Immunotherapy Using Cyclosporine, Interferon Gamma, and Interleukin-2 After High-Dose Myeloablative Chemotherapy With Autologous Stem Cell Transplantation in Treating Patients With Refractory or Relapsed Hodgkin's Lymphoma

OBJECTIVES:

Primary

• Phase II

• Determine the feasibility and toxicity of immunotherapy comprising cyclosporine, interferon gamma, and interleukin-2 after high-dose myeloablative chemotherapy with autologous stem cell transplantation (ASCT) in patients with refractory or relapsed Hodgkin's lymphoma.

• Phase II part of the study was completed and should have proceeded to Phase III; however long delay occurred due to some proposed protocol changes to Phase III , so long that the study got permanently closed ***********
• Phase III

• Compare the event-free and overall survival of patients treated with vs without this immunotherapy regimen.

Secondary

• Determine the event-free and overall survival rates, toxic effects, and response rates to reinduction chemotherapy followed by hyperfractionated involved-field radiotherapy, high-dose chemotherapy comprising carmustine, etoposide, cytarabine, and melphalan, and ASCT in these patients.
• Correlate tumor biologic characteristics with response in patients treated with these regimens.
• Determine the effectiveness of this immunotherapy regimen in producing autologous graft-vs-host disease (GVHD) and auto-reactive cytotoxic T-lymphocyte activity in these patients.
• Correlate greater levels of autologous GVHD and in vitro cytolytic activity with improved event-free and overall survival in patients treated with these regimens.
• Determine whether treatment with immunotherapy can overcome the negative prognostic significance of p53 mutation and high serum levels of interleukin-10 and interleukin-2 receptor in these patients.
• Determine the genotoxicity of retrieval therapy and the incidence of hypermutability by longitudinal genotoxic biomonitoring in these patients.
• Correlate HLA class II invariant peptide (CLIP) expression in tumor cells with improved event-free and overall survival in patients treated with immunotherapy regimen.

OUTLINE: This is a nonrandomized, multicenter phase II study followed by a randomized, multicenter phase III study. Patients are stratified according to study phase (II vs III).

Patients receive 2 courses of salvage induction therapy on COG-AHOD00P1 or equivalent. Within 2-5 weeks after completion of salvage induction therapy, patients receive protocol therapy.

• Phase II: All patients receive the following treatment:

• Hyperfractionated involved-field radiotherapy: Patients who have completed prior salvage induction therapy and have not received full tissue tolerance from prior radiotherapy may receive hyperfractionated involved-field radiotherapy twice daily for 7 days.
• High-dose preparative regimen: Beginning within 7 days after radiotherapy, patients receive carmustine IV over 3 hours on day -6; etoposide IV over 1 hour and cytarabine IV over 1 hour on days -5 to -2; and melphalan IV over 30 minutes on day -1.
• Autologous stem cell transplantation: Patients undergo autologous bone marrow or peripheral blood stem cell transplantation on day 0. Patients then receive filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 1 and continuing until blood counts recover.
• Immunotherapy: Patients receive cyclosporine IV twice daily beginning on day 0 and continuing until the completion of the course of interferon gamma and interleukin-2. When sufficiently recovered, patients also receive interferon gamma SC every other day for 10 doses. Beginning 2 days after the start of interferon gamma, patients also receive interleukin-2 SC once daily for 18 days.
• Phase III: Patients who respond to prior salvage induction therapy are randomized to 1 of 2 treatment arms. Patients who have progressive disease after 2 courses of prior salvage induction therapy are assigned to arm I.

• Arm I: Patients receive treatment as in phase II.
• Arm II: Patients receive treatment as in phase II without immunotherapy. In both phases, treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed at 1 year.

PROJECTED ACCRUAL: A total of 156 patients (25 for phase II and 131 for phase III) will be accrued for this study within 5.4 years.

DISEASE CHARACTERISTICS:

• Diagnosis of Hodgkin's lymphoma

• Histologically confirmed at original diagnosis AND at relapse or disease progression
• Relapsed or refractory to conventional therapy
• No recurrence without B symptoms or bulky disease at least 1 year after completion of minimal systemic therapy defined by either of the following:

• Stage IA/IIA with nodal disease previously treated with radiotherapy only
• Stage IA/IIA with nodal disease previously treated with less than 3 courses of standard dose chemotherapy
• Concurrently enrolled on the COG-AHOD00P1 salvage chemotherapy study OR received other appropriate salvage therapy (e.g., ifosfamide and vinorelbine)

PATIENT CHARACTERISTICS:

Age

• Under 30

Performance status

• ECOG 0-2 (for adults)
• Lansky 50-100% (for children)

Life expectancy

• At least 2 months

Hematopoietic

• Absolute neutrophil count at least 500/mm^3

Hepatic

• Bilirubin no greater than 1.5 times normal
• SGPT less than 2.5 times normal

Renal

• Creatinine no greater than 1.5 times normal OR
• Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min/1.73 m^2

Cardiovascular

• Shortening fraction at least 27% by echocardiogram OR
• Ejection fraction at least 50% by MUGA

Pulmonary

• No evidence of dyspnea at rest
• No exercise intolerance
• DLCO at least 50% (patients 8 years of age and over)

Other

• Not pregnant or nursing
• Negative pregnancy test
• No concurrent serious illness

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Recovered from prior immunotherapy
• At least 1 week since prior antineoplastic biologic agents
• More than 1 week since prior growth factors
• No prior stem cell transplantation
• No other concurrent immunomodulating agents

Chemotherapy

• See Disease Characteristics
• More than 2 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas) and recovered
• No other concurrent anticancer chemotherapy

Endocrine therapy

• No concurrent steroids, including dexamethasone as an antiemetic

Radiotherapy

• See Disease Characteristics
• Recovered from prior radiotherapy

Surgery

• Not specified

Other

• No concurrent participation in another COG therapeutic study