reduced-intensity hematopoietic stem cell transplant for high risk lysosomal and peroxisomal disorders

Conditions: Lysosomal Storage Disease; Peroxisomal Disorder

Summary: this study is designed to test the ability to achieve donor hematopoietic engraftment while maintaining low rates of transplant-related mortality (trm) in patients with high-risk lysosomal and peroxisomal disorders using a novel conditioning regimen for hematopoietic cell transplantation (hct). after a reduced-intensity conditioning regimen using volumetric-modulated arc therapy (vmat)-delivered low-dose total body irradiation (tbi) with highly conformal marrow boosting, patients will be transplanted using either a related or unrelated allograft. the cell source may be marrow, peripheral blood or cord blood based on donor availability.

the conditioning regimen consists of alemtuzumab (campath-1h), clofarabine, melphalan, and vmat-delivered low-dose tbi with boosted marrow irradiation. additional graft-versus-host disease prophylaxis consists of mycophenolate mofetil and cyclosporine.

Eligibility criteria:
inclusion criteria: * adrenoleukodystrophy (ald): 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, * metachromatic leukodystrophy (mld): patients from 0-55 years of age diagnosed with mld as determined by arylsulfatase a activity. * globoid cell leukodystrophy (gld): patients from 0-55 years of age diagnosed with gld as determined by galactocerebrosidase activity will be eligible for this protocol * wolman's disease, gm1 gangliosidosis, tay sachs disease, sanfilippo syndrome, sandhoff disease or other inherited metabolic diseases including but not limited to i-cell disease (mucolipidosis ii): patients who are determined to be sufficiently advanced or high risk based on the following reasons: * symptomatic disease, as based on neurologic examination or evidence of deterioration based on subsequent neuropsychologic evaluations. * evidence of an expected poor outcome based on genetic testing or a prior family history of aggressive disease. * 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. * donor availability * transplantation using sufficiently matched related donors (such as matched siblings) or unrelated donors will be considered. both granulocyte-colony stimulating factor (g-csf) stimulated peripheral blood grafts and bone marrow grafts will be considered, although bone marrow will be the priority. * cord blood grafts, both related and unrelated, are also eligible. as this protocol will use a reduced intensity regimen, this protocol will use the current recommendations of the university of minnesota for choosing cord blood grafts. if a single cord blood unit cell dose is insufficient, double cord transplantation should be considered if sufficiently matched cord blood units are available. the priority of choosing cord blood donors is based on the current institutional recommendations. * exclusion of metabolic disorder carrier status from related donor and unrelated cord blood grafts as appropriate for primary disease. * adequate organ function - measured within 30 days of study enrollment * signed consent exclusion criteria: * inability to receive total body irradiation (tbi) with marrow boosting per protocol guidelines as determined by the radiation oncologist * pregnant - menstruating females must have a negative serum pregnancy test within 14 days of treatment start. * 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.

Keywords: bone marrow transplantation reduced intensity conditioning adrenoleukodystrophy metachromatic leukodystrophy globoid cell leukodystrophy wolman's disease gm1 gangliosidosis tay sachs disease sanfilippo syndrome sandhoff disease inherited metabolic i-cell disease mucolipidosis ii