HSCT for High Risk Inherited Inborn Errors

• Transplant Related Mortality [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
  In the field of transplantation, toxicity is high and all deaths without previous relapse or progression are usually considered as related to transplantation.
• Concentrations of mycophenylate mofetil (MMF) [ Time Frame: Day 3 ] [ Designated as safety issue: No ]
  MMF levels are to be sent on day +3 to the main laboratory for determinations of MMF kinetics.
• Changes in Magnetic Resonance Imaging (MRI) [ Time Frame: Day 30, 60, 100 and 1 and 2 Years ] [ Designated as safety issue: No ]
• Changes in Neuropsychometric Function [ Time Frame: 6 Months, 1 Year, 2 Years, 3 Years ] [ Designated as safety issue: No ]
• Incidence of Acute Graft Versus Host Disease [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
  Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.
• Incidence of Chronic Graft Versus Host Disease [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]
  Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cells into a foreign host.

Hematopoietic stem cell transplantation has proven effective therapy for individuals with adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD) or globoid cell leukodystrophy (GLD, or Krabbe disease). This protocol also considers other inherited metabolic diseases such as, but not limited to, GM1 gangliosidosis, Tay Sachs disease, Sanfilippo syndrome or Sandhoff disease, I-cell disease (mucolipidosis II).

For patients with advanced or rapidly progressive disease, the morbidity and mortality with transplantation is unacceptably high. Unfortunately, there are no viable alternative therapeutic options for these patients; if transplantation is not performed the patients are sent home to die. Our group at Minnesota has developed a new protocol incorporating transplantation using a reduced intensity conditioning regimen designed to decrease toxicity associated with the transplant procedure. This regimen will make use of the drug clofarabine, which has lympholytic and immune suppressive properties without the neurologic toxicity observed in the related compound, fludarabine, commonly used for transplantation. In addition, several agents providing anti-oxidant and anti-inflammatory properties will be used to assist in the stabilization of the disease processes. This revised transplant protocol will test the following: 1) the ability to achieve engraftment with the reduced intensity protocol, 2) the mortality associated with transplant by day 100, 3) patient outcomes, based on differential neurologic, neuropsychologic, imaging and biologic evaluations prior to transplantation and at designated points after transplantation (day 100, 6 months, 1, 2 and 5 years). Additional biologic studies will include pharmacokinetics of clofarabine and mycophenolate mofetil (MMF). In addition, for patients undergoing lumbar puncture studies, cerebrospinal fluid (CSF) will be requested for determinations of biologic parameters.

Hematopoietic stem cell transplantation has proven effective therapy for individuals with adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD) or globoid cell leukodystrophy (GLD, or Krabbe disease). However, for patients with advanced or rapidly progressive disease, the morbidity and mortality with transplantation is unacceptably high. Unfortunately, there are no viable alternative therapeutic options for these patients; if transplantation is not performed the patients are sent home to die. Our group at Minnesota has developed a new protocol incorporating transplantation using a reduced intensity conditioning regimen designed to decrease toxicity associated with the transplant procedure. This regimen will make use of the drug clofarabine, which has lympholytic and immune suppressive properties without the neurologic toxicity observed in the related compound, fludarabine, commonly used for transplantation. In addition, several agents providing anti-oxidant and anti-inflammatory properties will be used to assist in the stabilization of the disease processes. This revised transplant protocol will test the following: 1) the ability to achieve engraftment with the reduced intensity protocol, 2) the mortality associated with transplant by day 100, 3) patient outcomes, based on differential neurologic, neuropsychologic, imaging and biologic evaluations prior to transplantation and at designated points after transplantation (day 100, 6 months, 1, 2 and 5 years). Additional biologic studies will include pharmacokinetics of clofarabine and mycophenolate mofetil (MMF), develop experience in kinetics of N-acetylcysteine, and evaluate biologic markers of oxidative status during transplantation. In addition, for patients undergoing lumbar puncture studies, cerebrospinal fluid (CSF) will be requested for determinations of biologic parameters.

• Adrenoleukodystrophy
• Metachromatic Leukodystrophy
• Globoid Cell Leukodystrophy
• Tay Sachs Disease
• Sandhoffs Disease
• Wolman Disease
• I-Cell Disease
• Sanfilippo Syndrome
• GM1 Gangliosidosis

