Allogeneic Bone Marrow Transplantation Using Less Intensive Therapy

Study Overview
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Brief Summary
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RATIONALE: A peripheral stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy, or that have become cancer. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclophosphamide and fludarabine together with total-body irradiation followed by cyclosporine and mycophenolate mofetil before the transplant may stop this from happening. PURPOSE: This clinical trial is studying how well giving combination chemotherapy together with radiation therapy followed by cyclosporine and mycophenolate mofetil works in treating patients who are undergoing a donor stem cell transplant for hematologic cancer, metastatic breast cancer, or kidney cancer.

Detailed Description
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OBJECTIVES: Determine if a nonmyeloablative regimen comprising cyclophosphamide, fludarabine, and radiotherapy followed by cyclosporine and mycophenolate mofetil provides a prompt and durable donor engraftment in patients with hematologic malignancies or kidney cancer who are undergoing allogeneic stem cell transplantation. Determine the safety of this nonmyeloablative transplantation regimen in these patients. Determine the risk of graft-versus-host-disease in patients treated with this regimen. Determine the antineoplastic potency of nonmyeloablative stem cell transplantation in patients treated with this regimen. Determine the effect of lower doses of daily fludarabine on treatment-related mortality (TRM) OUTLINE: Patients are stratified according to risk (standard vs high). Preparative regimen*: Patients receive cyclophosphamide intravenously (IV) over 2 hours on day -6 and fludarabine IV over 1 hour on days -6 to -2. Patients undergo total body irradiation on day -1. Some patients also receive anti-thymocyte globulin (ATG)** IV every 12 hours on days -6 to -4. Patients who receive ATG* include the following: Related donor recipients who have not received combination chemotherapy within the past 6 months Unrelated donor recipients who have not received combination chemotherapy within the past 3 months Unrelated donor recipients who have received only 1 induction course for the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or blastic phase chronic myelogenous leukemia (CML) NOTE: **Patients who underwent prior autologous stem cell transplantation in the past year do not receive ATG. Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo allogeneic PBSCT on day 0. Graft-versus-host-disease prophylaxis: Patients receive cyclosporine IV over 2 hours beginning on day -3 and continuing until at least day 100. Patients also receive mycophenolate mofetil IV or orally twice daily on days -3 to 30. Donor lymphocyte infusion (DLI): Patients without active GVHD but deteriorating donor chimerism may receive DLI IV over 2 hours. After completion of study treatment, patients are followed periodically for 2 years. PROJECTED ACCRUAL: A total of 300 patients will be accrued for this study.

Official Title
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Allogeneic Bone Marrow Transplantation Using Less Intensive Therapy

Conditions
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Kidney Cancer, Leukemia, Lymphoma, Multiple Myeloma, Plasma Cell Neoplasm, Myelodysplastic Syndromes

