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

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with autologous stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. Giving immunotherapy using cyclosporine, interferon gamma, and interleukin-2 after stem cell transplantation may help the transplanted cells make an immune response and kill any remaining cancer cells. It is not yet known whether high-dose chemotherapy followed by autologous stem cell transplantation is more effective with or without immunotherapy. PURPOSE: This randomized phase II/III trial is studying how well high-dose chemotherapy followed by autologous stem cell transplantation, cyclosporine, interferon gamma, and interleukin-2 works and compares it to high-dose chemotherapy followed by autologous stem cell transplantation only in treating patients with refractory or relapsed Hodgkin's lymphoma.

Detailed Description
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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.

Official Title
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A Phase II/III Study of Immunomodulation After High Dose Myeloablative Therapy With Autologous Stem Cell Rescue for Refractory/Relapsed Hodgkin Disease

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: aldesleukin
* Biological: filgrastim
* Biological: recombinant interferon gamma
* Drug: carmustine
* Drug: cyclosporine
* Drug: cytarabine
* Drug: etoposide
* Drug: melphalan
* Procedure: autologous bone marrow transplantation
* Procedure: bone marrow ablation with stem cell support
* Procedure: peripheral blood stem cell transplantation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hyperfractionated Involved-Field Radiotion-immunotherapy<br>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, 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. ASCT: Autologous bone marrow or peripheral blood stem cell transplantation on day 0. Filgrastim (oral or IV) beginning on day 1 and continuing until blood counts recover. IMMUNOTHERAPY: Cyclosporine IV twice daily beginning on day 0 and continuing until the completion of the course of recombinant interferon gamma and interleukin-2. When sufficiently recovered, Aldesleukin once daily for 18 days. | Biological: aldesleukin<br>* Given IV<br>* Other names: NSC # 373364;Biological: filgrastim<br>* Given IV<br>* Other names: NSC #614629;Biological: recombinant interferon gamma<br>* Given IV<br>* Other names: NSC #600662;Drug: carmustine<br>* Given IV<br>* Other names: NSC #40996;Drug: cyclosporine<br>* Given IV<br>* Other names: NSC #290193;Drug: cytarabine<br>* Given IV<br>* Other names: NSC #063878;Drug: etoposide<br>* Given IV<br>* Other names: NSC #141540;Drug: melphalan<br>* Given IV<br>* Other names: NSC #008806;Procedure: autologous bone marrow transplantation<br> <br> Procedure: bone marrow ablation with stem cell support<br> <br> Procedure: peripheral blood stem cell transplantation<br> <br> |
| Experimental: Hyperfractionated Involved-Field Radiotion-no immunotherapy<br>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, 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. ASCT: Autologous bone marrow or peripheral blood stem cell transplantation on day 0. Filgrastim (oral or IV) beginning on day 1 and continuing until blood counts recover. | Biological: filgrastim<br>* Given IV<br>* Other names: NSC #614629;Drug: carmustine<br>* Given IV<br>* Other names: NSC #40996;Drug: cyclosporine<br>* Given IV<br>* Other names: NSC #290193;Drug: cytarabine<br>* Given IV<br>* Other names: NSC #063878;Drug: etoposide<br>* Given IV<br>* Other names: NSC #141540;Drug: melphalan<br>* Given IV<br>* Other names: NSC #008806;Procedure: autologous bone marrow transplantation<br> <br> Procedure: bone marrow ablation with stem cell support<br> <br> Procedure: peripheral blood stem cell transplantation<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of death, excluding death due to disease, during the period of time from day 0 (transplant) through day 100 post transplant | Death, excluding death due to disease, during the period of time from Day 0 (transplant) through Day 100 post transplant. | Day 0 (transplant) through Day 100 (Post transplant) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult Hodgkin lymphoma, recurrent/refractory childhood Hodgkin lymphoma