Pembrolizumab in Combination With Chemotherapy for the Treatment of Frail Hodgkin Lymphoma Patients Ineligible for Standard Treatment

Inclusion Criteria:

* Documented informed consent of the participant and/or legally authorized representative

  * Assent, when appropriate, will be obtained per institutional guidelines
* Agreement to allow the use of archival tissue from diagnostic tumor biopsies

  * If unavailable, exceptions may be granted with study principal investigator (PI) approval
* Meets at least one of the following criteria indicating unsuitability for conventional anthracycline-based frontline chemotherapy, as determined by the investigator:

  * Age ≥ 75 years
  * Eastern Cooperative Oncology Group (ECOG) 2-4
  * Left ventricular ejection fraction (LVEF) \< 50%
  * Creatinine clearance \< 60 mL/min, using Cockcroft-Gault formula or equivalent
  * Pulmonary function impairment: forced expiratory volume in 1 second (FEV1) \< 50% and/or diffusion capacity of the lung for carbon monoxide (DLCO) \< 50%
* ECOG ≤ 2
* Age ≥ 18 years
* Histologically confirmed new diagnosis of classical Hodgkin lymphoma (excluding nodular lymphocyte predominant Hodgkin lymphoma) according to the World Health Organization (WHO) classification, with hematopathology review at the participating institution
* No prior systemic treatment for classical Hodgkin lymphoma with the following exceptions: a course of systemic corticosteroids for palliation of symptoms related to the classical Hodgkin lymphoma is allowed but must be stopped by cycle 1 day 1 (C1D1) as well as prior treatment with P-G as part of this clinical trial for patients will receive P-BV-D
* Measurable disease (at least one non-bone fludeoxyglucose F-18 \[FDG\]-avid lesion ≥ 1.5 cm in long axis)
* Absolute neutrophil count (ANC) ≥ 1,000/mm\^3

  * NOTE: Growth factor is not permitted within 7 days of ANC assessment unless cytopenia is secondary to disease involvement
* Platelets ≥ 50,000/mm\^3

  * NOTE: Platelet transfusions are not permitted within 7 days of platelet assessment unless cytopenia is secondary to disease involvement
* Total bilirubin ≤ 2 × upper limit of normal (ULN) or direct bilirubin ≤ 2 × ULN for patients with Gilbert's disease
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN
* AST and ALT ≤ 3 x ULN unless there is liver involvement by lymphoma in which case AST and ALT \< 5 x ULN
* For patients for whom P-BV-D therapy is planned, creatinine clearance of ≥ 30 mL/min per 24-hour urine test or the Cockcroft-Gault formula
* If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin (PT) ≤ 1.5 x ULN

  * If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants
* If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN

  * If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants
* Seronegative for hepatitis C virus (HCV), hepatitis B virus (HBV) (surface antigen negative) OR

  * If seropositive for HBV or HCV, nucleic acid quantitation must be performed. Viral load must be undetectable. Patients with occult or prior HBV infection (defined as negative hepatitis B virus surface antigen \[HBsAg\] and positive hepatitis B core antibody \[HBcAb\]) may be included if HBV DNA is undetectable, if they are willing to undergo DNA testing on day 1 of every cycle and every three months for at least 12 months after the last cycle of study treatment
* Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

  * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* A male participant must agree to use a contraception during the treatment period and for at least 6 months after the last dose of study treatment and refrain from donating sperm during this period
* A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

  * Not a woman of childbearing potential (WOCBP) OR
  * A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least (X days/weeks \[corresponding to time needed to eliminate any study treatment(s)\] \[pembrolizumab and/or any active comparator/combination\] plus 30 days \[a menstruation cycle\] for study treatments with risk of genotoxicity) after the last dose of study treatment
* TO PROCEED WITH SALVAGE TREATMENT: ECOG ≤ 2
* TO PROCEED WITH SALVAGE TREATMENT: Resolution of treatment-related adverse events (AEs) to baseline or grade 1, whichever is higher
* TO PROCEED WITH SALVAGE TREATMENT: Measurable disease (at least one non-bony FDG-avid lesion ≥ 1.5 cm in long axis)
* TO PROCEED WITH SALVAGE TREATMENT: Peripheral neuropathy ≤ grade 2
* TO PROCEED WITH SALVAGE TREATMENT: ANC ≥ 1,000/mm\^3

