Total-Body Irradiation and Cyclophosphamide in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer and Other Diseases

Study Overview
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Brief Summary
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RATIONALE: Giving total-body irradiation and chemotherapy, such as cyclophosphamide, before a donor stem cell transplant helps stop the patient's immune system from rejecting the donor's stem cells and helps stop the growth of cancer or abnormal cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving immunosuppressive therapy before or after transplant may stop this from happening. PURPOSE: This phase II trial is studying how well giving total-body irradiation together with cyclophosphamide works in treating patients who are undergoing donor stem cell transplant for hematologic cancer and other diseases.

Detailed Description
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OBJECTIVES: Primary Evaluate the potential efficacy of targeting cyclophosphamide to a metabolic endpoint when given together with total-body irradiation, in terms of day 200 nonrelapse mortality, in patients with hematologic cancer and other diseases who are undergoing allogeneic hematopoietic stem cell transplantation. Secondary Determine the overall survival of patients treated with this regimen. Determine the rate of relapse in patients treated with this regimen. Determine the occurrence of sinusoidal obstruction syndrome in patients treated with this regimen. Determine the occurrence of acute renal failure in these patients. Determine the occurrence of respiratory failure in these patients. OUTLINE: Conditioning regimen: Patients undergo total-body irradiation twice daily on days -6 to -4. Patients also receive cyclophosphamide IV over 1 hour on day -3 and then IV at a metabolism-based dose* on day -2. NOTE: *Patients undergo frequent blood sampling after completion of the first cyclophosphamide infusion for pharmacokinetic studies in order to determine the dose for the second cyclophosphamide infusion. Allogeneic stem cell transplantation: Patients undergo allogeneic bone marrow or peripheral blood stem cell transplantation on day 0. Graft-versus-host disease (GVHD) prophylaxis: Patients receive GVHD prophylaxis as per the attending physician, including one of the following regimens: cyclosporine and methotrexate; tacrolimus and methotrexate; tacrolimus and mycophenolate mofetil; or sirolimus, tacrolimus, and methotrexate (as per the GVHD prophylaxis regimen chosen for each patient). After completion of study treatment, patients are followed periodically for at least 200 days. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

Official Title
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A Phase II Trial of Total Body Irradiation Plus Metabolism-Based Cyclophosphamide Dosing as Preparative Therapy for Allogeneic Hematopoietic Cell Transplant for Patients With Hematological Malignancy

Conditions
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Leukemia, Lymphoma, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: cyclophosphamide
* Drug: cyclosporine
* Drug: methotrexate
* Drug: mycophenolate mofetil
* Drug: sirolimus
* Drug: tacrolimus
* Other: pharmacological study
* Procedure: allogeneic bone marrow transplantation
* Procedure: allogeneic hematopoietic stem cell transplantation
* Procedure: peripheral blood stem cell transplantation
* Radiation: total-body irradiation


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of a hematologic cancer or other disease that is unlikely to respond to conventional treatment, including any of the following: Chronic myelogenous leukemia Acute myeloid leukemia Acute lymphocytic leukemia Myelodysplastic syndromes Lymphoma Patients who have bulky tumor mass must not require additional involved-field irradiation Planning to undergo conditioning for transplantation at the Seattle Cancer Care Alliance and University of Washington Medical Center Must have an HLA-matched donor available No donors who are mismatched for > 1 HLA class I antigen or allele Negative anti-donor lymphocytotoxic crossmatch PATIENT CHARACTERISTICS: Life expectancy must not be severely limited by diseases other than malignancy No moribund patients Creatinine ≤ 1.2 mg/dL Oxygen saturation on room air ≥ 93% Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No HIV positivity No cirrhosis No hepatic fibrosis with bridging No fulminant hepatic failure No acute liver injury No persistent cholestasis No infection requiring systemic antibiotic or antifungal therapy No coronary artery disease No congestive heart failure requiring therapy PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior hematopoietic stem cell transplantation No prior radiation therapy to the liver or adjacent organs More than 30 days since prior cytoreductive chemotherapy for patients with a large body burden of tumor cells No concurrent enrollment in a phase I study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

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
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: cyclophosphamide|nan|
|Drug: cyclosporine|nan|
|Drug: methotrexate|nan|
|Drug: mycophenolate mofetil|nan|
|Drug: sirolimus|nan|
|Drug: tacrolimus|nan|
|Other: pharmacological study|nan|
|Procedure: allogeneic bone marrow transplantation|nan|
|Procedure: allogeneic hematopoietic stem cell transplantation|nan|
|Procedure: peripheral blood stem cell transplantation|nan|
|Radiation: total-body irradiation|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-relapse mortality (NRM) at 200 days |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  |  | 
| Relapse rate |  |  | 
| Sinusoidal obstruction syndrome (SOS) |  |  | 
| Acute renal failure |  |  | 
| Respiratory failure |  |  | 
| Cause of death |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), accelerated phase chronic myelogenous leukemia, adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, blastic phase chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, de novo myelodysplastic syndromes, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, noncontiguous stage II adult Burkitt lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult lymphoblastic lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, noncontiguous stage II mantle cell lymphoma, noncontiguous stage II marginal zone lymphoma, noncontiguous stage II small lymphocytic lymphoma, previously treated myelodysplastic syndromes, recurrent adult acute lymphoblastic leukemia, recurrent adult acute myeloid leukemia, recurrent adult Burkitt lymphoma, recurrent adult Hodgkin lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, recurrent mycosis fungoides/Sezary syndrome, recurrent small lymphocytic lymphoma, relapsing chronic myelogenous leukemia, secondary acute myeloid leukemia, secondary myelodysplastic syndromes, splenic marginal zone lymphoma, stage III adult Burkitt lymphoma, stage III adult Hodgkin lymphoma, stage III adult diffuse large cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage III adult lymphoblastic lymphoma, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage III mantle cell lymphoma, stage III marginal zone lymphoma, stage III small lymphocytic lymphoma, stage IV adult Burkitt lymphoma, stage IV adult Hodgkin lymphoma, stage IV adult diffuse large cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, stage IV adult immunoblastic large cell lymphoma, stage IV adult lymphoblastic lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage IV mantle cell lymphoma, stage IV marginal zone lymphoma, stage IV small lymphocytic lymphoma