Fludarabine, Total-Body Irradiation, and Donor Stem Cell Transplant Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Chronic Myelogenous Leukemia

OBJECTIVES:

Primary

• Determine whether increasing the intensity of a nonmyeloablative conditioning regimen comprising fludarabine and total body irradiation allows achievement of a donor T-cell chimerism level of > 40% on day 28 post-transplantation in 90% or more of patients with chronic myelogenous leukemia undergoing allogeneic peripheral blood stem cell transplantation and immunosuppression comprising cyclosporine and mycophenolate mofetil.
• Determine the feasibility of reducing the day 84 graft rejection rate/graft failure to < 10% in patients treated with this regimen.
• Determine the feasibility of maintaining the incidence of grade 4 acute graft-versus-host disease at < 10% in patients treated with this regimen.
• Determine the feasibility of maintaining the day 200 nonrelapse mortality rate at < 15% in patients treated with this regimen.

Secondary

• Determine the rate of complete cytogenetic remission in patients treated with this regimen.
• Determine the probability of actuarial disease-free survival of patients treated with this regimen.
• Determine the pharmacokinetics of mycophenolate mofetil and fludarabine in these patients.

OUTLINE: This is a multicenter, dose-escalation study of fludarabine and total-body irradiation (TBI).

• Nonmyeloablative conditioning regimen: Patients receive fludarabine IV on days -4 to -2 OR days -6 to -2. Patients undergo TBI on day 0.
• Allogeneic peripheral blood stem cell transplantation (PBSCT): After the completion of TBI, patients undergo allogeneic PBSCT on day 0.
• Immunosuppression: Patients receive oral cyclosporine twice daily on days -3 to 100 followed by a taper to day 177 in the absence of graft-versus-host disease (GVHD). Beginning within 4-6 hours after the completion of PBSCT, patients receive oral mycophenolate mofetil 2-3 times daily on days 0-40 followed by a taper to day 96 in the absence of GVHD.

Cohorts of 5-25 patients receive cumulative doses of fludarabine and escalating doses of TBI until 2 of 5, 3 of 10-15, 4 of 20, or 5 of 25 patients experience a day 28 post-transplant T-cell chimerism level ≤ 40% and/or a day 84 post-transplant graft rejection rate of > 10%.

After completion of study transplantation, patients are followed 3 times weekly for 3 months, at 6, 12, and 18 months, annually for 5 years, and then periodically thereafter.

PROJECTED ACCRUAL: A total of 5-75 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Diagnosis of chronic myelogenous leukemia (CML), meeting 1 of the following criteria:

• First or second chronic phase

• Philadelphia chromosome-positive (Ph+) disease by cytogenetics or fluorescent in situ hybridization (FISH)
• First accelerated phase, meeting any of the following criteria:

• More than 10% but < 30% myeloblasts and promyelocytes in bone marrow or peripheral blood
• Any additional clonal cytogenetic abnormalities
• Increasing splenomegally
• Extramedullary tumor
• WBC, platelet count, or hematocrit pertubations not controlled by therapy with hydroxyurea, interferon, or imatininb mesylate
• Persistent unexplained fever or bone pain
• Less than 5% blasts in marrow at time of transplant

• No blast crisis
• No other curative therapy exists
• Received prior imatinib mesylate AND meets ≥ 1 of the following criteria:

• Hematologic evidence of disease progression
• Lack of complete hematologic response after 3 months of treatment with imatinib mesylate
• Cytogenetic evidence of disease progression, defined as an increase in Ph+ cells or BCR/ABL-positive (BCR/ABL+) cells of > 25%
• Lack of complete cytogenetic remission (no Ph+ cells by cytogenetic analysis or BCR/ABL+ cells by FISH) after 1 year of treatment with imatinib mesylate
• At least 65% Ph+ cells by cytogenetic analysis or BCR/ABL+ cells by FISH after 6 months of treatment with imatinib mesylate
• Less than 3-log reduction in BCR/ABL mRNA levels by quantitative polymerase chain reaction (Q-PCR) compared to a standard baseline level after 1 year of treatment with imatinib mesylate
• Molecular evidence of disease progression, defined as > 1 log increase in BCR/ABL mRNA levels by Q-PCR, detected in 2 samples
• Experienced adverse events with imatinib mesylate treatment that would preclude further administration of the drug
• Patient refused further treatment with imatinib mesylate despite lack of disease progression
• Refused conventional myeloablative allogeneic stem cell transplantation OR at high risk for regimen-related toxicity due to pre-existing medical conditions (for patients < 50 years of age)
• Unrelated donor available

• Matched at HLA-A, -B, -C, -DRB1, and -DQB1 by high-resolution typing

• A single allele* disparity for HLA-A, -B, or -C allowed
• Negative anti-donor cytotoxic crossmatch
• Not a marrow donor NOTE: *Patient and donor pairs homozygous at a mismatched allele (e.g., the patient is A*0101 and the donor is A*0201) are considered a two-allele mismatch and are not allowed
• No CNS involvement with disease that is refractory to intrathecal chemotherapy

PATIENT CHARACTERISTICS:

Age

• Any age

Performance status

• Karnofsky 70-100%
• Lanksy 50-100% (for pediatric patients)

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 prolongation of PT
• No ascites related to portal hypertension
• No bacterial or fungal liver abscess
• No biliary obstruction
• No chronic viral hepatitis AND bilirubin > 3 mg/dL
• No symptomatic biliary disease

Renal

• Not specified

Cardiovascular

• Ejection fraction ≥ 40%
• No cardiac failure requiring therapy
• No poorly controlled hypertension (i.e., blood pressure ≥ 150/90 mm Hg despite standard medication)

Pulmonary

• DLCO ≥ 35% (corrected)
• No requirement for supplementary continuous oxygen
• Pulmonary nodules allowed at the discretion of the principal investigator

Immunologic

• HIV negative
• No uncontrolled systemic infection
• No fungal infection with radiological progression after treatment with amphotericin B or active triazole for > 1 month

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception during and for 12 months after completion of study treatment
• No other active malignancy except nonmelanoma skin cancer
• No prior localized malignancy at high risk (≥ 20%) of recurrence

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics
• See Chemotherapy

Chemotherapy

• See Disease Characteristics
• More than 3 weeks since prior cytotoxic chemotherapy

• Imatinib mesylate and interferon are not considered cytotoxic chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified