Phase II Study of Pidilizumab (MDV9300) in Patients With Diffuse Large B-Cell Lymphoma Following First Remission

• 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