RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy. Sometimes the transplanted cells can make an immune response against the body's normal tissues. Cyclosporine and methotrexate may prevent this from happening.

PURPOSE: Phase II trial to study the effectiveness of combining cyclosporine with methotrexate in preventing graft-versus-host disease following chemotherapy and allogeneic stem cell transplantation in patients who have refractory or relapsed hematologic cancer, myelodysplastic syndrome, or myeloproliferative disorder.

OBJECTIVES:

Primary

• Determine the efficacy of cyclosporine and mini-dose methotrexate as prophylaxis for acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (HSCT) after a modified induction chemotherapy regimen comprising etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, fludarabine, and rituximab (EPOCH-F/R) and reduced-intensity conditioning comprising fludarabine and cyclophosphamide in patients with refractory or relapsed hematologic malignancies or myelodysplastic syndromes or myeloproliferative disorders.

Secondary

• Determine the toxicity of EPOCH-F/R in these patients.
• Determine the impact of this GVHD prophylaxis regimen on hematologic recovery and donor/recipient chimerism in these patients.
• Determine the efficacy of EPOCH-F/R, in terms of anti-tumor activity and sequential host immune depletion prior to allogeneic HSCT, in these patients.
• Determine the overall response rate of patients with disease progression after allogeneic HSCT treated with salvage therapies.

OUTLINE: This is a pilot study.

• Induction chemotherapy: Patients receive fludarabine IV over 30 minutes, etoposide IV continuously over 24 hours, doxorubicin IV continuously over 24 hours, and vincristine IV continuously over 24 hours on days 1-4. Patients also receive oral prednisone on days 1-5 and cyclophosphamide IV over 30 minutes on day 5. Patients receive filgrastim (G-CSF) subcutaneously (SC) daily beginning on day 6 and continuing until blood counts recover. Patients with CD20+ B-cell malignancies receive rituximab IV on day 1. Treatment repeats every 21 days for up to 3 courses in the absence of unacceptable toxicity or disease progression.
• Transplantation conditioning: Within 7-21 days after the completion of induction chemotherapy, patients receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours daily on days -6 to -3.
• Allogeneic stem cell transplantation (ASCT): Patients undergo allogeneic stem cell transplantation on day 0. Patients receive G-CSF SC beginning on day 0 and continuing until blood counts recover.
• Graft-versus-host disease prophylaxis: Patients receive cyclosporine IV over 2 hours or orally every 12 hours on day -1 until day 180. Patients also receive methotrexate IV over 15 minutes on days 1, 3, 6, and 11.

Patients with persistent or progressive disease after ASCT or mixed chimerism that does not improve after tapering or discontinuing immune suppression may receive donor lymphocyte infusions.

Patients are followed twice weekly for 3 months, monthly for 3 months, every 3 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 8-40 patients will be accrued for this study within 2 years.

• Chronic Myeloproliferative Disorders
• Graft Versus Host Disease
• Leukemia
• Lymphoma
• Multiple Myeloma and Plasma Cell Neoplasm
• Myelodysplastic Syndromes
• Myelodysplastic/Myeloproliferative Diseases

• Biological: filgrastim
• Biological: rituximab
• Biological: therapeutic allogeneic lymphocytes
• Drug: cyclophosphamide
• Drug: cyclosporine
• Drug: doxorubicin hydrochloride
• Drug: etoposide
• Drug: fludarabine phosphate
• Drug: methotrexate
• Drug: prednisone
• Drug: vincristine sulfate
• Procedure: peripheral blood stem cell transplantation

DISEASE CHARACTERISTICS:

• Diagnosis of a hematologic malignancy of 1 of the following types:

  • Chronic lymphocytic leukemia, meeting 1 of the following criteria:

    • Relapsed after fludarabine therapy
    • No complete remission (CR) after salvage regimen

  • Hodgkin's or non-Hodgkin's lymphoma (all types, including mantle cell lymphoma and hepatosplenic gamma/delta T-cell lymphoma) or multiple myeloma, meeting 1 of the following criteria:

    • Primary treatment failure*
    • Relapsed after autologous stem cell transplantation (SCT)*
    • No CR after salvage regimen (for multiple myeloma only) NOTE: *Requirement waived for patients with hepatosplenic gamma/delta T-cell lymphoma

  • Acute myeloid leukemia*, meeting 1 of the following criteria:

    • First CR with high-risk cytogenetics (abnormalities other than t [8;21], t [15;17], or inv [16])
    • Second CR or greater

  • Acute lymphoblastic leukemia*, meeting 1 of the following criteria:

    • First CR with high-risk cytogenetics (e.g., t [4;11], t [1;19], t [8;14], t [9;22], or bcr-abl rearrangement)
    • Second CR or greater NOTE: *Patients with acute leukemia must be in hematologic remission, defined as less than 5% blasts in blood or bone marrow

OR

• Diagnosis of a myelodysplastic syndrome of 1 of the following types:

  • Refractory anemia with excess blasts (RAEB)
  • RAEB in transformation (if blasts are less than 10% in marrow and blood after induction chemotherapy) OR

• Diagnosis of a myeloproliferative disorder of 1 of the following types:

  • Idiopathic myelofibrosis
  • Polycythemia vera
  • Essential thrombocytosis
  • Chronic myelomonocytic leukemia

  • Chronic myelogenous leukemia, meeting 1 of the following criteria:

    • Chronic or accelerated phase (in patients 50 to 75 years old)
    • Not eligible for myeloablative allogeneic hematopoietic SCT (in patients 18 to 50 years old)
• No active CNS involvement

• First-degree relative matched donor available

  • Matched at 6/6 HLA antigens (A, B, and DR)

PATIENT CHARACTERISTICS:

Age

• 18 to 75

Performance status

• ECOG 0-2 OR
• Karnofsky 60-100%

Life expectancy

• At least 3 months

Hematopoietic

• See Disease Characteristics
• Absolute neutrophil count at least 1,000/mm^3*
• Platelet count at least 20,000/mm^3* (without transfusion) NOTE: Values below these levels may be acceptable at the discretion of the principal investigator if thought to be due to bone marrow involvement by the malignancy

Hepatic

• Bilirubin less than 2.5 mg/dL
• AST and ALT no greater than 2.5 times upper limit of normal* (higher levels accepted if there is liver involvement)

• No chronic active hepatitis B

  • Hepatitis B core antibody positive allowed if surface antigen negative and no evidence of active infection
• No hepatitis C infection NOTE: *If these values do not normalize during induction chemotherapy, patients will not be eligible for the transplantation phase, and thus will be taken off study

Renal

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

Cardiovascular

• LVEF greater than 45% by MUGA or 2-D echocardiogram

Pulmonary

• DLCO greater than 50% of expected (corrected for hemoglobin)

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• No active infection not responding to antimicrobial therapy
• No psychiatric disorder that would preclude study compliance or ability to give informed consent

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics

Chemotherapy

• See Disease Characteristics
• At least 2 weeks since prior cytotoxic chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• At least 2 weeks since prior anticancer therapy and recovered
• No concurrent combination of trimethoprim and sulfamethoxazole (i.e., co-trimoxazole) or nonsteroidal anti-inflammatory drugs during methotrexate therapy