Personalized Reduction of Chemotherapy Intensity Through ctDNA Evaluation for the Treatment of Patients With Advanced Hodgkin Lymphoma

Inclusion Criteria:

* Classical Hodgkin lymphoma without prior systemic therapy, stage 3 or 4. Corticosteroids for symptom relief are allowed
* Measurable disease per Lugano criteria
* Patients must be appropriate candidates for 6 cycles of combination chemotherapy including an anthracycline
* No evidence of active central nervous system lymphoma
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Absolute neutrophil count (ANC) ≥ 500/mm\^3. Growth factor and/or transfusion support is permissible to stabilize participant prior to study treatment if needed. There is no lower limit to cytopenias if related to bone marrow involvement or underlying Hodgkin lymphoma
* Platelets ≥ 50,000/mm\^3 (without transfusion or growth factor support). Growth factor and/or transfusion support is permissible to stabilize participant prior to study treatment if needed. There is no lower limit to cytopenias if related to bone marrow involvement or underlying Hodgkin lymphoma
* Hemoglobin ≥ 8 g/dL. Growth factor and/or transfusion support is permissible to stabilize participant prior to study treatment if needed. There is no lower limit to cytopenias if related to bone marrow involvement or underlying Hodgkin lymphoma
* Serum creatinine \< 1.5 x upper limits of normal (ULN) or creatinine clearance greater than 30/ml per minute by Cockcroft Gault formula
* Total bilirubin ≤ 1.5 times upper limit of normal OR direct bilirubin ≤ ULN for participants with total bilirubin levels \> 1.5 × ULN). Patients with Gilbert Syndrome and direct bilirubin \< 1.5 x ULN or confirmatory UGT1A1 testing are allowed to enroll
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times upper limit of normal (≤ 5 × ULN for participants with liver involvement)
* Patients must be age 18 or older
* All patients must be informed of the investigational nature of this study and have given written consent in accordance with institutional and federal guidelines
* Patients must be anticipated to complete all planned study therapy
* Male patients who are not surgically sterile, including those who have not undergone vasectomy with documented azoospermia or other confirmed sterilization, and who have a partner of childbearing potential must agree that they and/or their partner will use effective contraception beginning with the first dose of study therapy and continuing through 120 days after the last dose of study therapy. Acceptable methods include participant use of barrier contraception and/or partner use of a highly effective contraceptive method, including an intrauterine device or system, hormonal implant, bilateral tubal occlusion, or other methods considered highly effective according to institutional standards. Partners who are not of childbearing potential, including those who are surgically sterile or postmenopausal, do not necessitate contraception by the participant for pregnancy prevention
* Female patients of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine pregnancy test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Patients with recent fertility preservation may falsely test human chorionic gonadotropin (HCG) positive, and may be allowed on study with principal investigator (PI) approval
* Female patients of childbearing potential must agree to use effective contraception or abstain from heterosexual activity beginning with the first dose of study therapy and continuing through 120 days after the last dose of study medication. Acceptable methods include two methods of birth control, one of which may be a barrier method, or a highly effective contraceptive method such as an intrauterine device or system, hormonal implant, bilateral tubal occlusion, or other methods considered highly effective according to institutional standards. Female patients are considered not of childbearing potential if they have been surgically sterilized or have been free from menses for more than 1 year

Exclusion Criteria:

* Patients known positive for HIV or infectious hepatitis type B or C with a detectable viral load may not participate. Hepatitis B/C, and HIV testing are not required at screening unless mandated by local health authority.

  * Patients living with HIV, on anti-viral treatment and undetectable viral load are allowed
  * Patients with positive hepatitis (hep) B core antibody are allowed on study with an undetectable viral load and appropriate prophylaxis
  * Patients with positive hepatitis C antibody are allowed with undetectable viral load
* Pregnant or nursing women. Men or women of reproductive potential may not participate unless they have agreed to use an effective contraceptive method
* Patients with other prior malignancies except for adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, breast or cervical cancer in situ, or other cancer from which the patient has been disease-free for 2 years or greater, unless approved by the principal investigator
* Patients who have other medical conditions that would contraindicate treatment with aggressive chemotherapy (including active infection, uncontrolled hypertension, congestive heart failure, unstable angina pectoris, or myocardial infarction within the past 6 months, uncontrolled arrhythmia, severe pulmonary disease or requirement of supplemental oxygen)
* Active ischemic heart disease (eg. myocardial infarction within 6 months) or congestive heart failure (eg. left ventricular ejection fraction \< 50%)
* Concurrent use of other anti-cancer agents or experimental treatments
* Known current or prior autoimmune disease with the exception of vitiligo. Patients with a history of autoimmune thyroid disease on a stable dose of thyroid hormone are also allowed
* Active or prior history of pneumonitis/interstitial lung disease that required corticosteroids
* Current use of supplemental oxygen
* Is known to have received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of trial treatment. Other non-live or live-attenuated vaccines (eg. COVID, Influenza) are allowed