Intervention / Treatment
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* Biological: anti-thymocyte globulin
* Drug: cyclophosphamide
* Drug: cyclosporine
* Drug: fludarabine
* Drug: mycophenolate mofetil
* Procedure: stem cell transplantation
* Radiation: total body irradiation
* Drug: filgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Standard patients will be enrolled into Arms 1-6. High risk patients (transplant with aplasia) will be considered separately in Arm 7. Age and Graft criteria (all patients) Patient's < or = 75 years old with a 5/6 or 6/6 related donor match are eligible. Patient's < or = 75 years who have a 7-8/8 HLA-A,B,C,DRB1 allele matched unrelated volunteer marrow and/or peripheral blood stem cell (PBSC) donor match are eligible. Disease Criteria (standard risk patients) Acute myelogenous leukemia Acute lymphocytic leukemia Chronic myelogenous leukemia all types except blast crisis (note treated blast crisis in chronic phase is eligible). Non-Hodgkins lymphoma (NHL), Hodgkins, chronic lymphocytic leukemia, multiple myeloma demonstrating chemosensitive disease Acquired bone marrow failure syndromes Myelodysplastic syndrome of all subtypes including refractory anemia (RA) or all IPSS categories if severe pancytopenia, transfusion requirements not responsive to therapy, or high risk cytogenetics. Blasts must be less than 5%. If >5% requires therapy (induction or Hypomethylating agents) pre-transplant to decrease disease burden. Renal cell cancer, Chronic myeloproliferative disorder, i.e. myelofibrosis Disease Criteria (High risk patients on Arm 7) Patients with refractory leukemia or MDS may be taken to transplant in aplasia after induction or re-induction chemotherapy or radiolabeled antibody. These high risk patients will be analyzed separately in Arm 7. Adequate organ function and performance status (all patients) Exclusion Criteria: Pregnancy or breast feeding Evidence of HIV infection or known HIV positive serology Active serious infection Congenital bone marrow failure syndrome Previous irradiation that precludes the safe administration of an additional dose of 200 cGy of total body irradiation (TBI) Chronic myelogenous leukemia (CML) in refractory blast crisis Intermediate or high grade NHL, mantle cell NHL, and Hodgkins disease that is progressive on salvage therapy. Stable disease is acceptable to move forward provided it is non-bulky. Multiple Myeloma progressive on salvage chemotherapy. DONOR ELIGIBILITY Related will undergo apheresis - if donor is unable to undergo apheresis, a bone marrow harvest is acceptable; unrelated volunteer donors must be able to undergo bone marrow harvest or apheresis. All donors must be able to give informed consent. Donors weighing less than 40 kg (children) will need evaluation by a pediatrician for suitability of the apheresis procedure. Informed consent must be obtained from parent or guardian as applicable for minors.

