• Overall survival 1 year post-transplant [ Designated as safety issue: No ]
• Incidence of graft rejection [ Designated as safety issue: No ]
• Incidence of acute graft-vs-host disease (GVHD) and chronic extensive GVHD [ Designated as safety issue: Yes ]
• Compare rates of disease progression and/or relapse-related mortality 1 year post-transplant [ Designated as safety issue: No ]
• Compare immune reconstitution and the risks of infections [ Designated as safety issue: Yes ]

• Overall survival 1 year post-transplant
• Incidence of graft rejection
• Incidence of acute graft-vs-host disease (GVHD) and chronic extensive GVHD
• Compare rates of disease progression and/or relapse-related mortality 1 year post-transplant
• Compare immune reconstitution and the risks of infections

RATIONALE: Giving low doses of chemotherapy, such as fludarabine, and radiation therapy before a donor stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after transplant may stop this from happening. It is not yet known whether total-body irradiation followed by donor stem cell transplant is more effective with or without fludarabine in treating hematologic cancer.

PURPOSE: This randomized phase III trial is studying total-body irradiation and fludarabine to see how it works compared with total-body irradiation alone followed by donor stem cell transplant in treating patients with hematologic cancer.

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).

• Nonmyeloablative conditioning regimen: 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 periodically for 1.5 years 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.

• Leukemia
• Lymphoma
• Multiple Myeloma and Plasma Cell Neoplasm
• Myelodysplastic Syndromes

• Drug: fludarabine phosphate
• Radiation: radiation therapy

• Experimental: Patients receive fludarabine IV on days -4 to -2. Patients then undergo low-dose total body irradiation (TBI) on day 0.
• Experimental: Patients undergo low-dose TBI on day 0.

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 remission (CR) between courses of conventional therapy

  • Mantle cell lymphoma

    • In first CR

  • Chronic lymphocytic leukemia

    • Meets 1 of the following criteria:

      • Failed to meet NCI Working Group criteria for complete or partial response after therapy with a regimen containing fludarabine (FLU) (or another nucleoside analog, e.g., 2-CDA, pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog)
      • Failed FLU-CY-Rituximab (FCR) combination chemotherapy at any time point
      • Have "17p deletion" cytogenetic abnormality (patients should have received induction chemotherapy but could be transplanted in first CR)

  • Hodgkin's lymphoma

    • Received and failed front-line therapy
    • Failed or were not eligible for autologous transplantation

  • Multiple myeloma

    • Chemosensitive disease after failed autografting
    • No autografting prior (within 6 months) to nonmyeloablative hematopoietic cell transplantation (HCT)

  • Acute myeloid leukemia

    • Less then 5% marrow blasts at the time of transplantation and beyond first CR
    • No circulating leukemic blasts in the peripheral blood

  • Acute lymphoblastic leukemia

    • Less than 5% marrow blasts at the time of transplantation and beyond first CR
    • No circulating leukemic blasts in the peripheral blood

  • 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
    • No circulating leukemic blasts in the peripheral blood

  • 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

  • Patients under 12 must be approved by the principal investigator

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 despite multiple hypertensive drugs
• No symptomatic coronary artery disease*
• No other cardiac failure requiring therapy* NOTE: *For patients with a history of cardiac disease or anthrocycline use

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 nonhematologic malignancy except localized nonmelanoma skin cancer
• No nonhematologic malignancy not in complete remission with > 20% risk of disease recurrence except nonmelanoma skin cancer

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics
• More than 6 months since prior autograft immediately before nonmyeloablative HSCT (tandem approach)
• More than 3 weeks (from the initiation of conditioning) since prior cytotoxic agents for "cytoreduction, " except tyrosine kinase inhibitors (e.g., imatinib mesylate), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or rituxan

Chemotherapy

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

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified