Pregnancy and Reproduction)
• The patient is unwell or unable to participate in all required study evaluations and procedures
• Participants who have received a live / attenuated vaccine within 30 days of first treatment.

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.