Ages Eligible for Study
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Maximum Age: 75 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Risk Patients<br>Nonmyeloablative conditioning using fludarabine, cyclophosphamide and low dose Total Body Irradiation with or without anti-thymocyte globulin followed by allogeneic hematopoietic stem cell transplantation, immunosuppressive cyclosporine and mycophenolate mofetil and post-transplant use of bone marrow-stimulating filgrastim. | Biological: anti-thymocyte globulin<br>* ATG dose is 15 mg/kg intravenous (IV) every 12 hours for 6 doses on days -6, -5, and -4. Those that should/will receive ATG in the preparative regimen: Related donor recipients who have not had exposure to combination chemotherapy in the 6 months preceding transplant should Unrelated donor recipients who have not had exposure to combination chemotherapy in the 3 months preceding transplant will Unrelated donor recipients who have had only a single induction cycle for the treatment of ALL/AML or MDS or CML blast crisis should Recipients with a prior autologous transplant in the year prior to second transplant do not require ATG.<br>* Other names: ATG;Drug: cyclophosphamide<br>* Cyclophosphamide will be given in a two hour infusion, total dose 50 mg/kg on day -6.<br>* Other names: Cytoxan;Drug: cyclosporine<br>* Patients will receive cyclosporine A (CSA) therapy beginning on day -3 maintaining a level of >200. For adults the initial dose will be 2.5 mg/kg IV over 2 hours every 12 hours. For children < 40 kg the initial dose will be 2.5 mg/kg IV over 2 hours every 8 hours. Patients will receive CSA until day +100.<br>* Other names: CSA;Drug: fludarabine<br>* Fludarabine 30 mg/m^2/day intravenous (IV) on day -6 through day -2., total dose 150 mg/m^2 for 5 days.<br>* Other names: Fludara;Drug: mycophenolate mofetil<br>* Mycophenolate mofetil (MMF) 1.5 gram twice a day (BID) or if < 50 kg will be given 15 mg/kg orally(po) BID,beginning on day -3, and discontinue at day +30 or 7 days after engraftment (3 consecutive days of absolute neutrophil count (ANC) > 0.5 x 109 /L).<br>* Other names: MMF;Procedure: stem cell transplantation<br>* On day 0, if related donor, stem cells are infused via central line. If unrelated donor, marrow/PBSC is infused after arrival and processing on day 0.<br>* Other names: bone marrow transplant;Radiation: total body irradiation<br>* The dose of TBI will be 200 cGy given in a single fraction on day -1.<br>* Other names: TBI;Drug: filgrastim<br>* Patients with white blood cell (WBC) counts < 2500 any time after stem cell infusion will be started on G-CSF support at Day +5 at a dose of 5 mcg/kg intravenously or subcutaneously (IV/SQ) daily rounded to vial size until absolute neutrophil count (ANC) > 2500 for 2 consecutive days.<br>* Other names: G-CSF;|
| Experimental: Standard Risk Patients<br>Nonmyeloablative conditioning using fludarabine, cyclophosphamide and low dose Total Body Irradiation with or without anti-thymocyte globulin followed by allogeneic hematopoietic stem cell transplantation, immunosuppressive cyclosporine and mycophenolate mofetil and post-transplant use of bone marrow-stimulating filgrastim. | Biological: anti-thymocyte globulin<br>* ATG dose is 15 mg/kg intravenous (IV) every 12 hours for 6 doses on days -6, -5, and -4. Those that should/will receive ATG in the preparative regimen: Related donor recipients who have not had exposure to combination chemotherapy in the 6 months preceding transplant should Unrelated donor recipients who have not had exposure to combination chemotherapy in the 3 months preceding transplant will Unrelated donor recipients who have had only a single induction cycle for the treatment of ALL/AML or MDS or CML blast crisis should Recipients with a prior autologous transplant in the year prior to second transplant do not require ATG.<br>* Other names: ATG;Drug: cyclophosphamide<br>* Cyclophosphamide will be given in a two hour infusion, total dose 50 mg/kg on day -6.<br>* Other names: Cytoxan;Drug: cyclosporine<br>* Patients will receive cyclosporine A (CSA) therapy beginning on day -3 maintaining a level of >200. For adults the initial dose will be 2.5 mg/kg IV over 2 hours every 12 hours. For children < 40 kg the initial dose will be 2.5 mg/kg IV over 2 hours every 8 hours. Patients will receive CSA until day +100.<br>* Other names: CSA;Drug: fludarabine<br>* Fludarabine 30 mg/m^2/day intravenous (IV) on day -6 through day -2., total dose 150 mg/m^2 for 5 days.<br>* Other names: Fludara;Drug: mycophenolate mofetil<br>* Mycophenolate mofetil (MMF) 1.5 gram twice a day (BID) or if < 50 kg will be given 15 mg/kg orally(po) BID,beginning on day -3, and discontinue at day +30 or 7 days after engraftment (3 consecutive days of absolute neutrophil count (ANC) > 0.5 x 109 /L).<br>* Other names: MMF;Procedure: stem cell transplantation<br>* On day 0, if related donor, stem cells are infused via central line. If unrelated donor, marrow/PBSC is infused after arrival and processing on day 0.<br>* Other names: bone marrow transplant;Radiation: total body irradiation<br>* The dose of TBI will be 200 cGy given in a single fraction on day -1.<br>* Other names: TBI;Drug: filgrastim<br>* Patients with white blood cell (WBC) counts < 2500 any time after stem cell infusion will be started on G-CSF support at Day +5 at a dose of 5 mcg/kg intravenously or subcutaneously (IV/SQ) daily rounded to vial size until absolute neutrophil count (ANC) > 2500 for 2 consecutive days.<br>* Other names: G-CSF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neutrophil and Donor Cell Engraftment | Successful sustained engraftment is defined as primary neutrophil engraftment by day 42 and e90% donor cells at day 100, with or without DLI. Engraftment based on absolute neutrophil count of donor origin > 0.5 x 10e9 /L for 3 days by day 42 | Day 42 and Day 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serious Adverse Events | Safety by development of severe adverse events within 100 days of transplant | Day 100 | 
| Transplant Related Mortality | > 30% transplant related mortality at 100 days (non-relapse). | Day 100 | 
| Overall Survival |  | 1 year | 
| Acute Graft-Versus-Host Disease | Grade III-IV graft versus host disease | Day 100 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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leukemia, lymphoma, myeloma