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

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

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)

What this study is about