• Drug: Clofarabine
  days -7 through -3: 40 mg/m^2 intravenously over 2 hours
  Other Name: Clolar
• Procedure: Total body Irradiation
  Administration of TBI: The dose of TBI will be 200 cGy given in a single fraction on day -1. The dose rate will be between 10-19 cGy/minute prescribed to the midplane of the patient at the level of the umbilicus.
  Other Name: TLI
• Drug: Melphalan
  day -2: 140 mg/m^2 intravenously over 30 minutes
  Other Name: Alkeran
• Biological: Hematopoietic Stem Cell Transplantation
  receives infusion of stem cells on day 0
• Drug: Alemtuzumab
  0.3 mg/kg intravenously (IV) days -12 through -8
  Other Name: Campath 1-H
• Drug: mycophenylate mofetil
  Day -3 through Day 30: 1 gram three times daily (total daily dose 3 grams/day) if the recipient is >50 kg, or 15 mg/kg three times daily if the recipient is ≤50 kg. The same dosage is used orally or intravenously. Consider dose modification if renal impairment (GFR<25 mL/minute corrected)
  Other Name: MMF
• Device: Cyclosporine A

  Patients will receive CsA therapy beginning on day -3. Dosing of CsA will be 2.5 mg/kg/dose intravenously (IV); if the recipient body weight is <40 kg, dosing will be 3 times daily, and if > 40 kg twice daily. An attempt will be made to maintain a trough cyclosporine level of 250 mg/L to 350 mg/L. Once the patient can tolerate oral medications and has a normal gastrointestinal transit time, CsA will be converted to an oral form at a dose 2.5 x the current IV dose (maximum 12.5 mg/kg/day as initial oral dose).

  CsA taper begins at day +100.

  Other Name: CsA

Inclusion Criteria:

Adrenoleukodystrophy: Patients from 0-55 years of age diagnosed with ALD as determined by very long chain fatty acid testing will be eligible for this protocol if they have evidence of cerebral or cerebellar disease based on MRI testing, AND they are determined high risk for any of the following reasons:

1. Age >18 years
2. MRI score >10
3. Evidence of aggressive disease that in the judgment of the Inherited Metabolic and Storage Disease group is sufficiently concerning to consider transplantation with a reduced intensity regimen instead of a standard full preparative regimen.

Metachromatic Leukodystrophy: Patients from 0-55 years of age diagnosed with MLD as determined by determinations of arylsulfatase A testing will be eligible for this protocol IF they are determined high risk for any of the following reasons:

1. Age >18 years
2. Symptomatic disease, as based on neurologic examination, or evidence of deterioration based on subsequent neuropsychologic evaluations.
3. Evidence of aggressive disease such as rapidly changing MRI determinations that in the judgment of the Inherited Metabolic and Storage Disease group is sufficiently concerning to consider transplantation with a reduced intensity regimen instead of a standard full preparative regimen.

Globoid Cell Leukodystrophy: Patients from 0-55 years of age diagnosed with GLD as determined by determinations of galactocerebrosidase testing will be eligible for this protocol IF they are determined high risk for any of the following reasons:

1. Age >18 years
2. Symptomatic disease, as based on neurologic examination, or evidence of deterioration based on subsequent neuropsychologic evaluations.
3. Evidence of aggressive disease such as rapidly changing MRI determinations that in the judgment of the Inherited Metabolic and Storage Disease group is sufficiently concerning to consider transplantation with a reduced intensity regimen instead of a standard full preparative regimen.

Patients with GM1 gangliosidosis, Tay Sachs disease, Sanfilippo syndrome, Wolman disease or Sandhoff disease or other inherited metabolic diseases including but not limited to I-cell disease (mucolipidosis II) who are determined to be sufficiently advanced or high risk based on the following reasons:

1. Symptomatic disease, as based on neurologic examination, or evidence of deterioration based on subsequent neuropsychologic evaluations.
2. Evidence of an expected poor outcome based on genetic testing or a prior family history of aggressive disease.
3. Other metabolic disorders, including but not limited to I-cell disease, that are deemed to be high-risk for a poor outcome with a standard transplant regimen due to anticipated toxicity based on experience gained at the University of Minnesota or other centers.

Exclusion criteria:

Major organ dysfunction. Evidence of major organ impairment, including:

1. Cardiac: ejection fraction <25%
2. Renal: serum Cr >3 x normal or Cr clearance <20 mL/min.
3. Hepatic: total bilirubin >5 x normal, or ALT > 5 x normal
4. Pulmonary: requirement for respiratory support, as defined by continuous requirement for oxygen supplementation Pregnancy HIV: Evidence of HIV infection or known HIV positive serology Inability to Obtain Consent: Patients or parents are psychologically incapable of undergoing BMT with associated strict isolation or documented history of medical non-compliance.

Advanced Disease Exclusion: Following evaluation, if a consensus of the members of the Inherited Metabolic and Storage Disease Program is that a patient is too advanced to benefit in a measurable and meaningful way from transplant, this will be communicated to the family, and transplant will not be offered. Measures to assist in those determinations may include: neurologic/neurocognitive functions such as activities of daily living, motor function, vision, hearing, interaction with environment, toileting, swallowing, or other standardized measures