  * NOTE: Growth factors are permitted
* TO PROCEED WITH SALVAGE TREATMENT: Platelets ≥ 50,000/mm\^3

  * NOTE: Platelet transfusions are permitted
* TO PROCEED WITH SALVAGE TREATMENT: Hemoglobin ≥ 8 g/dL (no transfusion allowed within 3 days prior to screening)
* TO PROCEED WITH SALVAGE TREATMENT: Total bilirubin ≤ 2 x ULN or direct bilirubin ≤ 2 x ULN for patients with Gilbert's disease
* TO PROCEED WITH SALVAGE TREATMENT: AST ≤ 3 x ULN, or less then 5 x ULN for patients with liver involvement by lymphoma
* TO PROCEED WITH SALVAGE TREATMENT: ALT ≤ 3 x ULN, or less then 5 x ULN for patients with liver involvement by lymphoma
* TO PROCEED WITH SALVAGE TREATMENT: Creatinine clearance of ≥ 30 mL/min per 24-hour urine test or the Cockcroft-Gault formula

Exclusion Criteria:

* Concomitant investigational therapy
* Live vaccine within 30 days prior to day 1 of protocol therapy (e.g. measles, mumps, rubella, varicella, yellow fever, rabies, Bacille Calmette Guerin \[BCG\], oral polio vaccine, and oral typhoid)
* Grade ≥ 2 peripheral neuropathy
* Requirement for hemodialysis or peritoneal dialysis. Estimated glomerular filtration rate (EGFR) \> 30 for pembrolizumab + BV + dacarbazine
* Known active central nervous system (CNS) involvement by lymphoma including parenchymal and/or lymphomatous meningitis
* History of prior ≥ grade 3 hypersensitivity to either brentuximab vedotin or pembrolizumab
* Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)
* History of another primary malignancy that has been in remission for fewer than 3 years, with the following exceptions:

  * Non-melanoma skin cancer treated with curative intent
  * In situ cervical cancer
  * If the malignancy is expected to not require any systemic treatment for at least 2 years (this exception should be discussed with the study PI)
* Condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of study drug administration. Exceptions are:

  * Inhaled or topical steroids and
  * Adrenal replacement doses \> 10 mg daily prednisone equivalents in the absence of active autoimmune disease
  * Up to 7 days of 20 mg daily prednisone equivalent after C1D1 for management of lymphoma-related symptoms
* History of progressive multifocal leukoencephalopathy (PML)
* Active pneumonitis or interstitial lung disease
* Prior solid organ or allogeneic stem cell transplantation
* History of known or suspected hemophagocytic lymphohistiocytosis (HLH)
* Active, known or suspected autoimmune disease. The following are exceptions:

  * Vitiligo
  * Psoriasis not requiring systemic treatment
  * Hemolytic anemia associated with the lymphoma
  * Type I diabetes mellitus, if adequately controlled with therapy
  * Thyroid disease, if adequately controlled with therapy
  * Conditions not expected to recur in the absence of an external trigger (such exceptions should be discussed with the study PI)
* Active history of:

  * Hepatitis B (HBV) or C (HCV) infection. Patients with past HBV infection (defined as negative HBsAg and positive hepatitis B core antibody \[HBcAb\]) are eligible if HBV DNA is undetectable. Patients who are positive for HCV antibody are eligible if polymerase chain reaction (PCR) is negative for HCV RNA
* HIV positive
* History of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association class III-IV within 6 months prior to day 1 of protocol therapy
* Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
* Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)