Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism - Full Text View

Purpose

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).

Condition	Intervention	Phase
Hurler's Syndrome Maroteaux-Lamy Syndrome Sly Syndrome Alpha Mannosidosis Fucosidosis Aspartylglucosaminuria Sphingolipidoses Krabbe Disease Wolman's Disease Niemann-Pick Disease Type B Niemann-Pick Disease, Type C	Procedure: Stem Cell Transplantation Drug: Cyclophosphamide Drug: Campath-1H Drug: Busulfan	Phase 2


Study Type:	Interventional
Study Design:	Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Treatment of Lysosomal and Peroxisomal Inborn Errors of Metabolism by Hematopoietic Cell Transplantation

Resource links provided by NLM:

Genetics Home Reference related topics: CHMP2B-related frontotemporal dementia GRN-related frontotemporal dementia Krabbe disease Niemann-Pick disease RNAse T2-deficient leukoencephalopathy alpha-mannosidosis aspartylglucosaminuria frontotemporal dementia with parkinsonism-17 fucosidosis leukoencephalopathy with vanishing white matter lysosomal acid lipase deficiency megalencephalic leukoencephalopathy with subcortical cysts

Genetic and Rare Diseases Information Center resources: Pick's Disease Frontotemporal Dementia Frontotemporal Dementia, Ubiquitin-positive Primary Progressive Aphasia Semantic Dementia Niemann-Pick Disease Type A Niemann-Pick Disease Type C1 Mucopolysaccharidosis Type VI Peroxisomal Biogenesis Disorders Hurler Syndrome Leukodystrophy Alpha-mannosidosis Krabbe Disease Wolman Disease Cholesteryl Ester Storage Disease Lysosomal Acid Lipase Deficiency Mucopolysaccharidosis Type VII Sphingolipidosis Fucosidosis Aspartylglycosaminuria Niemann-Pick Disease Type B Mucopolysaccharidosis Mucopolysaccharidosis Type I

U.S. FDA Resources

Further study details as provided by Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:

Number of Patients Achieving Engraftment [ Time Frame: 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 Outcome Measures:

Overall Survival [ Time Frame: Day 100, 1 Year, 3 Years ]
Number of patients alive at timepoints.


Enrollment:	18
Study Start Date:	March 2008
Study Completion Date:	February 2010
Primary Completion Date:	February 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Intent-to-Treat All patients treated with study regimen.	Procedure: Stem 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. Other Name: Bone Marrow Transplant, cord blood transplant Drug: Cyclophosphamide 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 Other Name: Cytoxan Drug: Campath-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 Other Name: Alemtuzamab Drug: Busulfan 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 Other Name: Busulfex

Arms

Assigned Interventions

Experimental: Intent-to-Treat

All patients treated with study regimen.

Procedure: Stem 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.

Other Name: Bone Marrow Transplant, cord blood transplant

Drug: Cyclophosphamide

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

Other Name: Cytoxan

Drug: Campath-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

Other Name: Alemtuzamab

Drug: Busulfan

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

Other Name: Busulfex

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.

Eligibility


Ages Eligible for Study:	up to 21 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00668564

Locations


United States, Minnesota
University of Minnesota, Fairview
Minneapolis, Minnesota, United States, 55455

Sponsors and Collaborators

Masonic Cancer Center, University of Minnesota

Investigators


Principal Investigator:	Paul Orchard, MD	University of Minnesota Medical Center

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Miller WP, Rothman SM, Nascene D, Kivisto T, DeFor TE, Ziegler RS, Eisengart J, Leiser K, Raymond G, Lund TC, Tolar J, Orchard PJ. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood. 2011 Aug 18;118(7):1971-8. doi: 10.1182/blood-2011-01-329235. Epub 2011 May 17.


Responsible Party:	Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:	NCT00668564 History of Changes
Other Study ID Numbers:	MT2008-02 0801M25202 ( Other Identifier: IRB, University of Minnesota )
Study First Received:	April 25, 2008
Results First Received:	June 14, 2011
Last Updated:	November 6, 2012

Keywords provided by Masonic Cancer Center, University of Minnesota:


Inborn errors of metabolism Sphingolipidoses Recessive Leukodystrophies- GLD, Krabbe disease, MLD Peroxisomal Disorders	Wolman syndrome Niemann-Pick B patients Niemann-Pick C subtype 2

Additional relevant MeSH terms:


Fucosidosis Syndrome Metabolism, Inborn Errors Pick Disease of the Brain Aphasia, Primary Progressive Frontotemporal Dementia Niemann-Pick Diseases Niemann-Pick Disease, Type A Niemann-Pick Disease, Type C Mannosidase Deficiency Diseases alpha-Mannosidosis Mucopolysaccharidosis I Wolman Disease Leukodystrophy, Globoid Cell Sphingolipidoses	Mucopolysaccharidosis VI Mucopolysaccharidosis VII Aspartylglucosaminuria Niemann-Pick Disease, Type B Disease Pathologic Processes Genetic Diseases, Inborn Metabolic Diseases Frontotemporal Lobar Degeneration Dementia Brain Diseases Central Nervous System Diseases Nervous System Diseases Neurocognitive Disorders Mental Disorders

ClinicalTrials.gov processed this record on July 13, 2017