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AUSTIN, Texas -- Survival in children with cerebral adrenoleukodystrophy (ALD) appeared to be improved with allogeneic hematopoietic cell transplants compared with untreated patients, a researcher said here.

Estimated 5-year survival probability in 65 children with cerebral ALD undergoing cell transplant in a retrospective, multicenter analysis was 74%, compared with 55% in untreated children evaluated at the same institutions (P not calculated), reported , of the University of Minnesota in Minneapolis.

However, he told attendees at the Child Neurology Society's annual meeting, the improved survival did not translate into freedom from disability progression. He reported that, among 40 children receiving hematopoietic cell transplants who had neurological evaluations 2 years later, 15 (38%) had acquired at least one new major disability such as wheelchair confinement or cortical blindness.

The best outcomes were in children in the best physical shape at the time of transplant, and in those whose donors were HLA-matched siblings, Raymond said.

He noted also that the transplants were toxic to many of the children. Treatment-related mortality in the first year after transplant was 18.5%, and half the children developed chronic or acute graft-versus-host disease (GVHD). The rate of serious GVHD during the first year post-transplant was 15%.

Bluebird Bio of Cambridge, Mass., sponsored the retrospective study of childhood cerebral ALD patients at four centers in the U.S. and one in France treated since 1990. It is testing a gene therapy for ALD applied to autologous hematopoietic cells. The study's purpose was to provide a baseline against which the company's treatment can be compared, since a randomized, controlled trial would be infeasible because of the disease's rarity.

The study's size -- a total of 137 patients -- makes it the largest ever to trace the natural history of childhood cerebral ALD in children receiving only supportive therapy as well those transplanted with donor hematopoietic cells.

ALD is an X-linked disorder caused by mutations in the ABCD1 gene that lead to inadequate peroxisomal beta oxidation and buildup of very long chain fatty acids, Raymond explained. It only afflicts boys, with symptom onset from age 4 to 10 after normal initial development.

About 35% of children with these mutations develop cerebral manifestations mainly driven by leukocyte proliferation and a resulting inflammatory demyelination. MRI scans with gadolinium contrast show massive, symmetrical, white matter lesions in the adrenal cortex. Clinical symptoms include widespread, progressive loss of neurologic function and, within a few years, death.

There is a predominantly peripheral form of the disease as well, and some individuals can carry the mutations without ever showing symptoms -- indicating that some unknown nongenetic factor must be present as well to cause disease, Raymond said.

The purpose of allogeneic hematopoietic cell transplant is to repopulate the marrow with cells producing a normal ABCD1 gene product.

Among the 137 patients whose records were included in the analysis, 72 did not undergo hematopoietic cell transplant. For the most part, this was because they were diagnosed before the procedure was considered appropriate for childhood cerebral ALD. Other reasons included lack of a suitable donor, very advanced or rapid disability progression at diagnosis, or the presence of a very slowly progressing form of the disease that militated against the risks of cell transplant.

All of the patients who were transplanted were diagnosed after 2000, Raymond noted, as another factor making the two groups not strictly comparable.

But in other ways the two groups were similar, he said. Age at diagnosis, family histories, clinical symptoms, and diagnostic workups all appeared to be nearly identical.

Mean follow-up was somewhat longer in the untreated patients, at 81.8 months, although the median of 52.2 months was nearly the same as in the transplanted patients. The difference stemmed from prolonged survival among 11 "slow progressors" in the untreated group who, despite the diagnosis of cerebral ALD, showed little white matter involvement in MRI scans initially and little change in it over time.

Overall in the untreated cohort, median survival time was 92 months. Forty of the 72 patients were dead at last follow-up.

Among the transplanted patients, no median for survival was reached because only 16 of the 65 patients had died. One factor that seemed to predict better survival was receiving the donor cells from an HLA-matched sibling. Among such patients, 92% had survived to last follow-up, compared with 72% of patients with other types of donors (most of whom were unmatched nonrelatives).

Raymond stressed that disability progression continued in many of the transplanted children, as manifested by wheelchair confinement, cortical blindness, loss of speech, resort to tube feeding, total incontinence, and/or cessation of voluntary movement.

One particularly striking finding in the study was that the transplanted patients began to show resolution of the white matter lesions within 2 weeks of the procedure. At 3 months, Raymond reported, the amount of gadolinium retained during MRI scans fell by a mean of about 33% from baseline.

, of Weill Cornell Medical College in New York City, who was not involved in the study, commented that perhaps the myeloablative conditioning regimens used to prepare patients for the transplants was responsible. He suggested that the transplant would not have had such a rapid onset of action.

Raymond agreed that this was possible. He noted that, in 12 of the patients, the transplant failed to engraft. Nevertheless, he said, disability progression in these patients appeared to slow anyway.

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