Acyl-CoA Oxidase Deficiency, Adrenoleukodystrophy With Cerebral Involvement, Alpha-Mannosidosis, Alpha-methylacyl-CoA Racmase Deficiency, Aspartylglucosaminuria, D-Bifunctional Enzyme Deficiency, Fucosidosis, Globoid Cell Leukodystrophy, Glycoprotein Metabolic Disorders, Hereditary Leukoencephalopathy With Axonal Spheroids (HDLS; CSF1R Mutation), Hunter Syndrome, Hurler Syndrome, Infantile Refsum Disease, Inherited Metabolic Disorders, Maroteaux Lamy Syndrome, Metachromatic Leukodystrophy, Mitochondrial Neurogastrointestingal Encephalopathy, Mucopolysaccharidosis Disorders, Multifunctional Enzyme Deficiency, Neonatal Adrenoleukodystrophy, Niemann-Pick B, Niemann-Pick C Subtype 2, Peroxisomal Disorders, Recessive Leukodystrophies, Severe Osteopetrosis, Sly Syndrome, Sphingolipidoses, Sphingomyelin Deficiency, Zellweger Syndrome
Conditions
Keywords
allogeneic hematopoietic cell transplantation, bone marrow transplantation, IMD, AMACRD, MNGIE, HDLS, OP, ALD
Brief summary
This single-institution, phase II study is designed to test the ability to achieve donor hematopoietic engraftment while maintaining low rates of transplant-related mortality (TRM) using busulfan- and fludarabine-based conditioning regimens with busulfan therapeutic drug monitoring (TDM) for patients with various inherited metabolic disorders (IMD) and severe osteopetrosis (OP).
Interventions
Infusion given on Day 0
* Anti-thymocyte Globulin (ATG) * Fludarabine * Busulfan
* Anti-thymocyte Globulin (ATG) * Fludarabine * Busulfan * Thiotepa
* Rituximab * Alemtuzumab * Busulfan * Fludarabine
N-acetylcysteine start day +1 through day +28
N-acetylcysteine start day +1through day +56
N-acetylcysteine and celecoxib start day of admission (prior to conditioning regimen) and continue through day +100
N-acetylcysteine, celecoxib, vitamin E and alpha lipoic acid start day of admission (prior to conditioning regimen) and continue through day +100
Sponsors
Study design
Eligibility
Inclusion criteria
* 0 through 55 years of age * Adequate graft available * Adequate organ function * Eligible Diseases: * Mucopolysaccharidosis Disorders: * MPS IH (Hurler syndrome) * MPS II (Hunter syndrome) if the patient has no or minimal evidence of symptomatic neurologic disease but is expected to have a neurologic phenotype * MPS VI (Maroteaux-Lamy syndrome) * MPS VII (Sly syndrome) * Glycoprotein Metabolic Disorders: * Alpha mannosidosis * Fucosidosis * Aspartylglucosaminuria * Sphingolipidoses and Recessive Leukodystrophies: * Globoid cell leukodystrophy * Metachromatic leukodystrophy * Niemann-Pick B patients (sphingomyelin deficiency) * Niemann-Pick C subtype 2 * Peroxisomal Disorders: * Adrenoleukodystrophy with cerebral involvement * Zellweger syndrome * Neonatal Adrenoleukodystrophy * Infantile Refsum disease * Acyl-CoA-Oxidase Deficiency * D-Bifunctional enzyme deficiency * Multifunctional enzyme deficiency * Alpha-methylacyl-CoA Racmase Deficiency (AMACRD) * Mitochondrial Neurogastrointestingal Encephalopathy (MNGIE) * Severe Osteopetrosis (OP) * Hereditary Leukoencephalopathy with axonal spheroids (HDLS; CSF1R mutation) * Other Inherited Metabolic Disorders (IMD): Patients will also be considered who have other life-threatening, rare lysosomal, peroxisomal or other similar inherited disorders characterized by white matter disease or other neurologic manifestations for which there is rationale that transplantation would be of benefit, such as certain patients with Wolman's disease, GM1 gangliosidosis, I-cell disease, Tay-Sachs disease, Sandhoff disease or others. * Voluntary written consent
Exclusion criteria
* Pregnancy - menstruating females must have a negative serum or urine pregnancy test within 14 days of study treatment start * Prior myeloablative chemotherapy exposure within 4 months of the start of conditioning on this protocol (patients excluded for this reason may be eligible for other institutional protocols) * Uncontrolled bacterial, fungal or viral infections including HIV (including active infection with Aspergillus or other mold within 30 days)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of subjects who achieve high-level donor hematopoietic engraftment | Day +42 post-transplant | Defined as neutrophil recovery by Day +42 post-transplant and ≥ 80% donor cells on the myeloid fraction of peripheral blood at Day +100 post-transplant |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Graft-versus-host disease | Day +100 post-transplant | Incidence and severity of GvHD |
| Transplant-related mortality | Day +100 post-transplant | Incidence of TRM |
| Regimen-related toxicity | Day +100 post-transplant | Defined as infection, acute renal failure, respiratory failure, cardiac failure, and veno-occlusive disease |
| Post-HSCT changes in disease | 1 year | Incidence of radiographic, physiologic, neuro-psychologic, and/or biochemical aspects of the disease as assessed on a disease-specific basis |
Countries
United States