HSCT for High Risk Inherited Inborn Errors
Condition: Adrenoleukodystrophy; Metachromatic Leukodystrophy; Globoid Cell Leukodystrophy; Tay Sachs Disease; Sandhoffs Disease; Wolman Disease; I-Cell Disease; Sanfilippo Syndrome; GM1 Gangliosidosis
MeSH terms: Mucolipidoses; Adrenoleukodystrophy; Gangliosidoses; Leukodystrophy, Metachromatic; Tay-Sachs Disease; Gangliosidosis, GM1; Sandhoff Disease; Leukodystrophy, Globoid Cell; Mucopolysaccharidosis III; Wolman Disease
Intervention: Clofarabine; Total body Irradiation; Melphalan; Hematopoietic Stem Cell Transplantation; Alemtuzumab; mycophenylate mofetil; Cyclosporine A; Hydroxyurea
Intervention description: days -7 through -3: 40 mg/m^2 intravenously over 2 hours; 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.; day -2: 140 mg/m^2 intravenously over 30 minutes; receives infusion of stem cells on day 0; 0.3 mg/kg intravenously (IV) days -12 through -8; 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); 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.; hydroxyurea (HU) beginning day -28 and continuing through alemtuzumab administration
Intervention MeSH terms: Cyclosporine; Melphalan; Alemtuzumab; Hydroxyurea; Clofarabine; Cyclosporins
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 38.0
Sex: All
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Stem cell transplantation; Inborn errors of metabolism; Adrenoleukodystrophy (ALD); Metachromatic leukodystrophy (MLD); Globoid cell leukodystrophy (GLD or Krabbe); Tay Sachs; Sandhoff; Sanfilippo syndrome; Mucopolysaccharidosis III (MPS-III); GM1 gangliosidosis; I-cell; mucolipidosis

Summary:

      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.
    

Eligibility criteria:

        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.

          -  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