BMT For Children With Inborn Errors Of Metabolism

Bone marrow transplantation is the only known treatment for a variety of genetic diseases sometimes called "inborn errors of metabolism" or "storage diseases." Each of these diseases is due to the deficiency of a specific substance in the body called an enzyme, which results in the accumulation of toxic chemicals inside the cells. Depending upon the enzyme abnormality and the chemicals that accumulate, specific patterns of tissue damage and organ failure occur. These include central nervous system deterioration, growth failure, bone abnormalities and joint disability, enlargement of the liver and spleen in the abdomen, heart disease, airway obstruction, lung disease, corneal clouding and hearing loss. The eventual organ damage and outcome of the different diseases is quite variable, although the ones in which BMT has been evaluated are those that have a naturally progressive downward course ultimately ending in death in childhood.

BMT for children with genetic diseases

The purpose of BMT in these disorders is to provide special marrow-derived cells, which travel to various organs in the body including the liver (Kupffer cells), skin (Langerhan's cells), lung (alveolar macrophages), spleen (macrophages), lymph nodes, tonsils and the brain (microglia). The storage disease that has received the most attention is Hurler's mucopolysaccharidosis. There have been more than 300 patients with Hurler's disease treated by bone marrow transplantation throughout the world. In the large majority of cases, the donors have been HLA matched siblings, and the conditioning regimen has utilized high doses of chemotherapy (cyclophosphamide and busulfan). In successfully engrafted patients, the abnormal facial and body features are ameliorated, the joint function is improved, and the cardiopulmonary and hepatic and splenic abnormalities disappear. The longer term effect on growth and skeletal maturation, and the effects on existing bone disease are not well defined. Of greatest significance is the effect on the central nervous system. While the damage to the brain which has occurred up to the time of transplant is not reversed, it does appear in long term studies that further psychomotor degeneration is either prevented or markedly reduced.

Unfortunately, at least 80% of children with a storage disease who might benefit from a bone marrow transplant will not have an HLA matched sibling donor. Matched unrelated donors have been identified in a relatively large number of situations for children with Hurler's. In a review of 40 such patients, there was a significant graft failure rate (40%) which was thought to be due to abnormal metabolism of busulfan by children with Hurler's. There also was a high incidence of GVHD.

Optimizing chances for engraftment and minimizing toxicity

To overcome the graft failure, we have evaluated the busulfan pharmacokinetics in a large number of children undergoing BMT. We found that while children engrafted at a wide range of steady state busulfan concentrations (200-900), all of the graft rejections occurred at a steady concentration of <600. We have recently completed a study of targeted busulfan in which the pharmacokinetics is measured prior to admission using a half dose of busulfan. The dose is then adjusted in order to obtain a steady state concentration of 600-800. Because the combination of busulfan and cytoxan has been associated with significant toxicity we have further modified the conditioning regiment to replace the cytoxan with fludarabine. In this study, we are prospectively evaluating the targeted busulfan/fludarabine regimen in children with storage diseases in which the targeted level of busulfan will be fixed at 600. We believe this will optimize the chances for engraftment while minimizing complications. For more information about this specific protocol go to marrow stem cell defects

Eligibility

Patients who are eligible for this protocol have one of the following diagnoses:

• A lysosomal storage disease or other inborn error for which BMT has been performed with positive results in at least one patient. This would include Hurler's, Morquio, Maroteaux-Lemy and forms of metachromatic leukodystrophy, globoid cell leukodystrophy, adrenoleukodystrophy, Gaucher's disease.
• Documentation of specific enzyme deficiency.
• Acceptable cognitive-psychosocial development.
  • No history of pervasively and chronically delayed development reported by health care providers, parents and others who have worked with the child.
  • Above or at the level of mild retardation on 2 or more standardized tests.
  • Observed by nursing and mental health care providers of the child's interactions with parents and health care provider, which show that the child can interact constructively with others, learn from experiences and adapt to situations over time.
  • Recognition by the parent(s) that existing delays will not be reversed and the need for ongoing interventions and evaluation to chart progress.
• Cardiac ejection fraction >25%
• Pulmonary diffusion capacity >60%