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

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.

• Stem Cell Transplantation (Procedure), also known as Bone Marrow Transplant, cord blood transplant: 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.
• Cyclophosphamide (Drug), also known as Cytoxan: 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
• Campath-1H (Drug), also known as Alemtuzamab: 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
• Busulfan (Drug), also known as Busulfex: 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

Primary outcomes

• 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 outcomes

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

Sex: All, ages: any to 21 Years

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.

Participant flow

Outcome results

• Number of Patients Achieving Engraftment (Primary), Number, Participants: Intent-to-Treat 14
• Overall Survival (Secondary), Number, Participants: Intent-to-Treat 14

Adverse events

Time frame: Day 1 through Day 100 post-transplant.

Serious adverse events by term

Limitations and caveats: Other secondary objectives outlined in study protocol were not analyzed; number of patients were too few to be relevant.

• Results publication: 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. PMID 21586746

• Paul Orchard, MD, Principal investigator, University of Minnesota Medical Center