Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders

Study Overview
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Brief Summary
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Rationale: Chemotherapy administration before a donor stem cell transplant is necessary to stop the patient's immune system from rejecting the donor's stem cells. When healthy stem cells from a donor are infused into the patient, the donor white blood cells can provide the missing enzyme that causes the metabolic disease. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving a monoclonal antibody, alemtuzumab, before transplant and cyclosporine and mycophenolate mofetil before and after transplant may stop this from happening. This may be an effective treatment for inherited metabolic disorders. Purpose: The design of this study is to achieve donor cell engraftment in patients with standard-risk inherited metabolic diseases with limited peri-transplant morbidity and mortality. This will be achieved through the administration of the chemotherapy regimen described. The intention is to follow transplanted patient for years after transplant monitoring them for complications of their disease and assisting families with a multifaceted interdisciplinary approach.

Detailed Description
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Primary Objective: To estimate the proportion of patients with donor derived engraftment at day 100 post transplant as defined by 80% or greater donor cells in the CD3 (T cell) fraction Secondary Objectives: To determine the incidence and severity of graft-versus-host disease (GVHD) by day 100 To determine the incidence of peri-transplant mortality (death by day 100) To monitor donor cell chimerism at various time points following allogeneic transplantation with this transplant regimen as determined at day 28, 42, 100, 6 months and yearly for 5 years.

Official Title
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Allogeneic Hematopoietic Stem Cell Transplantation for Standard Risk Inherited Metabolic Disorders

Conditions
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Mucopolysaccharidosis, Hurler Syndrome, Hunter Syndrome, Maroteaux-Lamy Syndrome, Sly Syndrome, Alpha Mannosidosis, Fucosidosis, Aspartylglucosaminuria, Adrenoleukodystrophy (ALD), Krabbe Disease, Metachromatic Leukodystrophy (MLD), Sphingolipidoses, Peroxisomal Disorders

Intervention / Treatment
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* Drug: Campath-1H
* Drug: Cyclophosphamide
* Drug: Busulfan
* Procedure: Allogeneic stem cell transplantation
* Drug: Cyclosporine A
* Drug: Mycophenolate Mofetil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have diagnosis of one of the following: mucopolysaccharidosis disorder, glycoprotein metabolic disorder, sphingolipidoses or inherited leukodystrophy, peroxisomal disorder or other inherited diseases of metabolism Must have an acceptable graft source as defined by University of Minnesota criteria Adequate organ function Exclusion Criteria: Pregnant - menstruating females must have a negative serum pregnancy test within 14 days of treatment start Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology

