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

PURPOSE: This phase I/II trial is studying the side effects and best dose of fludarabine and total-body irradiation followed by cyclosporine and mycophenolate mofetil and to see how well they work in treating patients who are undergoing a donor stem cell transplant for chronic myelogenous leukemia.

Condition	Intervention	Phase
accelerated phase chronic myelogenous leukemia Philadelphia chromosome positive chronic myelogenous leukemia relapsing chronic myelogenous leukemia chronic phase chronic myelogenous leukemia	Drug: cyclosporine  Drug: fludarabine  Drug: mycophenolate mofetil  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 I Phase II

Further Study Details: 

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 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 in 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.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of chronic myelogenous leukemia (CML), meeting 1 of the following criteria:
• First or second chronic phase
• First accelerated phase
• No other curative therapy exists
• Philadelphia chromosome-positive (Ph+) disease
• 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 fluorescent in situ hybridization [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

• 18 and over

Performance status

• Karnofsky 70-100%

Life expectancy

• Not specified

Hematopoietic

• Not specified

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 (≥ 10%) 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

Please refer to this study by ClinicalTrials.gov identifier  NCT00119340

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
      Universita 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:  CDR0000432959; FHCRC-1939.00; NCT00119340
Record last reviewed:  July 2005
Last Updated:  July 25, 2005
Record first received:  July 12, 2005
ClinicalTrials.gov Identifier:  NCT00119340
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-07-26