This phase II trial studies the side effects and efficacy of bortezomib with ifosfamide and vinorelbine in children and young adults with Hodgkin's lymphoma that was recurrent or did not respond to previous therapy. Bortezomib is an inhibitor of protein degradation. Bortezomib degrades short-lived regulatory proteins in the cell, and has been reported to increase the tumor cells. Bortezomib may increase the effectiveness of ifosfamide and vinorelbine (two standard drugs given to children with Hodgkin Lymphoma that has come back after initial treatment) by making cancer cells more sensitive to effectiveness of standard chemotherapy by preventing anti-death responses in these drugs. Giving bortezomib together with ifosfamide and vinorelbine tartrate should kill more cancer cells than are killed with ifosfamide and vinorelbine alone.

PRIMARY OBJECTIVES:

I. Determine the efficacy and safety of bortezomib (as a chemosensitizing agent) in pediatric patients and young adults with primary refractory Hodgkin's lymphoma (HL) or HL in first relapse.

II. Determine the response rate in patients treated with bortezomib, ifosfamide, and vinorelbine ditartrate (vinorelbine tartrate) (IVB) and compare the response rate to the historical response rate in patients treated with ifosfamide and vinorelbine ditartrate alone.

SECONDARY OBJECTIVES:

I. Determine the overall response rate (complete and partial response) and induction success rate after 2 or 4 courses of therapy and the reinduction rate (complete response) after 4 courses of therapy.

II. Determine the proportion of patients able to mobilize sufficient hematopoietic stem cells (CD34+) after 2 courses of IVB.

OUTLINE: This is a multicenter, open-label, pilot study.

Patients receive ifosfamide intravenously (IV) continuously over days 1-4, vinorelbine tartrate IV over 6-10 minutes on days 1 and 5, and bortezomib intravenously on days 1, 4, and 8, and filgrastim (G-CSF) by vein or subcutaneously beginning on day 6 and continuing until blood counts recover or peripheral blood stem cells (PBSC) are harvested. Treatment cycles repeat every 21 days for up to 2 or 4 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo autologous PBSC harvesting according to institutional guidelines after the second course of therapy.

After completion of study treatment, patients are followed every 6 months for 2 years and then annually thereafter.

Inclusion Criteria:

• Histologically confirmed Hodgkin's lymphoma at time of relapse or disease progression, meeting all of the following criteria:

  • Stage I-IV disease
  • No morphologically unclassifiable disease

• Meets 1 of the following criteria:

  • Mixed cellularity
  • Lymphocytic depletion (LD)
  • LD, diffuse fibrosis
  • LD, reticular
  • Lymphocyte predominance (LP)
  • LP, diffuse
  • LP, nodular
  • Nodular sclerosis (NS)
  • NS, cellular phase
  • NS, lymphocytic predominance
  • NS, mixed cellularity
  • NS, LD
  • Not otherwise specified

• Primary refractory disease OR disease in first relapse, except for the following:

  • Patients who achieved a complete response after treatment on protocol COG-AHOD0431 who experience a biopsy-proven recurrence after doxorubicin hydrochloride, vincristine, prednisone, and cyclophosphamide without involved-field radiotherapy
  • Patients on the observation-only arm of protocol COG-AHOD0431

• Any measurable, focal mass lesion of a visceral organ (e.g., liver, spleen, or kidney)

• Patients with metastatic disease to bone marrow and granulocytopenia, anemia, and/or thrombocytopenia are allowed provided both of the following criteria are met:

  • Platelet count ≥ 20,000/mm³ (platelet transfusion allowed)
  • Hemoglobin ≥ 8 g/dL (packed red blood cell transfusion allowed)

• Karnofsky performance status (PS) 60-100% (for patients > 16 years of age) OR Lanksy PS 60-100% (for patients =< 16 years of age)

• Life expectancy >= 2 months

• Absolute neutrophil count >= 1,000/mm^3

• Platelet count >= 75,000/mm^3 (transfusion independent) (for patients with no bone marrow involvement)

• Creatinine =< 1.5 times upper limit of normal (ULN)

• Creatinine clearance or radioisotope glomerular filtration rate >= 70 mL/min/1.73 m^2

• AST and ALT =< 2.5 times ULN

• Bilirubin =< 1.5 times ULN

• Shortening fraction >= 27% by echocardiogram OR LVEF >= 50% by gated radionuclide study

• Patients with a seizure disorder are eligible if on a nonenzyme-inducing anticonvulsant and seizures are well controlled

• No CNS toxicity > grade 2

• No serious intercurrent illnesses

• No known hypersensitivity to E. coli-derived proteins, filgrastim (G-CSF), or any component of the study drugs

• No peripheral neuropathy > grade 1

• No known hypersensitivity to bortezomib, boron, or mannitol

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

  • Concurrent corticosteroids allowed for treatment or prophylaxis of anaphylactic reactions
  • No dexamethasone or aprepitant as an antiemetic

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• Recovered from prior therapy

• No prior bortezomib or other proteasome inhibitors

• At least 3 weeks since prior chemotherapy (4 weeks for nitrosoureas)

• More than 14 days since prior investigational drugs

• No concurrent enzyme inducing anticonvulsants that alter p450 metabolism, including phenytoin, carbamazepine, phenobarbital, or other anticonvulsants

  • Benzodiazepine or gabapentin allowed