Adrenoleukodystrophy, Batten Disease, Fucosidosis, Gaucher's Disease, Globoid Cell Leukodystrophy, GM1 Gangliosidosis, Metachromatic Leukodystrophy, Niemann-Pick Disease, Sandhoff Disease, Tay Sachs Disease, Wolman Disease
Conditions
Keywords
Inborn errors, Storage disease, errors of metabolism, stem cell transplant
Brief summary
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 an inherited metabolic storage disease.
Detailed description
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 (ATG) intravenously (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.
Interventions
PROCEDUREStem Cell Transplant
The purpose of hematopoietic cell transplantation is to introduce hematopoietic cells from a normal donor that contains an 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).
DRUGBusulfan, Cyclophosphamide, Antithymocyte Globulin
Subjects will receive BUSULFAN intravenously (IV)- patients \< or= 12 kg 1.1 mg/kd/dose IV every 6 hours for 16 doses; patients \> 12kg 0.8 mg/kg/dose IV every 6 hours for 16 doses - via the Hickman line four times daily for 4 days, CYCLOPHOSPHAMIDE intravenously (50 mg/kg/day IV over 2 hours) via the Hickman line once a day for 4 days, and ANTI-THYMOCYTE GLOBULIN IV (15 mg/kg/day over 2 hours) 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.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Patients with adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy, Gaucher's disease, Fucosidosis, Wolman disease, Niemann-Pick disease and Batten disease (CLN3) who have a human leukocyte antigen (HLA)-identical or haplotype mismatched (at 1-3 antigens) related marrow, or umbilical cord blood donor. One or two umbilical cord blood (UCB) units may be used. * Patients with GM1 gangliosidosis, Tay Sachs disease or Sandhoff disease who have a HLA-identical or 1 antigen mismatched related or unrelated donor, or suitably matched umbilical cord blood unit(s). One or two UCB units may be used. * Patients with adrenoleukodystrophy must have magnetic resonance imaging (MRI) findings, neurological and neuropsychometric function consistent with the diagnosis, and for boys with parietal-occipital dysmyelination a performance intelligence quotient (IQ) ≥80. In cases, when the performance IQ is not ≥80, the protocol committee may recommend transplant if the patient's clinical condition and neuropsychometric status are deemed to be acceptable based upon consideration of such factors as age at onset of cerebral disease, magnitude of change in performance IQ and neurologic deficits. * Patients with arylsulfatase A deficiency (Metachromatic Leukodystrophy) must have either the presymptomatic late infantile, juvenile or adult form of the disease and must have acceptable neurological and neuropsychometric function. * Patients with galactocerebrosidase deficiency (Globoid Cell Leukodystrophy) must have acceptable neurological and neuropsychometric function. * Patients with acid lipase deficiency (Wolman disease) must have a liver biopsy that documents no evidence of hepatic cirrhosis, and acceptable neurological and neuropsychometric function. * Patients with fucosidase deficiency (Fucosidosis) must have acceptable neurological and neuropsychometric function. * Patients with glucocerebrosidase deficiency (Gaucher's Disease) must have acceptable neurologic and neuropsychometric function. * Patients with Batten's disease (CLN3) must have acceptable Neurological and neuropsychometric function. * Absence of major organ dysfunction. Organ evaluation results as follows: * Cardiac: ejection fraction \>30% * Renal: serum creatinine \<2x normal or creatinine clearance 60 mL/min. * Hepatic: total bilirubin \<2x normal and Aspartate aminotransferase (AST) \<2x normal * Signed consent.
