This phase III trial is studying how well giving combination chemotherapy together with radiation therapy works in treating young patients with newly diagnosed Hodgkin lymphoma. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high energy x-rays to kill cancer cells. Giving combination chemotherapy together with radiation therapy may kill more cancer cells.

PRIMARY OBJECTIVES:

I. To maintain the overall survival (as defined by 4-year "second-event" free survival) for subjects with high risk Hodgkin lymphoma at or above 95%.

SECONDARY OBJECTIVES:

I. To maintain 3-year event-free survival for subjects with high risk Hodgkin lymphoma at or above 93%.

II. To maintain comparable overall survival (as defined by 4-year "second-event" free survival) between subjects with high risk Hodgkin lymphoma who have a rapid or slow response to the initial 2 cycles of ABVE-PC* by intensifying therapy through the addition of 2 cycles of ifosfamide/vinorelbine in those with a slow early response.

III. To investigate whether very early response assessment measured by FDG-PET after 1 cycle of chemotherapy identifies a subject cohort that can be studied in future trials and that is distinguishable from currently defined RER after 2 cycles.

IV. To describe the patterns of relapse after ABVE-PC* and risk-adapted radiotherapy.

OUTLINE: This is a multicenter study.

INDUCTION THERAPY (ABVE-PC): Patients receive doxorubicin hydrochloride IV over 1-120 minutes and cyclophosphamide IV over 30-60 minutes on days 1 and 2, bleomycin sulfate IV over at least 10 minutes or subcutaneously (SC) and vincristine sulfate IV on days 1 and 8, etoposide phosphate IV over 1-2 hours on days 1-3, oral prednisone twice daily on days 1-7, and filgrastim* SC or IV daily beginning on day 4 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses in the absence of unacceptable toxicity or disease progression.

NOTE: *Patients do not receive filgrastim on day 8.

Patients undergo clinical restaging and response assessment after 2 courses of induction therapy. Patients with rapid early response (RER) or slow early response (SER) proceed to consolidation therapy. Patients with progressive disease go off study.

CONSOLIDATION THERAPY: Patients are assigned to 1 of 2 consolidation therapy regimens based on response to induction therapy. Patients who develop progressive disease after induction are taken off protocol therapy.

REGIMEN I (RER): Patients receive 2 more courses of ABVE-PC in the absence of unacceptable toxicity or disease progression.

REGIMEN II (SER): Patients receive ifosfamide IV continuously on days 1-4, vinorelbine ditartrate IV over 6-30 minutes on days 1 and 5, and filgrastim SC or IV daily beginning on day 6 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses in the absence of unacceptable toxicity or disease progression. Patients then receive 2 more courses of ABVE-PC in the absence of unacceptable toxicity or disease progression.

Patients with a continued response after completion of consolidation therapy proceed to risk-adapted radiotherapy.

RISK-ADAPTED RADIOTHERAPY: Beginning at 3 weeks after completion of consolidation chemotherapy, patients undergo radiotherapy once daily, 5 days a week, for 3 weeks (14 fractions) in the absence of unacceptable toxicity or disease progression. Patients classified as RER receive radiation therapy only to sites of bulky disease. Patients classified as SER receive radiation therapy to sites of bulky disease and areas that remain FDG-PET avid after induction therapy.

After completion of study therapy, patients are followed up periodically for 10 years.

Inclusion Criteria:

• Pathologically confirmed newly diagnosed Hodgkin lymphoma (HL) meeting one of the following criteria:

  • Classical disease
  • Nodular lymphocyte-predominant disease

• Stage III or IV disease with B symptoms, as defined by ≥ 1 of the following:

  • Unexplained weight loss > 10% within the past 6 months
  • Unexplained recurrent fever > 38°C within the past month
  • Recurrent drenching night sweats within the past month

• Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR maximum serum creatinine based on age/gender as follows:

  • 0.4 mg/dL (1 to 5 months)
  • 0.5 mg/dL (6 to 11 months)
  • 0.6 mg/dL (12 to 23 months)
  • 0.8 mg/dL (2 to 5 years)
  • 1 mg/dL (6 to 9 years)
  • 1.2 mg/dL (10 to 12 years)
  • 1.5 mg/dL (males) or 1.4 mg/dL (females) (13 to 15 years)
  • 1.7 mg/dL (males) or 1.4 mg/dL (females) (≥ 16 years)

• Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age

• AST or ALT < 2.5 times ULN for age

• Shortening fraction ≥ 27% by ECHO OR ejection fraction ≥ 50% by MUGA (unless due to large mediastinal mass from HL)

• FEV_1/FVC > 60% by pulmonary function tests (PFT) (unless due to large mediastinal mass fromHL)

  • For children who are unable to cooperate for PFTs, the criteria are:

    • No evidence of dyspnea at rest
    • No exercise intolerance
    • Pulse oximetry > 92% on room air

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No pathologic prolongation of QTc interval (> 450 milliseconds) on 12-lead ECG

• No prior chemotherapy, biological response modifiers (e.g., monoclonal antibody therapy), or radiotherapy

• At least 28 days since prior corticosteroids except for emergent treatment for respiratory distress or spinal cord compression, or for treatment of allergy to contrast agent required for CT scan

• No other concurrent cancer chemotherapy or immunomodulating agents (including steroids)

  • Concurrent corticosteroid therapy as treatment or prophylaxis for anaphylactic reactions allowed

• No concurrent pegfilgrastim