HSCT for High Risk Inherited Inborn Errors

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.

Conditions

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

Interventions

DRUG

Clofarabine

days -7 through -3: 40 mg/m\^2 intravenously over 2 hours

PROCEDURE

Total body Irradiation

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.

DRUG

Melphalan

day -2: 140 mg/m\^2 intravenously over 30 minutes

BIOLOGICAL

Hematopoietic Stem Cell Transplantation

receives infusion of stem cells on day 0

DRUG

Alemtuzumab

0.3 mg/kg intravenously (IV) days -12 through -8

DRUG

mycophenylate mofetil

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)

DEVICE

Cyclosporine A

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.

DRUG

Hydroxyurea

hydroxyurea (HU) beginning day -28 and continuing through alemtuzumab administration

Sponsors & Collaborators

• Masonic Cancer Center, University of Minnesota

  lead OTHER

Principal Investigators

• Paul Orchard, MD · Masonic Cancer Center, University of Minnesota

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Max Age

70 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2006-09-30

Primary Completion

2014-09-30

Completion

2014-09-30

Countries

• United States

Study Locations