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

Study Overview
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Brief Summary
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RATIONALE: Giving low doses of chemotherapy, such as fludarabine, and radiation therapy before a donor 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). 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 transplant may stop this from happening. PURPOSE: This phase I/II trial is studying the side effects and best dose of fludarabine, total-body irradiation, and donor stem cell transplant followed by cyclosporine and mycophenolate mofetil and to see how well they work in treating patients with chronic myelogenous leukemia.

Detailed Description
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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.

Official Title
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Fludarabine and Low-Dose TBI Dose Escalation to Determine the Optimal Regimen for Achieving High Rates Engraftment of Unrelated Donor Peripheral Blood Stem Cell in Patients With Chronic Myeloid Leukemia - A Multi-Center Trial

Conditions
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Leukemia

Intervention / Treatment
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* Drug: cyclosporine
* Drug: fludarabine phosphate
* Drug: mycophenolate mofetil
* Procedure: peripheral blood stem cell transplantation
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: cyclosporine|nan|
|Drug: fludarabine phosphate|nan|
|Drug: mycophenolate mofetil|nan|
|Procedure: peripheral blood stem cell transplantation|nan|
|Radiation: radiation therapy|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Increase number of patients with donor T-cell chimerism from > 40% to 90% on day 28 post-transplant |  |  | 
| Reduce graft rejection rate to < 10% day 84 post-transplant |  |  | 
| Maintain acute graft-vs-host disease (GVHD) incidence of 10% |  |  | 
| Maintain nonrelapse mortality incidence of < 15% on day 200 post-transplant |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of complete cytogenetic remission |  |  | 
| Probability of actuarial disease-free survival |  |  | 
| Pharmacokinetics |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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accelerated phase chronic myelogenous leukemia, Philadelphia chromosome positive chronic myelogenous leukemia, relapsing chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia