Pidilizumab in Treating Patients With Stage III-IV Diffuse Large B-Cell Lymphoma Following First Remission

Inclusion Criteria:

* Histologically confirmed de novo DLBCL by the 4th edition of the World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues published in 2008; patients with transform lymphoma are excluded; patients with known primary mediastinal large B-cell lymphoma (PMLBCL) are excluded; patients with known c-v-myc avian myelocytomatosis viral oncogene homolog (c-myc) translocation (by fluorescence in situ hybridization) positive DLBCL are eligible for enrollment; c-myc testing prior to study enrollment is not required; availability of diagnostic biopsy samples in encouraged for the exploratory analysis but not required for enrollment; patients with "double-hit" or "triple-hit" lymphoma are eligible for enrollment
* Previously completed anthracycline-based induction chemotherapy with standard regimens including rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP), dose adjusted (DA)-etoposide, prednisone, vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide (EPOCH), and rituximab (R), and R-hyper cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate, and cytarabine (CVAD); patients need a minimum of 6 cycles of treatment; initial treatment with pidilizumab must be administered between 30-90 days from last dose of induction chemotherapy
* Complete remission (CR) according to the Revised Response Criteria for Malignant Lymphoma after first-line treatment

  * Diagnostic CT scans with contrast of chest, abdomen, and pelvis must have been performed within 8 weeks from the first day of the last cycle of R-chemotherapy; a neck CT will be required if the patient had involvement of the neck region at initial diagnosis
  * A negative fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)/CT scan performed within 8 weeks from the first day of the last cycle of R-chemotherapy and confirming CR, with negative defined as a score of 1-3 on the Deauville 5-point scale used to quantify radionucleotide density in PET scans as determined locally; PET positive/indeterminate lesions which are confirmed on biopsy to harbor no active lymphoma will be considered negative for determination of CR status
  * If positive bone marrow involvement at initial diagnosis the patient must have a negative bone marrow biopsy following R-chemotherapy to confirm the CR
* Stage III/IV disease by Ann Arbor Staging
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
* Any National Comprehensive Cancer Network (NCCN)-International Prognostic Index (IPI) score; a calculated score required for enrollment
* Absolute neutrophil count (ANC) \>= 1000
* Platelet count \>= 50,000
* Total bilirubin =\< 2 x upper limit of normal (ULN) or if total bilirubin is \> 2 x ULN, the direct bilirubin must be normal
* Alkaline (Alk.) phosphatase =\< 3 x ULN
* Aspartate aminotransferase (AST) =\< 3 x ULN
* Creatinine =\< 2 x ULN or creatinine clearance (CrCl) \> 30 ml/min
* Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test at enrollment; FCBP must either commit to abstinence from heterosexual intercourse or commit to the use of 2 acceptable methods of birth control; a FCBP is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
* Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy
* All subjects must have given signed, informed consent prior to registration on study

Exclusion Criteria:

* Active malignancy requiring therapy such as radiation, chemotherapy, or immunotherapy; exceptions to this are as follows: localized nonmelanotic skin cancer and any cancer that in the judgment of the investigator has been treated with curative intent and will not interfere with the study treatment plan and response assessment
* Known central nervous system (CNS) involvement
* Prior stem cell transplantation (autologous or allogeneic)
* Persistent diarrhea or malabsorption \> National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade 2, despite medical management
* Subjects with known immunodeficiency, known autoimmune disease, or concurrent use of immunomodulatory agents
* Any cancer directed therapies between completion of induction chemotherapy and treatment on protocol
* Known hypersensitivity to murine or chimeric antibodies or proteins
* Presence of co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens; this includes, 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
* Subjects with known human immunodeficiency virus (HIV) infection
* Subjects with known active hepatitis B virus (HBV) and hepatitis C virus (HCV) infection
* Women must not be pregnant or breast-feeding
* Unwillingness or inability to comply with the protocol