Mannosidosis, Mucolipidosis Type II (I-cell Disease), Mucopolysaccharidosis I, Mucopolysaccharidosis VI
Conditions
Keywords
stem cell transplant, storage disease, errors of metabolism
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 Hurler syndrome, Maroteaux Lamy syndrome, Mannosidosis, or I-cell 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 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 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).
DRUGBusulfan, Cyclophosphamide, ATG
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.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percentage of Donor Cells in Study Population (Chimerism). | at 21 days, 42 days, 60 days, 100 days, 6 months, and 1 year | Donor-derived engraftment determined by restriction fragment length polymorphism (RFLP). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Surviving on Study | at 100 days, 1 year, and 3 years post transplant | Number of patients surviving (alive) at specified timepoints. |
| Number of Patients Who Failed Engraftment. | Day 42 Post Transplant | Toxicity (undesireable effect) of hematologic donor cell engraftment is determined by failure to engraft at Day 42. |
| Number of Patients With Grade III-IV Acute Graft-versus-host Disease (aGVHD). | Day 100 Post Transplant | Toxicity (undesireable effect) of this stem cell transplant preparative regimen due to acute graft-versus-host disease. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Transplant Patients Patients that received hematopoietic stem cell transplant. | 41 |
| Total | 41 |
Baseline characteristics
| Characteristic | Transplant Patients |
|---|---|
| Age, Categorical <=18 years | 41 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 1.8 years STANDARD_DEVIATION 1.4 |
| Region of Enrollment United States | 41 participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 41 |
| serious Total, serious adverse events | 0 / 41 |
Outcome results
Primary
Mean Percentage of Donor Cells in Study Population (Chimerism).
Donor-derived engraftment determined by restriction fragment length polymorphism (RFLP).
Time frame: at 21 days, 42 days, 60 days, 100 days, 6 months, and 1 year
Population: Day 21 (24 patients included), Day 42 (15 pts), Day 60 (29 pts), Day 100 (25 pts), 6 Months (18 pts), 1 Year (16 pts).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Transplant Patients | Mean Percentage of Donor Cells in Study Population (Chimerism). | 21 Days Post Transplant | 85.8 Percentage | Standard Deviation 28.4 |
| Transplant Patients | Mean Percentage of Donor Cells in Study Population (Chimerism). | 42 Days Post Transplant | 73.2 Percentage | Standard Deviation 31.6 |
| Transplant Patients | Mean Percentage of Donor Cells in Study Population (Chimerism). | 60 Days Post Transplant | 84.6 Percentage | Standard Deviation 27.9 |
| Transplant Patients | Mean Percentage of Donor Cells in Study Population (Chimerism). | 100 Days Post Transplant | 81.1 Percentage | Standard Deviation 26.8 |
| Transplant Patients | Mean Percentage of Donor Cells in Study Population (Chimerism). | 6 Months Post Transplant | 81.6 Percentage | Standard Deviation 29.6 |
| Transplant Patients | Mean Percentage of Donor Cells in Study Population (Chimerism). | 1 Year Post Transplant | 91.5 Percentage | Standard Deviation 18.8 |
Secondary
Number of Patients Surviving on Study
Number of patients surviving (alive) at specified timepoints.
Time frame: at 100 days, 1 year, and 3 years post transplant
Population: Day 100 and 1 Year timepoints include all 41 patients. Year 3 includes 36 patients (5 pts not yet at followup timepoint.)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Transplant Patients | Number of Patients Surviving on Study | Day 100 Post Transplant | 37 Participants |
| Transplant Patients | Number of Patients Surviving on Study | 1 Year Post Transplant | 28 Participants |
| Transplant Patients | Number of Patients Surviving on Study | 3 Years Post Transplant | 27 Participants |
Secondary
Number of Patients Who Failed Engraftment.
Toxicity (undesireable effect) of hematologic donor cell engraftment is determined by failure to engraft at Day 42.
Time frame: Day 42 Post Transplant
Population: 1 patient of 41 failed engraftment - per protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Transplant Patients | Number of Patients Who Failed Engraftment. | 1 Participants |
Secondary
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.
Time frame: Day 100 Post Transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Transplant Patients | Number of Patients With Grade III-IV Acute Graft-versus-host Disease (aGVHD). | 2 Participants |