Stem Cell Transplantation for Hurler

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and engraftment of donor hematopoietic cells using this conditioning regimen in patients undergoing a hematopoietic (blood forming) cell transplant for Hurler syndrome, Maroteaux Lamy syndrome, Mannosidosis, or I-cell disease.

Detailed Description
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Prior to transplantation, subjects will receive Busulfan intravenously (IV) via the Hickman line four times daily for 4 days, Cyclophosphamide intravenously via the Hickman line once a day for 4 days, and Anti-Thymocyte Globulin IV via the Hickman line twice daily for three days before the transplant. These three drugs are being given to subjects to help the new marrow take and grow. On the day of transplantation, the donor's hematopoietic cells will be transfused via central venous catheter. After hematopoietic cell transplant, subjects will then receive two drugs, cyclosporin and either methylprednisolone or Mycophenolate Mofetil (MMF). Cyclosporin and methylprednisolone or MMF are given to help prevent the complication of graft-versus-host disease and to decrease the chance that the new donor cells will be rejected.

Official Title
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Hematopoietic Stem Cell Transplantation for Hurler Syndrome, Maroteaux Lamy Syndrome (MPS VI), and Alpha Mannosidase Deficiency (Mannosidosis)

Conditions
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Mucopolysaccharidosis I, Mucopolysaccharidosis VI, Mannosidosis, Mucolipidosis Type II (I-cell Disease)

Intervention / Treatment
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* Procedure: Stem Cell Transplant
* Drug: Busulfan, Cyclophosphamide, ATG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with Mucopolysaccharidosis, type I (e.g., Hurler syndrome), Maroteaux-Lamy syndrome (MPS VI), Alpha Mannosidosis, or mucolipidosis type II (I-cell disease) who have an HLA-identical or mismatched (at 1 antigen) related marrow, PBSC, or cord blood donor. Patients with Mucopolysaccharidosis, type I, Maroteaux-Lamy syndrome (MPS VI), Alpha Mannosidosis, or mucolipidosis type II (I-cell disease) who have an HLA-identical or HLA-1 antigen mismatched unrelated marrow, PBSC, or HLA-0-2 antigen mismatched umbilical cord blood donor. Patients with MPS type I, Maroteaux Lamy Syndrome (MPS VI), or mucolipidosis type II (I-cell disease) will have a mental developmental index within two standard deviations of the normal mean, as best as can be determined using Bayley scales of infant development or other standardized testing, recognizing that these may be affected by speech and/or hearing impairment. Adequate organ function: Cardiac: ejection fraction >40%; no decompensated congestive heart failure or uncontrolled arrhythmia Renal: serum creatinine <2.0 mg/dl Hepatic: total bilirubin <3x Upper limits of normal transaminases < 5.0 x Upper limits of normal Signed consent. Exclusion Criteria: Presence of major organ dysfunction (see above) Pregnancy Evidence of HIV infection or known HIV positive serology Patients or parents are psychologically incapable of undergoing BMT with associated strict isolation or documented history of medical non-compliance Patients >50 kg may be at risk for having cell doses below the goal of ≥ 10 x 106 CD 34 cells/kg and therefore will not be eligible to receive unrelated PBSCs.
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 Arm<br>All patients treated with chemotherapy and transplantation. | Procedure: Stem Cell Transplant<br>* The purpose of hematopoietic cell transplantation is to introduce hematopoietic cells from a normal donor that contains the enzyme able to get rid of the substances that have accumulated in the body of patients with storage diseases. Hematopoietic cells can come from bone marrow, peripheral blood (i.e., the blood circulating in our body's blood vessels) or umbilical cord blood (i.e. blood taken from the umbilical cord after a baby is born and umbilical cord is cut).<br>* Other names: Bone Marrow Transplant;Drug: Busulfan, Cyclophosphamide, ATG<br>* Prior to transplantation, subjects will receive BUSULFAN intravenously (IV) via the Hickman line twice daily for 4 days, CYCLOPHOSPHAMIDE intravenously via the Hickman line once a day for 4 days, and ANTI-THYMOCYTE GLOBULIN IV via the Hickman line twice daily for three days before the transplant. These three drugs are being given to help the new marrow take and grow. METHYLPREDNISOLONE will be given as a pre-medication for the ATG.<br>* Other names: Busulfex, Cytoxan, Thymoglobulin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Percentage of Donor Cells in Study Population (Chimerism). | Donor-derived engraftment determined by restriction fragment length polymorphism (RFLP). | at 21 days, 42 days, 60 days, 100 days, 6 months, and 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Surviving on Study | Number of patients surviving (alive) at specified timepoints. | at 100 days, 1 year, and 3 years post transplant | 
| Number of Patients Who Failed Engraftment. | Toxicity (undesireable effect) of hematologic donor cell engraftment is determined by failure to engraft at Day 42. | Day 42 Post Transplant | 
| Number of Patients With Grade III-IV Acute Graft-versus-host Disease (aGVHD). | Toxicity (undesireable effect) of this stem cell transplant preparative regimen due to acute graft-versus-host disease. | Day 100 Post Transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stem cell transplant, storage disease, errors of metabolism