Patients suffering from diffuse large B-cell lymphoma (DLBCL) who relapse within 12 months of chemotherapy usually undergo salvage therapies, followed by autologous transplant with a low success rate. These treatments for relapse have significant toxicities and may not be tolerated well by the patients. These patients need an effective means of identifying relapse at an early time point to be treated effectively. Detection of circulating tumor DNA (ctDNA) has been reported to be a sensitive and more specific method to detect relapse at an early stage compared to PET/ CT scans. Purpose of this trial is to monitor patients who have undergone successful chemotherapy for the presence of ctDNA. Patients who test positive for ctDNA would be treated with Nivolumab for a period of 2 years to avoid complete relapse.

Primary Objective:

To determine if nivolumab administration, as a maintenance strategy in DLBCL patients with high risk of relapse, can convert positive ctDNA to negative ctDNA and/or result in relapse free survival (RFS-ctDNA) of 9 months or longer after positive ctDNA was documented.

Secondary Objectives:

1. To evaluate safety of nivolumab as maintenance drug in post-induction, post-salvage and post-autologous transplant setting
2. Relapse free survival (RFS-ctDNA) for nivolumab treated patients
3. Proportion of patients who are able to convert from ctDNA positive to ctDNA negative after nivolumab treatment
4. To validate NeoLabs assay platform by comparing the results to Clonoseq platform.

Inclusion Criteria:

• Patients must have a tissue diagnosis of diffuse large B cell lymphoma, with a negative PET/CT scan performed within 28 days of study enrollment, with one of the following clinical features: high risk IPI, ABC-subtype DLBCL, Double hit/ triple hit DLBCL, Ki67>90%, or MYC translocation.

• Patients can have any number of prior therapies and any amount of time period from the last therapy as long as they have complete response as seen in PET/CT at the time of enrolment.

• Patients with prior salvage chemo-immunotherapy, radiation therapy, autologous transplantation are included

• Prior radiation therapy must be completed at least 2 weeks prior to study enrollment

• Autologous transplant must have been done 100 days prior to the study enrollment

• Age > 18 years.

• ECOG performance status ≤ 2

• Life expectancy of at least 3 months

• A formalin fixed tissue block or equivalent of 24 slides of the tumor sample for analyses by Adaptive Sequenta and NeoGenomics must be available for analysis.

• Patients must be off cancer-directed therapy for at least 3 weeks (2 weeks for oral agents prior to day 1 of the study

• Patients must have suitable organ and marrow function as defined below

  • Absolute neutrophil count > 500/mm3
  • Platelets > 20,000/mm3
  • Total bilirubin < 2.5 times the ULN
  • AST/ALT (SGOT/SGPT) < 2 times institutional normal limits
  • Creatinine ≤1.5 times normal institutional limits OR
  • Creatinine clearance > 40 ml/min for patients

• Ability to understand and willingness to sign a written informed consent and HIPAA consent document

• WOCBP and sexually active, non-sterile men must be willing to use acceptable method of contraception. WOCBP must agree to not get pregnant and sexually active, non-sterile men must agree not to impregnate a woman for at least 18 weeks after the last dose of nivolumab

Exclusion Criteria:

• Patients with second malignancies (except monoclonal B cells of undetermined significance, antecendant indolent non Hodgkin lymphoma, non-melanomatous skin cancers, papillary thyroid carcinomas, ductal carcinoma in-situ, superficial bladder cancer, prostate cancer or in situ cervical cancers) are excluded unless a complete remission was achieved at least 3 years prior to enrollment and no additional therapy is required or anticipated to be required during the treatment.
• Subjects with active autoimmune disease or a syndrome that requires systemic corticosteroids
• Subjects who received non-oncology vaccine therapies for prevention of infectious disease within 4 weeks of study drug administration.
• Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent
• Any contraindication to therapy with nivolumab
• Prior allogeneic transplantation
• Known hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Patients with documented cure from HCV infection will be included
• Known uncontrolled human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS). Patients with documented controlled HIV infection (CD4 > 200 and undetectable viral load) will be included.
• Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease.
• History of anaphylactic reaction to monoclonal antibody therapy
• Poor psychiatric risk
• Patients receiving other investigational agents
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant or breast feeding. Refer to section 4.4 for further details