Conditions: Adrenoleukodystrophy Metachromatic Leukodystrophy Globoid Cell Leukodystrophy Tay Sachs Disease Sandhoffs Disease Wolman Disease I-Cell Disease Sanfilippo Syndrome GM1 Gangliosidosis
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
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 38
Healthy volunteers: no

Brief 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.

Detailed description:
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.

Arms:
arm 1: Patients receiving chemotherapy (Hydroxyurea, Alemtuzumab, Clofarabine, Melphalan), Hematopoietic Stem Cell Transplantation and radiation therapy (Total body Irradiation) mycophenylate mofetil and cyclosporine A.

Interventions: intervention 1: Clofarabine intervention 2: Total body Irradiation intervention 3: Melphalan intervention 4: Hematopoietic Stem Cell Transplantation intervention 5: Alemtuzumab intervention 6: mycophenylate mofetil intervention 7: Cyclosporine A intervention 8: Hydroxyurea
Intervention descriptions: intervention 1: days -7 through -3: 40 mg/m\^2 intravenously over 2 hours intervention 2: 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. intervention 3: day -2: 140 mg/m\^2 intravenously over 30 minutes intervention 4: receives infusion of stem cells on day 0 intervention 5: 0.3 mg/kg intravenously (IV) days -12 through -8 intervention 6: 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) intervention 7: 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. intervention 8: hydroxyurea (HU) beginning day -28 and continuing through alemtuzumab administration

Protocol document: