Alpha Mannosidosis, Aspartylglucosaminuria, Fucosidosis, Hurler's Syndrome, Krabbe Disease, Maroteaux-Lamy Syndrome, Niemann-Pick Disease Type B, Niemann-Pick Disease, Type C, Sly Syndrome, Sphingolipidoses, Wolman's Disease
Conditions
Keywords
Inborn errors of metabolism, Sphingolipidoses, Recessive Leukodystrophies- GLD, Krabbe disease, MLD, Peroxisomal Disorders, Wolman syndrome, Niemann-Pick B patients, Niemann-Pick C subtype 2
Brief summary
The primary objective of this clinical trial is to evaluate the ability to achieve and sustain donor engraftment in patients with lysosomal and peroxisomal inborn errors of metabolism undergoing hematopoietic stem cell transplantation (HCT).
Detailed description
This has been an ongoing area of interest by our group at the Univ. of Minnesota, but this is a new protocol to take the place of several older protocols. While survival has been very good on the prior protocols over the past decade, incomplete engraftment has remained somewhat problematic. Therefore, we have modified the preparative regimen somewhat to increase engraftment by replacing anti-thymocyte globulin (ATG) with Campath-1H, a drug that is more immune suppressive. In addition, we have modified the supportive care regimen. Based on this, we will monitor levels of an anti-oxidant therapy (N-acetylcysteine) and biomarkers of inflammation and oxidative stress for the families that consent to these research studies.
Interventions
PROCEDUREStem Cell Transplantation
The purpose of hematopoietic stem cell transplantation is to introduce blood producing cells from a normal donor. These cells can either provide what is missing in the body to the other cells, or can change the body's immune response to the substances that have accumulated in the body. These normal hematopoietic stem 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). The new donor cells repopulate the blood and bone marrow system and enter the organs of the body, including the brain. Wherever these cells go, they will produce the needed enzyme.
DRUGCyclophosphamide
Days before Transplant Drug Frequency * 4 Cyclophosphamide Once, given over 2 hours * 3 Cyclophosphamide Once, given over 2 hours * 2 Cyclophosphamide Once, given over 2 hours * 1 Cyclophosphamide Once, given over 2 hours
DRUGCampath-1H
Days before Transplant Drug Frequency 12 Campath-1H Once, given over 2 hours 11 Campath-1H Once, given over 2 hours 10 Campath-1H Once, given over 2 hours
DRUGBusulfan
Days before Transplant Drug Frequency 9 Busulfan Four times per day 8 Busulfan Four times per day 7 Busulfan Four times per day 6 Busulfan Four times per day
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
* Mucopolysaccharidosis (MPS) Disorders: * MPS IH (Hurler syndrome) * MPS-VI (Maroteaux-Lamy syndrome) * MPS VII (Sly syndrome). * Glycoprotein metabolic disorders: * Alpha mannosidosis * Fucosidosis * Aspartylglucosaminuria * Sphingolipidoses and Recessive Leukodystrophies: Presymptomatic patients with globoid cell leukodystrophy (GLD, also known as Krabbe disease) and metachromatic leukodystrophy (MLD) will be eligible for treatment on this protocol. White matter disease by magnetic resonance imaging (MRI) alone is not an exclusion if the patient is asymptomatic. * Peroxisomal Disorders: Presymptomatic patients with inherited peroxisomal disorders associated with of very long chain fatty acids (VLCFA) elevation, identified by family history or laboratory testing (including neonatal screening), are eligible for this protocol. White matter disease by MRI alone is not an exclusion if the patient is asymptomatic. * Other Inherited Diseases of Metabolism: * Wolman syndrome (acid lipase deficiency) * Niemann-Pick B patients (sphingomyelin deficiency) * Niemann-Pick C subtype 2 * Donor Availability: Patients considered for transplantation must have a sufficient graft as based on current criteria of the University of Minnesota Blood and Marrow Transplantation Program: Priority will be as follows, although in circumstances in which timing is of the essence, cord blood grafts may be chosen over an unrelated graft, despite the priority listed above. * Multidisciplinary Evaluation: Patients will be eligible for transplantation only after they are seen and evaluated by members of the Inherited Metabolic and Storage Disease Program (IMSD) team, and the team has offered transplantation to the patient/family.
Exclusion criteria
* Symptomatic patients with peroxisomal or lysosomal disorders are excluded but may be considered for other treatment protocols. * Major organ dysfunction. Evidence of major organ impairment, including: * Cardiac: left ventricular ejection fraction \<40% * Renal: serum creatinine \>2.5 x normal for age * Hepatic: total bilirubin \>3 x normal, or Alanine transaminase (ALT) \> 3 x normal * Pulmonary: requirement for continuous oxygen supplementation * Pregnancy * Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology * Patients \>21 years of age.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Achieving Engraftment | Day 100 | Rate of successful engraftment - patients who achieved and sustained donor engraftment; donor chimerism by day 100 of at least 90% after undergoing hematopoietic stem cell transplantation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Day 100, 1 Year, 3 Years | Number of patients alive at timepoints. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intent-to-Treat All patients treated with study regimen; Bone Marrow Transplant - cord blood transplant; Cyclophosphamide (50 mg/kg intravenous \[IV\] days 1-4 prior to transplant); Busulfan (if \< or = 12 kg: 1.1 mg/kg or if \> 12 kg: 0.8 mg/kg IV every 6 hours on days 6-9 before transplant) and Campath-1H (once per day 0.3 mg/kg IV on days 10-12 before transplant. | 18 |
| Total | 18 |
Baseline characteristics
| Characteristic | Intent-to-Treat |
|---|---|
| Age, Categorical <=18 years | 18 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 4.7 years STANDARD_DEVIATION 4.3 |
| Region of Enrollment United States | 18 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 18 |
| serious Total, serious adverse events | 8 / 18 |
Outcome results
Primary
Number of Patients Achieving Engraftment
Rate of successful engraftment - patients who achieved and sustained donor engraftment; donor chimerism by day 100 of at least 90% after undergoing hematopoietic stem cell transplantation.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intent-to-Treat | Number of Patients Achieving Engraftment | 14 Participants |
Secondary
Overall Survival
Number of patients alive at timepoints.
Time frame: Day 100, 1 Year, 3 Years
Population: Year 3 survival endpoint was not done due to study being terminated prematurely.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intent-to-Treat | Overall Survival | Day 100 | 14 Participants |
| Intent-to-Treat | Overall Survival | 1 Year | 12 Participants |