Cyclophosphamide and Anti-thymocyte Globulin Followed By Methotrexate and Cyclosporine in Preventing Chronic Graft-Versus-Host Disease in Patients With Severe Aplastic Anemia Undergoing Donor Bone Marrow Transplant

Study Overview
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Brief Summary
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This clinical trial is studying how well giving cyclophosphamide together with anti-thymocyte globulin followed by methotrexate and cyclosporine works in preventing chronic graft-vs-host disease (GVHD) in patients with severe aplastic anemia undergoing donor bone marrow transplant. Giving low doses of chemotherapy, such as cyclophosphamide, before a donor bone marrow transplant helps stop the growth of abnormal 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 abnormal cells. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving anti-thymocyte globulin before and methotrexate and cyclosporine after transplant may stop this from happening

Detailed Description
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PRIMARY OBJECTIVES: I. Minimize the incidence of chronic GVHD by restricting the transplanted marrow dose to 2.0-2.5 x 10^8 nucleated cells/kg. SECONDARY OBJECTIVES: I. Engraftment and overall survival. OUTLINE: CONDITIONING REGIMEN: Patients receive cyclophosphamide intravenously (IV) on days -5 to -2 and anti-thymocyte globulin IV over 4-10 hours on days -4 to -2. TRANSPLANTATION: Patients undergo allogeneic bone marrow transplantation on day 0. GVHD PROPHYLAXIS: Patients receive methotrexate IV on days 1, 3, 6, and 11 and cyclosporine IV over 1 hour or orally (PO) twice daily on days -1 to 50, followed by a taper until 6 months after grafting. After completion of study treatment, patients are followed up at on day 180, 1 year, 1.5 years, 2 years, 3 years, and yearly thereafter.

Official Title
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Cyclophosphamide and Antithymocyte Globulin Conditioning Regimen for Marrow Transplantation From HLA-Matched Family Members for Severe Aplastic Anemia: Effect of Marrow Cell Dose on Chronic Graft-vs.-Host Disease: A Multi-Center Trial

Conditions
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Aplastic Anemia

Intervention / Treatment
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* Drug: cyclophosphamide
* Biological: anti-thymocyte globulin
* Drug: cyclosporine
* Procedure: allogeneic bone marrow transplantation
* Drug: methotrexate
* Genetic: DNA analysis
* Other: flow cytometry
* Genetic: polymorphism analysis
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any patient who has aplastic anemia with marrow failure involving 2 of the three following criteria: granulocytes < 500/uL; a corrected reticulocyte count of < 1%; platelet count of < 20,000/uL Availability of an human leukocyte antigen (HLA)-matched family member DONOR: Family member who is HLA-matched DONOR: If more than one HLA-matched family member is available, priority will be given to a donor who is genotypically HLA-identical, of appropriate cytomegalovirus (CMV) serology, ABO compatible, and, in case of a female donor, non-parous Exclusion Criteria: Severe disease other than aplastic anemia that would severely limit the probability of survival during the graft procedure: Patients who have developed clonal cytogenetic abnormalities or myelodysplastic syndrome (preleukemia) Patients with Fanconi's anemia Aplasia secondary to radiation or cytotoxic chemotherapy Patients with paroxysmal nocturnal hemoglobinuria who have not developed aplastic anemia Severe organ toxicities: Cardiac insufficiency requiring treatment or symptomatic coronary artery disease; Severe hypoxemia , partial pressure of oxygen (pO2) < 70 mm Hg, with decreased diffusion capacity of carbon monoxide (DLCO) < 70% of predicted; or mild hypoxemia, pO2 < 80 mm Hg with severely decreased DLCO < 60% of predicted; Impaired renal function (creatinine > 2 times upper limit of normal or estimated creatinine clearance < 60 ml/min) Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month Human immunodeficiency virus (HIV)-positive patients Females who are pregnant or breast-feeding DONOR: Donors who have increase anesthetic risk and are not able psychologically and medically to tolerate the procedure DONOR: HIV-positive donors

Ages Eligible for Study
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Maximum Age: 65 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (conditioning regimen, transplant, GVHD prophylaxis)<br>Patients receive a conditioning regimen comprising cyclophosphamide IV on days -5 to -2 and anti-thymocyte globulin IV over 4-10 hours on days -4 to -2. Patients undergo allogeneic bone marrow transplantation on day 0. Patients then receive GVHD prophylaxis comprising methotrexate IV on days 1, 3, 6, and 11 and cyclosporine IV over 1 hour or PO twice daily on days -1 to 50, followed by a taper until 6 months after grafting. | Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Biological: anti-thymocyte globulin<br>* Given IV<br>* Other names: Thymoglobulin;Drug: cyclosporine<br>* Given IV or PO<br>* Other names: Sandimmune;Procedure: allogeneic bone marrow transplantation<br>* Undergo allogeneic bone marrow transplantation<br>* Other names: transplantation, allogenic bone marrow;Drug: methotrexate<br>* Given IV<br>* Other names: MTX;Genetic: DNA analysis<br>* Correlative studies<br>Other: flow cytometry<br>* Correlative studies<br>Genetic: polymorphism analysis<br>* Correlative studies<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Chronic GVHD | Analyzed using cumulative incidence estimates, treating death or rejection as competing risk events. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Days to Neutrophil Recovery to >500/uL | First of 3 consecutive days of neutrophils >500/uL | 100 days post-transplant | 
| Overall Survival | Number of patients alive at one year | From the time of enrollment until death from any cause up to one year |