Ages Eligible for Study
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Maximum Age: 21 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: Transplant Patients<br>Includes patients who received allogeneic stem cell transplantation following treatment plan of Campath-1H, cyclophosphamide, cyclosporine A, mycophenolate mofetil, and busulfan. | Drug: Campath-1H<br>* Administered Days -21, -20 and -19, 0.3 mg/kg subcutaneously (SQ) or intravenously (IV)<br>* Other names: Alemtuzumab;Drug: Cyclophosphamide<br>* Administered days -10 through -6, 50 mg/kg/day intravenous (IV) over 2 hours - with Mesna continuous infusion or 5 times daily.<br>* Other names: Cytoxan(R);Drug: Busulfan<br>* Administered every 6 hours: If < or = 12 kg then 1.1 mg/kg/dose intravenous (IV). If > 12 kg then 0.8 mg/kg/dose IV<br>* Other names: Busulfex(R);Procedure: Allogeneic stem cell transplantation<br>* Administered > 24 hours after last dose of busulfan.<br>* Other names: stem cell transplant;Drug: Cyclosporine A<br>* 2.5 mg/kg/dose intravenous (IV_ beginning on day -3. Frequency of daily dosing will be based on the recipient's body weight: If body weight is ≤ 40 kg dosing will be 3 times daily If body weight is > 40 kg dosing will be 2 times daily An attempt will be made to maintain a trough cyclosporine level of 250 mg/L to 350 mg/L. Once the patient can tolerate oral medications and has a normal gastrointestinal transit time, CsA will be converted to an oral form at a dose 2 times the current IV dose (maximum 12.5 mg/kg/day as initial oral dose).<br>* Other names: CsA;Drug: Mycophenolate Mofetil<br>* 15 mg/kg/dose (max dose of 1gram) IV three times a day beginning on Day -3 at a dose based on body weight: The same dosage is used orally or intravenously. Stop MMF at day +42 or 7 days after engraftment achieved (ANC>500 x 10^6 neutrophils/L x 3 days and chimerism >90%), whichever is later.<br>* Other names: MMF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Donor Derived Engraftment | Donor derived engraftment is defined as 80 percent or greater donor cells in the recipient's bone marrow and blood cells. | Day 100 Post Transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Grade 0 Graft-Versus-Host Disease (GVHD) | GVHD grading is performed using modified Glucksberg criteria and is as follows: grade 0: absence of any skin, liver and/or gastrointestinal (GI) involvement grade 1: skin stage 1 or 2 only grade 2: skin stage 3 or liver stage 1 or lower GI stage 1 or upper GI involvement grade 3: skin stage 0 - 3 plus liver stage 2-4 or lower GI stage 2-3 grade 4: skin stage 4 or lower GI stage 4 | Day 100 Post Transplant | 
| Number of Patients With Grade 1 Graft-Versus-Host Disease (GVHD) | GVHD grading is performed using modified Glucksberg criteria and is as follows: grade 0: absence of any skin, liver and/or gastrointestinal (GI) involvement grade 1: skin stage 1 or 2 only grade 2: skin stage 3 or liver stage 1 or lower GI stage 1 or upper GI involvement grade 3: skin stage 0 - 3 plus liver stage 2-4 or lower GI stage 2-3 grade 4: skin stage 4 or lower GI stage 4 | Day 100 Post Transplant | 
| Number of Patients With Grade 2 Graft-Versus-Host Disease (GVHD) | GVHD grading is performed using modified Glucksberg criteria and is as follows: grade 0: absence of any skin, liver and/or gastrointestinal (GI) involvement grade 1: skin stage 1 or 2 only grade 2: skin stage 3 or liver stage 1 or lower GI stage 1 or upper GI involvement grade 3: skin stage 0 - 3 plus liver stage 2-4 or lower GI stage 2-3 grade 4: skin stage 4 or lower GI stage 4 | Day 100 Post Transplant | 
| Number of Patients With Grade 3 Graft-Versus-Host Disease (GVHD) | GVHD grading is performed using modified Glucksberg criteria and is as follows: grade 0: absence of any skin, liver and/or gastrointestinal (GI) involvement grade 1: skin stage 1 or 2 only grade 2: skin stage 3 or liver stage 1 or lower GI stage 1 or upper GI involvement grade 3: skin stage 0 - 3 plus liver stage 2-4 or lower GI stage 2-3 grade 4: skin stage 4 or lower GI stage 4 | Day 100 Post Transplant | 
| Number of Patients With Grade 4 Graft-Versus-Host Disease (GVHD) | GVHD grading is performed using modified Glucksberg criteria and is as follows: grade 0: absence of any skin, liver and/or gastrointestinal (GI) involvement grade 1: skin stage 1 or 2 only grade 2: skin stage 3 or liver stage 1 or lower GI stage 1 or upper GI involvement grade 3: skin stage 0 - 3 plus liver stage 2-4 or lower GI stage 2-3 grade 4: skin stage 4 or lower GI stage 4 | Day 100 Post Transplant | 
| Number of Patients Who Died Peri-Transplant | Peri-transplant is defined as within 100 days of transplant. | By Day 100 Post Transplant | 
| Donor Cell Chimerism Following Transplant | Donor cell chimerism is defined as the percentage of bone marrow and blood cells in the recipient that are of donor origin. | Day 28 | 
| Donor Cell Chimerism Following Transplant | Donor cell chimerism is defined as the percentage of bone marrow and blood cells in the recipient that are of donor origin. | Day 42 | 
| Donor Cell Chimerism Following Transplant | Donor cell chimerism is defined as the percentage of bone marrow and blood cells in the recipient that are of donor origin. | Day 100 | 
| Donor Cell Chimerism Following Transplant | Donor cell chimerism is defined as the percentage of bone marrow and blood cells in the recipient that are of donor origin. | 6 months | 
| Donor Cell Chimerism Following Transplant | Donor cell chimerism is defined as the percentage of bone marrow and blood cells in the recipient that are of donor origin. | One year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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inherited metabolic disorders