Reduced Intensity Total Body Irradiation + Thymoglobulin Followed by Allogeneic PBSCT

Study Overview
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Brief Summary
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One of two different doses of thymoglobulin will allow bone marrow engraftment with minimal Graft-versus-Host Disease and allow adequate immune response to allow the transplanted stem cells to replace the tumor cells.

Detailed Description
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This randomized phase II trial studies how well giving low dose total-body irradiation (TBI) with anti-thymocyte globulin followed by donor peripheral blood stem cell transplant (PBSCT) works in treating patients with hematologic malignancies. Giving reduced intensity total-body irradiation and anti-thymocyte globulin before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem 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 total-body irradiation together with antithymocyte globulin before transplant may stop this from happening.

Official Title
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Reduced Intensity Myeloablative Total Body Irradiation and Thymoglobulin Followed by Allogeneic Peripheral Blood Stem Cell Transplantation

Conditions
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Non-Hodgkin's Lymphoma, Leukemia, Multiple Myeloma, Acute Myeloid Leukemia, Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
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* Biological: Thymoglobulin
* Radiation: Total-Body Irradiation
* Procedure: Allogeneic PBSCT or BMT
* Drug: Tacrolimus
* Drug: Mycophenolate Mofetil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with hematological malignancies for which allogeneic stem cell transplantation indicated including non-Hodgkin lymphoma (NHL), multiple myeloma (MM), acute myeloid leukemia (AML), Hodgkin lymphoma (HD), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) Patients with HLA compatible related or unrelated stem cell donor, willing and able to serve as an allogenic HSC donor. Unrelated donors have to be matched at HLA-A, B, C and DRB1 loci. A single locus mismatch will be tolerated in the event a more closely matched donor is not available. Patients age >/=40 to </=70 with an ECOG performance status < 2 Patients between 18 and 40 years of age will be eligible only if they have co-morbidities precluding conventional allogeneic transplantation with full intensity myeloablative conditioning Adequate cardiac, pulmonary, renal and hepatic function for transplant Negative serology for HIV Negative serum pregnancy test Patients who have received therapeutic radiation to a localized field will be eligible, provided critical structure tolerance doses have not been exceeded Patients who have had prior myeloablative autologous transplant will be eligible Exclusion Criteria: Evidence of uncontrolled viral, fungal, bacterial infection Evidence of active meningeal or CNS disease Prior therapy with rabbit ATG, prior treatment with equine ATG is allowed if more than 3 months ago Breast feeding mothers are excluded

Ages Eligible for Study
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Minimum Age: 40 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATG 1.7 mg/kg, TBI, transplant<br>(Rabbit-ATG;Thymoglobulin,Genzyme) ATG 5.1 mg/kg in three divided doses (1.7 mg/kg/d) given over three days (day -9 to -7) followed by 450 cGy TBI and tacrolimus plus MMF GVHD prophylaxis. Patients receive lower dose anti-thymocyte globulin IV on days -9 to -7. Patients undergo total-body radiation (TBI) twice daily (BID) on day -1 and once daily (QD) on day 0. Patients then undergo peripheral blood stem cells or bone marrow transplant on day 0. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: patients receive tacrolimus orally (PO) on days -2 to 90-120 with taper for 2 months, and mycophenolate mofetil (MMF) PO BID on days 0-30. | Biological: Thymoglobulin<br>* Patients eligible for participation in this study will be randomized between receiving rabbit ATG for 3 days. Thymoglobulin will be administered according to VCU BMT standard of care starting day -9 and continued daily through day -7.<br>* Other names: Rabbit-ATG;Radiation: Total-Body Irradiation<br>* Undergo TBI<br>* Other names: Total Body Irradiation [TBI];Procedure: Allogeneic PBSCT or BMT<br>* Undergo allogeneic PBSCT or BMT<br>* Other names: HSCT;Drug: Tacrolimus<br>* Given PO<br>* Other names: Protopic;Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;|
| Experimental: ATG 2.5 mg/kg/d, TBI, transplant<br>(Rabbit-ATG;Thymoglobulin,Genzyme) ATG 7.5 mg/kg in three divided doses (2.5 mg/kg/d) given over three days (day -9 to -7) followed by 450 cGy TBI and tacrolimus plus MMF GVHD prophylaxis. Patients receive higher dose anti-thymocyte globulin intravenously (IV) on days -9 to -7. Patients undergo total-body radiation (TBI) twice daily (BID) on day -1 and once daily (QD) on day 0. Patients then undergo peripheral blood stem cells or bone marrow transplant on day 0. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: patients receive tacrolimus orally (PO) on days -2 to 90-120 with taper for 2 months, and mycophenolate mofetil (MMF) PO BID on days 0-30. | Biological: Thymoglobulin<br>* Patients eligible for participation in this study will be randomized between receiving rabbit ATG for 3 days. Thymoglobulin will be administered according to VCU BMT standard of care starting day -9 and continued daily through day -7.<br>* Other names: Rabbit-ATG;Radiation: Total-Body Irradiation<br>* Undergo TBI<br>* Other names: Total Body Irradiation [TBI];Procedure: Allogeneic PBSCT or BMT<br>* Undergo allogeneic PBSCT or BMT<br>* Other names: HSCT;Drug: Tacrolimus<br>* Given PO<br>* Other names: Protopic;Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Comparison of Functional Immune Reconstitution at 6-9 Months Following Transplant as Measured by Antibody Response to Vaccination With Inactivated Hepatitis A or B Vaccine. | A positive test result will indicate immune reconstitution, while a negative test results will indicate lack of immune reconstitution. Participants not done (ND) will be counted with the negative (Neg). | Up to 9 months following transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Engraftment of Donor Hematopoietic Stem Cells, as Measured by Time in Days to Neutrophil and Platelet Count Recovery Following Allogeneic PBSCT. |  | Up to 52 weeks post transplant. | 
| Survival |  | 2-year survival rate (%) | 
| Treatment Related Mortality |  | Day 100 | 
| Event-free Survival |  | 2 years | 
| Relapse | Patients with different disease relapses was determined according to current clinical standards based on the disease. For example, AML or MDS relapse is determined by a bone marrow biopsy. Multiple myeloma relapse requires a number of labs and/or biopsy to diagnose such as SPEP, UPEP, immunofixation, serum and urine light chains. In lymphoma disease is followed using CT and/or PET scans. | 2 year relapse rate (%) | 
| Donor Lymphocyte Infusion |  | 2 year rate of DLI | 
| Acute Graft-Versus-Host Disease (GVHD) |  | 2 year rate (%) | 
| Chronic Graft-Versus-Host Disease (GVHD) |  | 2 year GVHD rate | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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total body irradiation, Allogeneic Peripheral Blood Stem Cell Transplantation, thymoglobulin