Reduced-Intensity Hematopoietic Stem Cell Transplant for High Risk Lysosomal and Peroxisomal Disorders

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Treatment of High Risk, Inherited Lysosomal and Peroxisomal Disorders by Reduced-Intensity Hematopoietic Cell Transplantation and Low-Dose Total Body Irradiation With Marrow Boosting by Volumetric-Modulated Arc Therapy (VMAT)

Conditions
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Lysosomal Storage Disease, Peroxisomal Disorder

Intervention / Treatment
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* Drug: Campath-1H
* Drug: Clofarabine
* Drug: Melphalan
* Radiation: Total Body Irradiation with Marrow Boosting
* Biological: Hematopoietic stem cell transplantation
* Drug: Cyclosporine A
* Drug: Mycophenolate mofetil


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intent-To-Treat Patients<br>Patients with high-risk lysosomal and peroxisomal disorders treated with preparative regimen (Campath-1H 0.3 mg/kg intravenous (IV) on days -12 through -8, clofarabine 40 mg/m^2 IV on days -9 through -5, melphalan 140 mg/m^2 IV on day -4 and Total Body Irradiation with Marrow Boosting [ first dose of 200 cGy single dose; 5 doses of 160cGy for marrow boosting - 1000cGy cumulative exposure] by Volumetric-Modulated Arc Therapy [VMAT] on days -3 through -1). Hematopoietic stem cell transplantation will be infused on Day 0. Post-transplant immunosuppression to follow: Mycophenolate mofetil (MMF) begin day -3 and continue to day +30 or 7 days after engraftment, whichever is later; Cyclosporine A (CsA) begin day -3 and then taper at day +100 if related donor, day +180 for unrelated donor. | Drug: Campath-1H<br>* A daily dose of 0.3 mg/kg IV over 2 hours will be administered on days - 12, -11, -10, -9, and -8.<br>* Other names: alemtuzumab-1H;Drug: Clofarabine<br>* A daily dose of 40 mg/m2 will be administered IV over 2 hours on days -9, -8, -7, -6, and -5.<br>* Other names: Clolar;Drug: Melphalan<br>* A single dose of 140 mg/m2 will be given IV on day -4 over 15 minutes.<br>* Other names: Alkeran;Radiation: Total Body Irradiation with Marrow Boosting<br>* Dose to total body 200 cGy in single dose Dose to bone marrow of the following bones 800 cGy in 5 divided daily fractions (160 cGy x 5 doses ). Treated with up to 3 abutting VMAT photon arcs from top of head to maximum inferior border.<br>* Other names: Volumetric-Modulated Arc Therapy (VMAT);Biological: Hematopoietic stem cell transplantation<br>* 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.<br>Drug: Cyclosporine A<br>* Patients will receive CsA therapy beginning on day -3. Dosing of CsA will be 2.5 mg/kg/dose 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 200 mg/L to 400 mg/L.<br>* Other names: CsA;Drug: Mycophenolate mofetil<br>* Patients will receive mycophenolate mofetil (MMF) therapy beginning on day -3. Dosing of MMF will be 1 gram three times daily (total daily dose 3 grams/day) if the recipient is >50 kg, or 15 mg/kg/dose three times daily if the recipient is ≤50 kg. The same dosage is used orally or intravenously.<br>* Other names: MMF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Donor (Allogeneic) Hematopoietic Engraftment | Number of patients who achieve hematopoietic engraftment - assessment of nucleated peripheral blood cells for donor (allogeneic) chimerism following this reduced-intensity HCT. | Day 100 Following Hematopoietic Cell Transplant (HCT) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transplant-Related Mortality | Incidence of death due to complications of HCT following this reduced-intensity conditioning regimen. | Day 100 following HCT | 
| Neurologic Outcomes | Depending upon underlying primary disease, a combination of evaluative tools (e.g. brain magnetic resonance imaging (MRI), clinical neurologic exam, neuropsychologic testing, electromyography) will be applied for assessment of neurologic function and how it may be affected by this reduced-intensity HCT regimen. | Changes from Baseline, Days 30, 60, 100, Year 1, Year 2, Year 3 Following HCT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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