Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism

Treatment of Lysosomal and Peroxisomal Inborn Errors of Metabolism by Hematopoietic Cell Transplantation

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).

Study Overview

• Status: Terminated
• Conditions: Sphingolipidoses; Niemann-Pick Disease, Type C; Krabbe Disease; Sly Syndrome; Fucosidosis; Aspartylglucosaminuria; Alpha Mannosidosis; Hurler's Syndrome; Maroteaux-Lamy Syndrome; Wolman's Disease; Niemann-Pick Disease Type B
• Intervention / Treatment: Procedure: Stem Cell Transplantation; Drug: Cyclophosphamide; Drug: Campath-1H; Drug: Busulfan

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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 Names: 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 Names: 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 Names: 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 Names: Busulfex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Day 100

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Number of patients alive at timepoints.	Day 100, 1 Year, 3 Years

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2008
• Primary Completion (ACTUAL): February 1, 2010
• Study Completion (ACTUAL): February 1, 2010

Study Registration Dates

• First Submitted: April 25, 2008
• First Submitted That Met QC Criteria: April 28, 2008
• First Posted (ESTIMATE): April 29, 2008

Study Record Updates

• Last Update Posted (ACTUAL): December 28, 2017
• Last Update Submitted That Met QC Criteria: December 3, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Keywords: Inborn errors of metabolism; Peroxisomal Disorders; Sphingolipidoses; Recessive Leukodystrophies- GLD, Krabbe disease, MLD; Wolman syndrome; Niemann-Pick B patients; Niemann-Pick C subtype 2
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Lymphatic Diseases; Demyelinating Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Disease; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Connective Tissue Diseases; Neurodegenerative Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Carbohydrate Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Lipid Metabolism Disorders; Dementia; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Language Disorders; Communication Disorders; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Speech Disorders; Frontotemporal Lobar Degeneration; Leukoencephalopathies; Aphasia; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Cholesterol Ester Storage Disease; Hereditary Central Nervous System Demyelinating Diseases; Mucopolysaccharidoses; Syndrome; Mucopolysaccharidosis I; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain; Metabolism, Inborn Errors; Niemann-Pick Diseases; Niemann-Pick Disease, Type A; Niemann-Pick Disease, Type C; Wolman Disease; Leukodystrophy, Globoid Cell; Sphingolipidoses; Mannosidase Deficiency Diseases; alpha-Mannosidosis; Fucosidosis; Mucopolysaccharidosis VI; Mucopolysaccharidosis VII; Aspartylglucosaminuria; Niemann-Pick Disease, Type B; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Cyclophosphamide; Busulfan; Alemtuzumab
• Other Study ID Numbers: MT2008-02; 0801M25202 (OTHER: IRB, University of Minnesota)