hsct for high risk inherited inborn errors

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

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.

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.

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

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