Pembrolizumab in Untreated B-Cell Non-Hodgkin Lymphoproliferative Diseases

Inclusion Criteria:

* Be willing and able to provide written informed consent/assent for the trial
* Must have measurable disease defined by at least one of the following criteria:

  \* Lesions greater than 1.5 cm that can be accurately measured in two dimensions by computed tomography (CT) (preferred), or magnetic resonance imaging (MRI)
* Must have indication for treatment (adapted from National Comprehensive Cancer Network \[NCCN\] 2015 guidelines)

  \* Any of the following constitute an indication for treatment:
  * Significant symptoms due to any iBCL: Which may include pain/discomfort, limitation of function, fatigue/malaise/constitutional symptoms, B-symptoms (fever, weight loss, night sweats), pruritus
  * Threatened end-organ function due to any iBCL
  * Progressive cytopenia secondary to any iBCL
  * Steady progression of follicular lymphoma (FL) and marginal zone lymphoma (MZL)
* Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
* Absolute neutrophil count (ANC) \>= 500/uL Note: Growth factor and/or transfusion support is permissible to stabilize participant prior to study treatment if needed. No lower limit if cytopenia is related to bone marrow involvement.
* Platelets \>= 25000/uL Note: Growth factor and/or transfusion support is permissible to stabilize participant prior to study treatment if needed. No lower limit if cytopenia is related to bone marrow involvement.
* Hemoglobin \>= 8 g/dL Note: Growth factor and/or transfusion support is permissible to stabilize participant prior to study treatment if needed. No lower limit if cytopenia is related to bone marrow involvement.
* Serum creatinine =\< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate \[GFR\] can also be used in place of creatinine or creatinine clearance \[CrCl\]) \>= 30 mL/min for participant with creatinine levels \> 1.5 x institutional ULN (GFR can also be used in place of creatinine or CrCl)

  \* Creatinine clearance should be calculated per institutional standard
* Serum total bilirubin =\< 1.5 x ULN OR direct bilirubin =\< ULN for participants with total bilirubin levels \> 1.5 x ULN
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x ULN ( =\< 5 x ULN for participants with liver metastases)
* International normalized ratio (INR) or prothrombin time (PT) =\< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
* Activated partial thromboplastin time (aPTT) =\< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
* Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year
* Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy

Exclusion Criteria:

* Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
* Has a known history of active TB (Bacillus tuberculosis)
* Hypersensitivity to pembrolizumab or any of its excipients
* Has had prior chemotherapy, radiation therapy, or immunotherapy for the diagnosis of iBCL
* Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Has 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
* Has known history of, or any evidence of active, non-infectious pneumonitis
* Has an active infection requiring systemic therapy
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
* Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
* Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
* Has known active hepatitis B (e.g., hepatitis B surface antigen \[HBsAg\] reactive) or hepatitis C (e.g., hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] \[qualitative\] is detected)
* Be in urgent need of therapy for lymphoma related complications (such as hyperviscosity syndrome) and those with bulky disease
* Has received a live vaccine within 30 days of planned start of study therapy

  * Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed