RATIONALE: Drugs used in chemotherapy, such as fludarabine, work in different ways to stop cancer cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage cancer cells. Donor peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy and radiation therapy. Sometimes the transplanted cells can reject the body's normal tissues. Mycophenolate mofetil and cyclosporine may prevent this from happening. It is not yet known whether total-body irradiation followed by donor stem cell transplantation is more effective with or without fludarabine in treating hematologic malignancies (cancer).

PURPOSE: Randomized phase III trial to study the effectiveness of total-body irradiation with or without fludarabine followed by allogeneic hematopoietic stem cell transplantation in treating patients who have hematologic cancer.

Condition	Treatment or Intervention	Phase
childhood Hodgkin's lymphoma childhood non-Hodgkin's lymphoma Leukemia Lymphoma plasma cell neoplasm	Drug: cyclosporine  Drug: fludarabine  Drug: mycophenolate mofetil  Procedure: biological response modifier therapy  Procedure: bone marrow ablation with stem cell support  Procedure: chemotherapy  Procedure: graft versus host disease prophylaxis/therapy  Procedure: graft versus tumor induction  Procedure: peripheral blood stem cell transplantation  Procedure: radiation therapy  Procedure: supportive care/therapy	Phase III

OBJECTIVES: Primary

• Compare the nonrelapse mortality 1 year after nonmyeloablative conditioning comprising low-dose total body irradiation (TBI) with vs without fludarabine followed by HLA-matched related allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies at low or moderate risk for graft rejection.

Secondary

• Compare the 1-year overall survival of patients after treatment with these regimens.
• Compare the incidence of graft rejection in patients treated with these regimens.
• Compare the incidence of grades II-IV acute graft-versus-host disease (GVHD) and chronic extensive GVHD in patients treated with these regimens.
• Compare the rates of disease progression and/or relapse-related mortality in patients treated with these regimens.
• Compare the immune reconstitution and risk of infection in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, disease risk (indolent vs aggressive), and prior conventional hematopoietic stem cell transplantation (yes vs no).

• Patients are randomized to 1 of 2 treatment arms.
• Arm I: Patients receive fludarabine IV on days -4 to -2. Patients then undergo low-dose total body irradiation (TBI) on day 0.
• Arm II: Patients undergo low-dose TBI on day 0.
• Allogeneic peripheral blood stem cell transplantation (PBSCT): After TBI, patients undergo PBSCT on day 0.
• Immunosuppression: Patients receive oral cyclosporine twice daily on days -3 to 56 in the absence of graft-versus-host disease (GVHD). Patients with no evidence of GVHD at day 56 begin a cyclosporine taper and continue the taper until day 180. Patients with evidence of disease progression and no evidence of GVHD prior to day 56 receive tapered doses of cyclosporine for 2 weeks. Patients also receive oral mycophenolate mofetil (MMF) twice daily on days 0-27 in the absence of GVHD. If treatment for GVHD is required before day 28, MMF is continued until a steroid taper begins. Patients are followed on days 28, 56, and 84, at 6, 12, 18, and 24 months, and then annually for 5 years post-transplantation.

PROJECTED ACCRUAL: A total of 200 patients (100 per treatment arm) will be accrued for this study within 3 years.

Ages Eligible for Study:  up to  74 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of a hematologic malignancy treatable with hematopoietic stem cell transplantation (HSCT) OR a B-cell malignancy, including any of the following:
• Aggressive non-Hodgkin's lymphoma (NHL) and other histologies, such as diffuse large B-cell non-Hodgkin's lymphoma (NHL)
• Not eligible for conventional myeloablative HSCT OR failed autologous HSCT
• No rapidly progressive aggressive NHL, unless in minimal disease state
• Low-grade NHL with less than 6 months duration of complete response (CR) between courses of conventional therapy
• Chronic lymphocytic leukemia
• Failed to achieve CR or partial response OR relapsed disease within 12 months after completing therapy with a regimen containing fludarabine or another nucleoside analog (e.g., cladribine or pentostatin)
• Hodgkin's lymphoma
• Received and failed front-line therapy
• Failed or were not eligible for autologous transplantation
• Multiple myeloma
• Chemosensitive disease after failed autografting
• Acute myeloid leukemia
• Less then 5% marrow blasts at the time of transplantation and beyond first CR
• Acute lymphoblastic leukemia
• Less than 5% marrow blasts at the time of transplantation and beyond first CR
• Chronic myelogenous leukemia
• Chronic phase (CP) beyond CP1 allowed provided the patient is beyond the first CP and was previously treated with myelosuppressive chemotherapy or HSCT and has less than 5% marrow blasts at time of transplantation
• Myelodysplastic syndromes
• Received prior myelosuppressive chemotherapy or HSCT and less than 5% marrow blasts at time of transplantation
• Not eligible for conventional allogeneic HSCT AND must have disease that is expected to be stable for at least 100 days without chemotherapy
• Not curable with an autologous transplantation
• Patients who refused to be treated on a conventional HSCT study are eligible
• Not eligible for a high priority curative autologous transplantation
• No chronic myelomonocytic leukemia or myeloproliferative disorder
• No concurrent CNS involvement with disease refractory to intrathecal chemotherapy
• Available HLA-matched related donor
• Genotypically identical in at least 1 haplotype
• Phenotypically or genotypically identical donor at the allele level at HLA-A, -B, -C, -DRB1, and -DQB1 allowed
• No identical twin NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.

PATIENT CHARACTERISTICS: Age

• Under 75

Performance status

• Karnofsky 50-100% (adult patients)
• Lansky 50-100% (pediatric patients)

Life expectancy

• Not severely limited by disease other than malignancy

Hematopoietic

• Not specified

Hepatic

• No fulminant liver failure
• No cirrhosis of the liver with evidence of portal hypertension
• No alcoholic hepatitis
• No esophageal varices
• No history of bleeding esophageal varices
• No hepatic encephalopathy
• No uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the PT
• No ascites related to portal hypertension
• No bacterial or fungal liver abscess
• No biliary obstruction
• No chronic viral hepatitis with bilirubin greater than 3 mg/dL
• No symptomatic biliary disease

Renal

• Not specified

Cardiovascular

• Ejection fraction at least 35%
• No poorly controlled hypertension
• No symptomatic coronary artery disease
• No other cardiac failure requiring therapy

Pulmonary

• DLCO at least 30%
• Total lung capacity at least 30%
• FEV_1 at least 30%
• No concurrent supplementary continuous oxygen
• No fungal pneumonia with radiological progression after receiving amphotericin formulation or mold-active azoles for more than 1 month

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception during and for up to 12 months after study participation
• HIV negative
• No active non-hematological malignancy except localized nonmelanoma skin cancer

PRIOR CONCURRENT THERAPY: Biologic therapy

• See Disease Characteristics
• More than 6 months since prior autograft immediately before nonmyeloablative HSCT (tandem approach)
• No concurrent growth factors (e.g., filgrastim [G-CSF]) during mycophenolate mofetil administration

Chemotherapy

• See Disease Characteristics
• More than 3 weeks since prior myelosuppressive chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

California
      Stanford Cancer Center at Stanford University Medical Center, Stanford,  California,  94305-5623,  United States; Recruiting
Oregon
      Cancer Institute at Oregon Health and Science University, Portland,  Oregon,  97239-3098,  United States; Recruiting
Utah
      Huntsman Cancer Institute, Salt Lake City,  Utah,  84112,  United States; Recruiting
Washington
      Fred Hutchinson Cancer Research Center, Seattle,  Washington,  98109-1024,  United States; Recruiting
Wisconsin
      Medical College of Wisconsin Cancer Center, Milwaukee,  Wisconsin,  53226,  United States; Recruiting
Germany
      Universitaet Leipzig, Leipzig,  D-04103,  Germany; Recruiting
Italy
      University of Turin, Turin,  10126,  Italy; Recruiting

Study chairs or principal investigators

Brenda Sandmaier, MD,  Principal Investigator,  Fred Hutchinson Cancer Research Center   

Study ID Numbers:  CDR0000346618; FHCRC-1813.00
Record last reviewed:  September 2004
Record first received:  January 9, 2004
ClinicalTrials.gov Identifier:  NCT00075478
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2004-11-17