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

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

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.

Study Overview

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

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Australia
  • Western Australia
    • Perth, Western Australia, Australia, 6001
      • Princess Margaret Hospital for Children
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Hopital Sainte Justine
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Saskatoon Cancer Centre at the University of Saskatchewan
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Comprehensive Cancer Center at University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85016-7710
      • Phoenix Children's Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
  • California
    • Los Angeles, California, United States, 90095-1781
      • Jonsson Comprehensive Cancer Center at UCLA
    • Oakland, California, United States, 94609-1809
      • Children's Hospital and Research Center - Oakland
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Sacramento, California, United States, 95825
      • Kaiser Permanente Medical Center - Oakland
  • Delaware
    • Wilmington, Delaware, United States, 19899
      • Alfred I. DuPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610-0232
      • University of Florida Shands Cancer Center
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center
    • Miami, Florida, United States, 33155
      • Miami Children's Hospital
    • St. Petersburg, Florida, United States, 33701
      • All Children's Hospital
    • Tampa, Florida, United States, 33607
      • St. Joseph's Cancer Institute at St. Joseph's Hospital
    • West Palm Beach, Florida, United States, 33407
      • Kaplan Cancer Center at St. Mary's Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital - Atlanta
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital - Chicago
    • Springfield, Illinois, United States, 62794-9620
      • Southern Illinois University School of Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Cancer Center
    • Indianapolis, Indiana, United States, 46260
      • St. Vincent Indianapolis Hospital
  • Kansas
    • Kansas City, Kansas, United States, 66160-7357
      • Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center
  • Kentucky
    • Louisville, Kentucky, United States, 40232
      • Kosair Children's Hospital
  • Louisiana
    • New Orleans, Louisiana, United States, 70118
      • Children's Hospital of New Orleans
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney kimmel comprehensive cancer center at johns hopkins
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0238
      • C.S. Mott Children's Hospital at University of Michigan
    • Detroit, Michigan, United States, 48201-1379
      • Barbara Ann Karmanos Cancer Institute
    • Flint, Michigan, United States, 48503
      • Hurley Medical Center
    • Grand Rapids, Michigan, United States, 49503-2560
      • Spectrum Health Cancer Care - Butterworth Campus
    • Grosse Pointe Woods, Michigan, United States, 48236
      • Van Elslander Cancer Center at St. John Hospital and Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Fairview University Medical Center - University Campus
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospital of Minnesota - Minneapolis
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216-4505
      • University of Mississippi Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center Cancer Center
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • Stony Brook, New York, United States, 11794-8174
      • Long Island Cancer Center at Stony Brook University Hospital
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106-5000
      • Rainbow Babies and Children's Hospital
    • Dayton, Ohio, United States, 45404-1815
      • Children's Medical Center - Dayton
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Cancer Institute at Milton S. Hershey Medical Center
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Hollings Cancer Center at Medical University of South Carolina
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
  • Texas
    • Amarillo, Texas, United States, 79106
      • Texas Tech University Health Sciences Center School of Medicine
    • Dallas, Texas, United States, 75390
      • Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
    • Fort Worth, Texas, United States, 76104-9958
      • Cook Children's Medical Center - Fort Worth
    • Lubbock, Texas, United States, 79410
      • Covenant Children's Hospital
    • San Antonio, Texas, United States, 78229-3993
      • Methodist Children's Hospital of South Texas
    • San Antonio, Texas, United States, 78229-3900
      • University of Texas Health Science Center at San Antonio
    • Temple, Texas, United States, 76508
      • CCOP - Scott and White Hospital
  • Virginia
    • Norfolk, Virginia, United States, 23507-1971
      • Children's Hospital of The King's Daughters
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54307-3508
      • St. Vincent Hospital Regional Cancer Center
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic - Marshfield Center
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 30 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hyperfractionated Involved-Field Radiotion-immunotherapy; 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.	Procedure: peripheral blood stem cell transplantation; Procedure: autologous bone marrow transplantation; Drug: carmustine; Given IV; Other Names: BCNU; BiCNU; bischloronitrosourea; NSC #40996; Drug: etoposide; Given IV; Other Names: VP-16; Etopophos; VePesid; NSC #141540; Drug: cytarabine; Given IV; Other Names: Cytosar; cytosine arabinoside; NSC #063878; AraC; Drug: melphalan; Given IV; Other Names: Alkeran; L-PAM; L-sarcolysin; L-PHENYLANINE mustard; NSC #008806; Procedure: bone marrow ablation with stem cell support; Biological: filgrastim; Given IV; Other Names: G-CSF; r-metHuG-CSF; Neupogen; NSC #614629; GRANULOCYTE COLONY-STIMULATING FACTOR; Biological: aldesleukin; Given IV; Other Names: Proleukin; IL-2; recombinant human Interleukin 2; NSC # 373364; Drug: cyclosporine; Given IV; Other Names: Sandimmune; Neoral; Gengraf; NSC #290193; cycloporine; Biological: recombinant interferon gamma; Given IV; Other Names: Actimmune; gamma interferon; INTERFERON GAMMA-1b; immune interferon; lymphocyte interferon; rIFN-gamma; T-interferon; NSC #600662
Experimental: Hyperfractionated Involved-Field Radiotion-no immunotherapy; 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.	Procedure: peripheral blood stem cell transplantation; Procedure: autologous bone marrow transplantation; Drug: carmustine; Given IV; Other Names: BCNU; BiCNU; bischloronitrosourea; NSC #40996; Drug: etoposide; Given IV; Other Names: VP-16; Etopophos; VePesid; NSC #141540; Drug: cytarabine; Given IV; Other Names: Cytosar; cytosine arabinoside; NSC #063878; AraC; Drug: melphalan; Given IV; Other Names: Alkeran; L-PAM; L-sarcolysin; L-PHENYLANINE mustard; NSC #008806; Procedure: bone marrow ablation with stem cell support; Biological: filgrastim; Given IV; Other Names: G-CSF; r-metHuG-CSF; Neupogen; NSC #614629; GRANULOCYTE COLONY-STIMULATING FACTOR; Drug: cyclosporine; Given IV; Other Names: Sandimmune; Neoral; Gengraf; NSC #290193; cycloporine

