RATIONALE: A peripheral blood stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy or radiation therapy. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Tacrolimus, mycophenolate mofetil, and sirolimus may stop this from happening.

PURPOSE: This randomized phase II trial is studying how well giving tacrolimus, mycophenolate mofetil, and sirolimus works compared to tacrolimus and mycophenolate mofetil alone in preventing acute graft-versus-host disease in patients who are undergoing donor stem cell transplant for hematologic cancer.

Condition	Treatment or Intervention	Phase
childhood Hodgkin's lymphoma childhood non-Hodgkin's lymphoma Graft Versus Host Disease hematopoietic and lymphoid cancer	Drug: fludarabine  Drug: mycophenolate mofetil  Drug: sirolimus  Drug: tacrolimus  Procedure: biological response modifier therapy  Procedure: bone marrow ablation with stem cell support  Procedure: chemotherapy  Procedure: graft versus host disease prophylaxis/therapy  Procedure: peripheral blood stem cell transplantation  Procedure: radiation therapy  Procedure: supportive care/therapy	Phase II

Further Study Details: 

OBJECTIVES: Primary

• Compare the efficacy of postgrafting immunosuppression comprising tacrolimus and mycophenolate mofetil with or without sirolimus in reducing the incidence of grades II-IV acute graft-vs-host disease (GVHD) to ≤ 40% after unrelated donor filgrastim (G-CSF)-mobilized peripheral blood mononuclear cell transplantation with nonmyeloablative conditioning in patients with hematologic malignancies.

Secondary

• Compare the efficacy of these regimens in reducing the incidence of nonrelapse mortality from infections and GVHD before day 200 to ≤ 15% in these patients.
• Compare the use of high-dose corticosteroids in patients treated with these regimens vs those treated on the following protocols: , , and .
• Compare overall survival and progression-free survival of patients treated with these regimens vs those treated on FHCRC-1463.00, FHCRC-1641.00, and FHCRC-1668.00.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to transplant center (FHCRC vs other), number of prior chemotherapy treatments (0-2 vs ≥ 3), and age (under 55 vs 55 and over).

• Conditioning regimen: Patients receive fludarabine IV over 30 minutes on days -4 to -2 and low-dose total body irradiation (TBI) on day 0.
• Allogeneic filgrastim (G-CSF)-mobilized peripheral blood mononuclear cell (G-PBMC) transplantation: After the completion of TBI, patients receive G-PBMCs on day 0.
• Patients are randomized to 1 of 3 treatment arms.
• Arm I: Beginning within 4-6 hours after G-PBMC infusion, patients receive oral mycophenolate mofetil (MMF) 3 times daily on days 0-29, and in the absence of graft-vs-host disease (GVHD), twice daily on days 30-96. MMF is tapered beginning on day 40 and continuing until day 96. Patients also receive oral tacrolimus twice daily on days -3 to 99 followed by a slow taper until day 180.
• Arm II: Beginning within 4-6 hours after G-PBMC infusion, patients receive oral MMF 3 times daily on days 0-29, and in the absence of GVHD, twice daily on days 30-180. Patients also receive oral tacrolimus twice daily on days -3 to 100.
• Arm III: Patients receive MMF and tacrolimus as in arm II. Patients also receive oral sirolimus once daily on days -3 to 80. After completion of study treatment, patients are followed every 6 months for 2 years and then annually for 5 years.

PROJECTED ACCRUAL: A total of 150 patients (50 per treatment arm) will be accrued for this study within 1.5 years.

Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of a hematologic malignancy, including, but not limited to, the following:
• Chronic lymphocytic leukemia and age ≤ 50 years, meeting one of the following criteria:
• Refractory to fludarabine
• Failed to achieve a complete response or partial response after therapy with a fludarabine-containing regimen (or another nucleoside analog [e.g., cladribine or pentostatin])
• Disease relapse within 12 months after completing a fludarabine-containing regimen (or another nucleoside analog)
• Aggressive non-Hodgkin's lymphoma (NHL), including, but not limited to, diffuse large B-cell NHL
• Not eligible for autologous hematopoietic stem cell transplantation (HSCT) or conventional myeloablative HSCT or failed prior autologous HSCT
• Mantle cell NHL in first complete remission (CR)
• Low-grade NHL
• < 6-month duration of CR between courses of conventional therapy
• Hodgkin's lymphoma
• Failed prior frontline therapy
• Multiple myeloma
• Must have received prior chemotherapy
• Consolidation of chemotherapy by autografting prior to nonmyeloablative HSCT allowed
• Acute myeloid leukemia (AML)
• < 5% marrow blasts
• Acute lymphoblastic leukemia
• < 5% marrow blasts
• Chronic myelogenous leukemia (CML)
• Chronic or accelerated phase
• Prior autografts after high-dose therapy or prior intensive chemotherapy with filgrastim (G-CSF)-mobilized peripheral blood mononuclear cell autologous or conventional HSCT for advanced CML allowed provided patient is in chronic phase or CR and has < 5% marrow blasts
• Myelodysplastic syndromes (MDS)
• Refractory anemia (RA) or RA with ringed sideroblasts only
• < 5% marrow blasts*
• Myeloproliferative disease (MPD)
• < 5% marrow blasts* NOTE: *Patients with MDS or MPD with > 5% marrow blasts (including those with transformation to AML) must have received prior cytotoxic chemotherapy
• Meets one of the following criteria:
• Treatable by unrelated HSCT and age > 50 years
• Treatable by allogeneic HSCT and age ≤ 50 years, meeting one of the following criteria:
• Considered high risk for regimen-related toxicity associated with a conventional transplant (> 40% risk of transplant-related mortality) due to pre-existing medical conditions or prior therapy
• Charleston comorbidity index score ≥ 1 allowed
• Refused conventional HSCT
• No rapidly progressive intermediate- or high-grade NHL
• No CNS involvement with disease refractory to intrathecal chemotherapy
• No nonhematologic tumors
• Must have an unrelated donor available meeting the following criteria:
• Matched for HLA-A, -B, -C, -DRB1, and -DQB1 by high-resolution typing
• Only a single allele disparity allowed for HLA-A, -B, or -C by high-resolution typing
• Homozygosity at a mismatched allele in the graft rejection vector is considered a two-allele mismatch
• Negative anti-donor cytotoxic crossmatch 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

• See Disease Characteristics
• Any age

Performance status

• Karnofsky 60-100%

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics

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 prolonged PT
• No ascites related to portal hypertension
• No bridging fibrosis
• No bacterial or fungal liver abscess
• No biliary obstruction
• No chronic viral hepatitis with bilirubin > 3 mg/dL
• No symptomatic biliary disease

Renal

• Not specified

Cardiovascular

• Ejection fraction ≥ 35%
• Required if prior anthracycline exposure or history of cardiac disease
• No hypertension > grade 2

Pulmonary

• DLCO ≥ 40%
• No supplementary continuous oxygen
• Pulmonary nodules allowed at discretion of principal investigator

Other

• HIV negative
• No fungal infection with radiological progression after treatment with amphotericin B or active triazole for > 1 month
• No active bacterial or fungal infections that are unresponsive to medical therapy
• Not pregnant
• Fertile patients must use effective contraception during and for 1 year after study treatment

PRIOR CONCURRENT THERAPY: Biologic therapy

• See Disease Characteristics
• Prior cytokines or rituximab for cytoreduction allowed
• No concurrent conventional allogeneic HSCT

Chemotherapy

• See Disease Characteristics
• More than 3 weeks since prior cytotoxic agents for cytoreduction except hydroxyurea, low-dose cytarabine, or chlorambucil
• No concurrent conventional chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No other concurrent radiotherapy

Surgery

• Not specified

Other

• Prior imatinib mesylate for cytoreduction allowed
• No concurrent voriconazole (arm III only)

California
      Stanford Cancer Center at Stanford University Medical Center, Stanford,  California,  94305-5623,  United States; Recruiting
Colorado
      Rocky Mountain Cancer Centers - Denver Midtown, Denver,  Colorado,  80218,  United States; Recruiting
Georgia
      Winship Cancer Institute of Emory University, Atlanta,  Georgia,  30322,  United States; Recruiting
Oregon
      Cancer Institute at Oregon Health and Science University, Portland,  Oregon,  97239-3098,  United States; Recruiting
Utah
      Huntsman Cancer Institute at University of Utah, 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
Denmark
      Rigshospitalet, Copenhagen,  2100,  Denmark; Recruiting
Germany
      Medizinische Universitaetsklinik I, Cologne,  D-50924,  Germany; Recruiting
      Universitaet Leipzig, Leipzig,  D-04103,  Germany; Recruiting
      Universitaetsklinikum Tuebingen, Tuebingen,  D-72076,  Germany; Recruiting
Italy
      Azienda Sanitaria Ospedale San Giovanni Battista Molinette di Torino, Turin,  10126,  Italy; Recruiting

Study chairs or principal investigators

Michael B. Maris, MD,  Principal Investigator,  Fred Hutchinson Cancer Research Center   

Study ID Numbers:  CDR0000407783; FHCRC-1938.00; NCT00105001
Record last reviewed:  February 2005
Last Updated:  March 15, 2005
Record first received:  March 3, 2005
ClinicalTrials.gov Identifier:  NCT00105001
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08