RATIONALE: Sirolimus may be effective in preventing graft-versus-host disease in patients who are undergoing allogeneic stem cell transplantation.

PURPOSE: Randomized phase II trial to compare the effectiveness of three different regimens of sirolimus-treated T cells and/or sirolimus by mouth in preventing graft-versus-host disease in patients who are undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies .

Condition	Treatment or Intervention	Phase
chronic myeloproliferative disorders Graft Versus Host Disease Leukemia Lymphoma myelodysplastic and myeloproliferative diseases plasma cell neoplasm	Drug: allogeneic lymphocytes  Drug: cyclophosphamide  Drug: cyclosporine  Drug: doxorubicin  Drug: etoposide  Drug: filgrastim  Drug: fludarabine  Drug: prednisone  Drug: rituximab  Drug: sirolimus  Drug: vincristine  Procedure: antibody therapy  Procedure: biological response modifier therapy  Procedure: bone marrow ablation with stem cell support  Procedure: chemotherapy  Procedure: colony-stimulating factor therapy  Procedure: cytokine therapy  Procedure: graft versus host disease prophylaxis/therapy  Procedure: graft versus tumor induction  Procedure: leukocyte therapy  Procedure: monoclonal antibody therapy  Procedure: peripheral blood lymphocyte therapy  Procedure: peripheral blood stem cell transplantation  Procedure: supportive care/therapy	Phase II

Further Study Details: 

OBJECTIVES: Primary

• Determine the safety and feasibility of sirolimus-generated Th2 cells with vs without in vivo sirolimus vs in vivo sirolimus alone for graft-versus-host disease (GVHD) prevention after allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies.
• Determine the GVHD rate in patients treated with these regimens.

Secondary

• Determine the pattern of post-transplantation CD4+ and CD8+ T-cell production of Th1- and Th2-type cytokines in patients treated with these regimens.
• Determine the kinetics of alloengraftment, incidence of opportunistic infection, and incidence of malignant disease in complete remission in patients treated with these regimens.
• Determine, preliminarily, whether T cells collected after transplantation have increased reactivity to patient tumor cells relative to donor T cells collected before transplantation.
• Determine the pattern of post-transplantation CD14+ monocyte production of inflammatory cytokines interleukin-1-alpha and tumor necrosis factor alpha in patients treated with these regimens.

OUTLINE: This is a randomized, pilot study. Patients are stratified according to age (18 to 45 vs 46 to 75).

• Induction chemotherapy: Patients with CD20+ B-cell malignancies receive rituximab IV on day 1. All patients receive fludarabine IV over 30 minutes and etoposide, doxorubicin, and vincristine IV continuously on days 1-4; cyclophosphamide IV over 30 minutes on day 5; oral prednisone on days 1-5; and filgrastim (G-CSF) subcutaneously (SC) beginning on day 6 and continuing until blood counts recover. Treatment repeats every 21 days for 1-3 courses depending on the quantity of host immune T cells remaining after each course. All patients, including those who develop progressive disease during induction chemotherapy, then proceed to transplantation chemotherapy.
• Transplantation chemotherapy: Patients receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -6 to -3.
• Patients undergo allogeneic peripheral blood stem cell transplantation on day 0. Patients receive G-CSF SC beginning on day 0 and continuing until blood counts recover. Patients also receive cyclosporine orally or IV over 2 hours twice daily beginning on day -1 and continuing until approximately day 100 followed by a taper until day 180. Patients are also randomized to 1 of 3 treatment arms.
• Arm I: Patients receive donor Th2 cells IV on day 1.
• Arm II: Patients receive donor Th2 cells as in arm I. Patients also receive an initial loading dose of oral sirolimus once on day -2 and then oral sirolimus once daily on days -1 to 1.
• Arm III: Patients receive oral sirolimus as in arm II.
• Donor lymphocyte infusion (DLI): Patients with persistent or progressive malignant disease after transplantation may receive DLI. DLI may be administered alone or in combination with chemotherapy. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed weekly for 6 weeks post-transplantation, at 3 months, every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter.