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Allen R. Chen, MD, PhD, MHS, Sidney kimmel comprehensive cancer center at johns hopkins; Study Chair: Sharon L. Gardner, MD, NYU Langone Health

Publications and helpful links

General Publications

• Chen AR, Hutchison R, Hess A, et al.: Clinical outcomes of patients with recurrent/refractory Hodgkin disease receiving cyclosporine, interferon-, and interleukin-2 immunotherapy to induce auto-reactivity after autologous stem cell transplantation with BEAM: a COG study. [Abstract] Blood 110 (11): A-1896, 2007.

Study record dates

Study Major Dates

• Study Start: November 1, 2003
• Primary Completion (Actual): June 1, 2005

Study Registration Dates

• First Submitted: October 3, 2003
• First Submitted That Met QC Criteria: October 6, 2003
• First Posted (Estimate): October 7, 2003

Study Record Updates

• Last Update Posted (Estimate): October 17, 2013
• Last Update Submitted That Met QC Criteria: October 16, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Keywords: recurrent adult Hodgkin lymphoma; recurrent/refractory childhood Hodgkin lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Adjuvants, Immunologic; Antifungal Agents; Calcineurin Inhibitors; Interferons; Aldesleukin; Etoposide; Lenograstim; Melphalan; Interferon-gamma; Cytarabine; Carmustine; Cyclosporine; Cyclosporins; Interleukin-2
• Other Study ID Numbers: AHOD0121; CDR0000330135 (Other Identifier: Clinical Trials.gov); COG-AHOD0121 (Other Identifier: Children's Oncology Group)