Exclusion criteria
* Patients with symptomatic late infantile form of metachromatic leukodystrophy. * Patients with symptomatic infantile globoid leukodystrophy. * Note: Patients with Hurler syndrome, mucopolysaccharidosis (MPS) VI, or Mannosidosis disease are no longer eligible for this protocol, but can be transplanted under protocol MT 9907 (NCT00176917 - Hematopoietic Cell Transplantation for Hurler Syndrome, Maroteaux Lamy Syndrome (MPS VI), and Alpha Mannosidase Deficiency (Mannosidosis)). * Pregnancy * Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology * Patients or parents are psychologically incapable of undergoing bone marrow transplant (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 10\^6 CD34 cells/kg and therefore will not be eligible to receive unrelated peripheral blood stem cells (PBSCs)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 100 Days, 1 Year and 3 Years | Number of patients alive at designated timepoints after transplant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Donor Engraftment | Day 100 | Number of patients with full donor chimerism (state in bone marrow transplantation in which bone marrow and host cells exist compatibly without signs of graft-versus-host rejection disease) by Day 100 post-transplant of at least 90%. |
| Number of Patients With Grade II-IV Acute Graft-Versus-Host Disease | Day 100 | Number of patients who exhibited acute graft-versus-host disease by Day 100 post transplant. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Grade I=mild, Grade II=moderate, Grade III=severe, Grade IV=life threatening. |
| Number of Patients With Grade III-IV Acute Graft-Versus-Host Disease | Day 100 | Number of patients who exhibited acute graft-versus-host disease by Day 100 post transplant. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Grade I=mild, Grade II=moderate, Grade III=severe, Grade IV=life threatening. |
| Number of Patients With Chronic Graft-Versus-Host Disease | 1 Year Post Transplant | Number of patients who exhibited chronic graft-versus-host disease by 1 Year post transplant. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Chronic GVHD is an extension of this syndrome. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Patients Treated With Stem Cell Transplant All patients treated with protocol regimen (chemotherapy and stem cell transplant). | 135 |
| Total | 135 |
Baseline characteristics
| Characteristic | Patients Treated With Stem Cell Transplant |
|---|---|
| Age, Categorical <=18 years | 117 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants |
| Age, Continuous | 8.7 years STANDARD_DEVIATION 8.9 |
| Region of Enrollment United States | 135 participants |
| Sex: Female, Male Female | 44 Participants |
| Sex: Female, Male Male | 91 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 135 |
| serious Total, serious adverse events | 62 / 135 |
Outcome results
Primary
Overall Survival
Number of patients alive at designated timepoints after transplant.
Time frame: 100 Days, 1 Year and 3 Years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patients Treated With Stem Cell Transplant | Overall Survival | Day 100 | 120 Participants |
| Patients Treated With Stem Cell Transplant | Overall Survival | 1 Year | 92 Participants |
| Patients Treated With Stem Cell Transplant | Overall Survival | 3 Years | 81 Participants |
Secondary
Number of Patients With Chronic Graft-Versus-Host Disease
Number of patients who exhibited chronic graft-versus-host disease by 1 Year post transplant. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Chronic GVHD is an extension of this syndrome.
Time frame: 1 Year Post Transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients Treated With Stem Cell Transplant | Number of Patients With Chronic Graft-Versus-Host Disease | 13 Participants |
Secondary
Number of Patients With Grade III-IV Acute Graft-Versus-Host Disease
Number of patients who exhibited acute graft-versus-host disease by Day 100 post transplant. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Grade I=mild, Grade II=moderate, Grade III=severe, Grade IV=life threatening.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients Treated With Stem Cell Transplant | Number of Patients With Grade III-IV Acute Graft-Versus-Host Disease | 13 Participants |
Secondary
Number of Patients With Grade II-IV Acute Graft-Versus-Host Disease
Number of patients who exhibited acute graft-versus-host disease by Day 100 post transplant. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Grade I=mild, Grade II=moderate, Grade III=severe, Grade IV=life threatening.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients Treated With Stem Cell Transplant | Number of Patients With Grade II-IV Acute Graft-Versus-Host Disease | 34 Participants |
Secondary
Overall Donor Engraftment
Number of patients with full donor chimerism (state in bone marrow transplantation in which bone marrow and host cells exist compatibly without signs of graft-versus-host rejection disease) by Day 100 post-transplant of at least 90%.
Time frame: Day 100
Population: 1 Patient not included due to early death (before day 40).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients Treated With Stem Cell Transplant | Overall Donor Engraftment | 123 Participants |