This is a phase II study using risk and response-adapted therapy for low, intermediate and high risk classical Hodgkin lymphoma. Chemotherapy regimens will be based on risk group assignment. Low-risk and intermediate- risk patients will be treated with bendamustine, etoposide, Adriamycin® (doxorubicin), bleomycin, Oncovin® (vincristine), vinblastine, and prednisone (BEABOVP) chemotherapy. High-risk patients will receive Adcetris® (brentuximab vedotin), etoposide, prednisone and Adriamycin® (doxorubicin) (AEPA) and cyclophosphamide, Adcetris® (brentuximab vedotin), prednisone and Dacarbazine® (DTIC) (CAPDac) chemotherapy. Residual node radiotherapy will be given at the end of all chemotherapy only to involved nodes that do not have an adequate response (AR) after 2 cycles of therapy for all risk groups.

PRIMARY OBJECTIVES

• To evaluate the efficacy (adequate response) after 2 cycles of BEABOVP (bendamustine substitution for mechlorethamine in the original Stanford V chemotherapy backbone) in low-risk and intermediate-risk patients with classical Hodgkin lymphoma (cHL).
• To estimate the event-free survival in high-risk patients with classical Hodgkin lymphoma (cHL).

SECONDARY OBJECTIVES

• To describe the acute hematologic and infectious toxicities of BEABOVP (bendamustine substitution for mechlorethamine in the original Stanford V chemotherapy backbone) in patients with low-risk and intermediate- risk cHL as they relate to transfusion requirements, hematopoietic growth factor support, episodes of febrile neutropenia and hospitalizations, according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
• To describe the acute hematologic, neuropathic, and infectious toxicities of AEPA/CAPDac in patients with high-risk cHL as they relate to transfusion requirements, hematopoietic growth factor support, episodes of grade 3 and 4 sensory or motor neuropathy, episodes of febrile neutropenia and hospitalizations, according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
• To evaluate patterns of failure in irradiated and non-irradiated patients.
• To estimate the EFS functions of LR and IR patients, and compare with those in previously published studies.
• To estimate the response rate in HR patients and compare with historical and literature rates.
• To compare response rates in LR and IR patients with historical and literature rates.
• To compare the EFS function of HR patients with that in previously published studies.

EXPLORATORY OBJECTIVES

• To evaluate the plasma pharmacokinetics of bendamustine along with predictors of its variability when used as part of BEABOVP regimen for pediatric cHL patients

• To explore the patterns and dynamics of T-cell clonality in classical Hodgkin lymphoma

• To explore the association between TARC, total metabolic tumor volume, stage, risk group and treatment response.

• To establish next generation sequencing of ctDNA as a reliable method of non-invasively profiling tumor-associated mutations in pediatric patients with HL.

• To determine if kinetics of ctDNA in patients with pediatric HL during treatment are predictive of outcome.

• To obtain baseline testing by St. Jude Lifetime Study (SJLIFE) to allow for enhanced survivorship follow-up:

  • Neurologic testing
  • Neurocognitive testing
  • Quantitative brain imaging
  • Polysomnography
  • Cardiovascular testing (valvular testing, arterial elasticity, carotid-femoral pulse wave velocity, orthostatic hypotension, heart rate variability
  • Neuropathy screening
  • Changes in body mass index composition during therapy

Low-risk and Intermediate-risk: Low-risk patients will receive 2 cycles of BEABOVP and Intermediate-risk patients will receive 3 cycles of BEABOVP.

BEABOVP regimen: Patients will receive bendamustine day 1, etoposide day 15, Adriamycin® (doxorubicin) days 1 and 15, bleomycin days 8 and 22, Oncovin® (vincristine) days 8 and 22, vinblastine days 1 and 15, and prednisone two or three times per day every other day of each cycle for a total of 14 days of steroids.

High-risk patients will receive 2 cycles of AEPA and 4 cycles of CAPDac.

AEPA regimen: Patients will receive Adcedris® (brentuximab vedotin) days 1, 8 and 15, etoposide days 1 to 5, prednisone two or three times daily days 1 to 15 and Adriamycin® (doxorubicin) days 1 and 15.

CAPDac regimen: Patients will receive cyclophosphamide days 1 and 8, Adcetris® (brentuximab vedotin) days 1 and 8, prednisone two or three times daily days 1 to 15 and Dacarbazine® (DTIC) days 1 to 3.

Residual node radiotherapy will be given at the end of all chemotherapy only to involved nodes that do not have an AR after 2 cycles of therapy for all risk groups.

Steroids will be omitted after 2 cycles for any IR or HR patient with an AR after 2 cycles of therapy.

Inclusion Criteria:

• Histologically confirmed, previously untreated CD30+ classical HL. (Participants are still eligible if they received limited emergent RT or steroid therapy - maximum of 7 days if within the last month or as approved by PI).

• Age ≤ 21 years at the time of diagnosis (i.e., participants are eligible until their 22nd birthday) for low-risk and intermediate-risk

• Age ≤ 25 years at the time of diagnosis (i.e., participants are eligible until their 26th birthday) for high-risk

• All Ann Arbor stages.

  • Low-Risk: IA, IIA (excluding patients with "E" lesions or mediastinal bulk)
  • Intermediate-Risk: IA or IIA with "E" lesions or bulky mediastinal adenopathy (mediastinal mass to thoracic cavity ratio 33% or greater by chest radiograph) and IB, IIIA.
  • High-Risk: IIB, IIIB, IV

• Adequate renal function based on GFR ≥ 70 ml/min/1.73m2 OR serum creatinine adjusted for age and gender as follows: Age 1 to < 2 years: maximum serum creatinine 0.6 mg/dL for males and 0.6 mg/dL for females, Age 2 to < 6 years: maximum serum creatinine 0.8 mg/dL for males and 0.8 mg/dL for females, Age 6 to < 10 years: maximum serum creatinine 1 mg/dL for males and 1 mg/dL for females, Age 10 to < 13 years: maximum serum creatinine 1.2 mg/dL for males and 1.2 mg/dL for females, Age 13 to < 16 years: maximum serum creatinine 1.5 mg/dL for males and 1.4 mg/dL for females, Age ≥16 years: maximum serum creatinine 1.7 mg/dL for males and 1.4 mg/dL for females

• Adequate hepatic function (total bilirubin ≤ 1.5 x ULN for age, and AST/ALT ≤ 2.5 x ULN for age).

• Adequate hematologic criteria at baseline, unless secondary to Hodgkin disease diagnosis

  • Absolute neutrophil count (ANC) ≥1000/µL
  • Platelets ≥ 75,000/µL

• Adequate cardiac function defined as shortening fraction of ≥ 27% by echocardiogram or MUGA, unless decreased function is due to large mediastinal mass or effusion related to HL.

• Adequate pulmonary function defined as no evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 92% on room air unless secondary to a large mediastinal mass or effusion related to HL.

• Female participant who is post-menarchal must have a negative urine or serum pregnancy test.

• Female or male participant of reproductive potential must agree to use an effective contraceptive method throughout duration of study treatment.

Exclusion Criteria:

• CD30 negative HL.
• Has received prior therapy for Hodgkin lymphoma
• Inadequate organ function
• High-risk participants with a history of ≥ grade 2 peripheral neuropathy or any active neurologic disease that would impede the ability to assess neurologic toxicities.
• Inability or unwillingness of research participant or legal guardian / representative to give written informed consent.