PROJECTED ACCRUAL: A total of 30-76 patients (approximately 10-25 per treatment arm) will be accrued for this study within 2.5-3.5 years.

Ages Eligible for Study:  18 Years   -   75 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following hematologic malignancies, myelodysplasia, or myeloproliferative disorders:
• Chronic lymphocytic leukemia
• Relapsed after fludarabine
• Non-complete remission (CR) after salvage regimen
• Hodgkin's or non-Hodgkin's lymphoma (all types, including mantle cell lymphoma)
• Primary treatment failure
• Relapsed after autologous stem cell transplantation (SCT)
• Non-CR after salvage regimen
• Multiple myeloma
• Primary treatment failure
• Relapsed after autologous SCT
• Non-CR after salvage regimen
• Acute myeloid leukemia
• In first CR (CR1) and at high risk [excludes t(8;21), t(15;17), or inv(16)]
• In second CR (CR2) or greater
• Acute lymphoblastic leukemia
• In CR1 and at high risk [t(9;22) or bcr-abl+; t(4;11), 1(1;19), t(8;14)]
• In CR2 or greater
• Myelodysplastic syndromes
• Refractory anemia with excess blasts (RAEB)
• RAEB in transformation (requires bone marrow and blood blasts of less than 10% after induction chemotherapy)
• Myeloproliferative disorders*
• Idiopathic myelofibrosis
• Polycythemia vera
• Essential thrombocythemia
• Chronic myelomonocytic leukemia NOTE: *Patients must be end-stage, primarily defined as disease severity refractory to splenectomy
• Chronic myelogenous leukemia refractory to imatinib mesylate
• Chronic phase
• Accelerated phase
• Acute leukemia must be in hematologic remission (less than 5% of blood or marrow blasts)
• Must have a first-degree relative donor matched at 6/6 HLA antigens (A, B, and DR)
• No active CNS involvement by malignancy

PATIENT CHARACTERISTICS: Age

• 18 to 75

Performance status

• ECOG 0-1

Life expectancy

• At least 3 months

Hematopoietic

• Not specified

Hepatic

• ALT and AST no greater than 2.5 times upper limit of normal*
• Bilirubin less than 2.5 mg/dL*
• No chronic active hepatitis B
• Hepatitis B core antibody-positive allowed, provided patient is surface antigen-negative and without evidence of active infection
• No hepatitis C infection NOTE: *Values above these levels may be accepted, at the discretion of the principal investigator or study chairman, if the elevations are due to liver involvement

Renal

• Creatinine no greater than 1.5 mg/dL
• Creatinine clearance at least 50 mL/min

Cardiovascular

• LVEF greater than 45% by 2-dimensional ECHO or MUGA

Pulmonary

• DLCO greater than 50% of expected

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 1 year after study participation
• HIV negative
• No active infection that is not responding to antimicrobial therapy
• No psychiatric illness that would preclude study compliance or informed consent

PRIOR CONCURRENT THERAPY: Biologic therapy

• See Disease Characteristics

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• No concurrent steroids as antiemetics during chemotherapy
• No concurrent steroids during transplantation

Radiotherapy

• Not specified

Surgery

• See Disease Characteristics

Other

• At least 2 weeks since prior therapy and recovered

Maryland
      Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support, Bethesda,  Maryland,  20892-1182,  United States; Recruiting

Study chairs or principal investigators

Michael R. Bishop, MD,  Study Chair,  National Cancer Institute (NCI)   

Study ID Numbers:  CDR0000350350; NCI-04-C-0055; NCT00077480
Record last reviewed:  January 2004
Last Updated:  December 6, 2004
Record first received:  February 10, 2004
ClinicalTrials.gov Identifier:  NCT00077480
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08