Busulfan, Fludarabine, and Total-Body Irradiation in Treating Patients Who Are Undergoing a Donor Stem Cell Transplant for Hematologic Cancer (Bu Flu TBI)

OHSU Knight Cancer Institute

Status and phase: Completed; Phase 2; Phase 1

Conditions: Multiple Myeloma and Plasma Cell Neoplasm; Precancerous Condition; Chronic Myeloproliferative Disorders; Lymphoma; Leukemia; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms

Treatments: Drug: Granulocyte colony-stimulating factor (G-CSF); Drug: busulfan; Procedure: peripheral blood stem cell transplantation; Biological: therapeutic allogeneic lymphocytes; Drug: mycophenolate mofetil; Drug: fludarabine phosphate; Drug: cyclosporine; Drug: Methotrexate; Radiation: Total Body Irradiation (TBI); Drug: Phenytoin

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00245037

IRB00000210

OHSU-HEM-05011-L (Other Identifier)

P30CA016058 (U.S. NIH Grant/Contract)

OHSU-210 (Other Identifier)

Details and patient eligibility

About

RATIONALE: Giving low doses of chemotherapy, such as fludarabine and busulfan, before a donor peripheral blood 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 and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this 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 the transplant may stop this from happening.

PURPOSE: This phase I/II trial is studying the side effects of giving busulfan and fludarabine together with total-body irradiation and to see how well they work in treating patients who are undergoing a donor stem cell transplant for hematologic cancer.

Full description

OBJECTIVES:

Primary

• To assess safety and toxicity of the addition of busulfan added to an established fludarabine and low-dose total-body irradiation (TBI) conditioning regimen for non-myeloablative allogeneic transplantation in patients with hematologic malignancies. (Phase I)
• To assess the non-relapse mortality 1-year after conditioning with busulfan and fludarabine/TBI in patients with hematologic malignancies at moderate to high risk for graft rejection and/or relapse of underlying disease. (Phase II)

Secondary

• To assess overall survival 1-year survival. (Phase II)
• To assess the incidence of graft rejection. (Phase II)
• To assess the incidence of grade II-IV acute graft-vs-host disease (GVHD) and chronic extensive GVHD. (Phase II)
• To assess rates of disease progression and/or relapse-related mortality. (Phase II)
• To determine non-hematologic grade III-IV organ specific toxicity. (Phase II)

OUTLINE:

• Nonmyeloablative-conditioning regimen: Patients receive busulfan IV on day -5 and fludarabine IV over 30 minutes on days -4 to -2. Patients undergo total body irradiation on day 0.
• Allogeneic peripheral blood stem cell transplantation (PBSC): Patients undergo donor PBSC infusion on day 0.
• Graft-versus-host disease prophylaxis: Patients receive oral cyclosporine twice daily on days -3 to 56 followed by a taper to day 180. Patients with a related stem cell donor receive oral mycophenolate mofetil twice daily on days 0-28. Patients with an unrelated stem cell donor receive oral mycophenolate mofetil 3 times daily on days 0-28 followed by a taper twice daily to day 56. Patients with evidence of relapse or persistent disease may also receive up to 3 donor lymphocyte infusions.

PROJECTED ACCRUAL: A total of 225 patients will be accrued for this study; 25 patients accrued into the Phase I and 200 patients into Phase II.

Enrollment: 147 patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

• Diagnosis of a hematologic malignancy of 1 of the following high-risk types:

  • Acute lymphoblastic leukemia
  • Acute myeloid leukemia
  • Chronic myelogenous leukemia
  • Chronic lymphocytic leukemia
  • Myelodysplastic syndromes
  • Myeloproliferative disorder
  • Multiple myeloma
  • Plasma cell dyscrasias
  • Non-Hodgkin lymphoma
  • Hodgkin disease

PATIENT CHARACTERISTICS:

Performance status

• Karnofsky 50-100%

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• No liver failure
• No cirrhosis with evidence of portal hypertension
• No alcoholic hepatitis
• No esophageal varices
• No chronic hepatitis
• No other liver disease

Renal

• Not specified

Cardiovascular

• Left Ventricular Ejection Fraction (LVEF) > 35%
• No symptomatic coronary artery disease or cardiac failure requiring therapy

Pulmonary

• Diffusing capacity of lung for carbon monoxide (DLCO) > 30%
• Total lung capacity > 30%
• Forced expiratory volume in 1 second (FEV_1) > 30%
• No supplementary continuous oxygen

Other

• HIV negative
• No active nonhematologic malignancy except localized skin cancer
• No overt organ dysfunction

PRIOR CONCURRENT THERAPY:

• Not specified

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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147 participants in 1 patient group

Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)

Experimental group

Description:

Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0

Treatment:

Drug: Methotrexate

Radiation: Total Body Irradiation (TBI)

Procedure: peripheral blood stem cell transplantation

Drug: cyclosporine

Drug: mycophenolate mofetil

Drug: fludarabine phosphate

Biological: therapeutic allogeneic lymphocytes

Drug: Phenytoin

Drug: Granulocyte colony-stimulating factor (G-CSF)

Drug: busulfan