By Jai S. Perumal, MD
Assistant Professor of Neurology, Weill Cornell Medical College
Dr. Perumal reports she receives grant/research support from Genzyme Corp., and is on the speakers bureau for Biogen Idec, Genzyme Corp., Acorda Therapeutics, and Teva Pharmaceuticals.
SYNOPSIS: Based on review of data from 14 patients with adult cerebral X-linked adrenoleukodystrophy who were treated with hematopoietic stem cell transplantation, the authors suggested that this might be an intervention that potentially could have long-term benefits and recommended further studies to evaluate this therapy.
SOURCE: Kuhl JS, Suarez F, Gillett GT, et al. Long-term outcomes of allogenic haematopoietic stem cell transplantation for adult cerebral x-linked adrenoleukodystrophy. Brain 2017:140;953-966.
X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disease caused by a defect in the ABCD1 gene that results in alterations in the peroxisomal oxidation of long-chain fatty acids. This leads to accumulation of very long-chain fatty acids in tissues. This disease primarily affects the brain and adrenal glands. Several phenotypes of this disease have been described, and they mainly are divided into the following four categories: cerebral inflammatory, adrenomyeloneuropathy (AMN), Addison’s disease only, and asymptomatic. The cerebral form is characterized by rapidly progressive neurologic impairment, including cognitive, behavioral, and sensory motor deficits, and is seen mostly in very young children, representing about one-third of the cases of ALD. This presentation is seen less commonly in adults, representing about 5-10%. This also can present as a later development in adults who have had the AMN phenotype for several years.
Allogenic hematopoietic stem cell transplantation (HSCT) is an established treatment for children with cerebral ALD based on several studies that showed benefits to survival and neurologic outcomes from treatment despite the risks associated with transplantation, as there is no alternative effective therapy. However, other than anecdotes, such data are not available for adults with cerebral ALD. But given the poor prognosis in adults with the cerebral form, HSCT has been tried in this patient population as compassionate use. The authors conducted a retrospective analysis of 14 adult patients with cerebral ALD who received HSCT in centers in Germany, France, and the United Kingdom to study the feasibility and long-term outcomes of this treatment.
All patients had detailed neurological/neuropsychological and neurophysiologic and magnetic resonance imaging (MRI) examinations before and at specified time points post-transplantation as well. Assessment tools included Adult X-linked ALD Clinical Symptom Score, Kurtzke Expanded Disability Status Scale (EDSS), modified Rankin scale, and Loes MRI severity score. Post-treatment assessment intervals were six months and about 24 months (at least 12 months). Survival was compared by Kaplan-Meier estimates and comparisons done by log method. Comparison
of continuous variables was performed by non-
The patients had a median age of 34 years (range 21-48 years), and eight of 14 patients were alive at a median follow-up of 65 months (range 38-116 months). The estimated overall probability of survival was 57.1 ± 13.2%. Among the 14 patients, two patients who received cord blood transplantation with reduced intensity conditioning and two patients who received peripheral stem cell transplantation after myeloablative conditioning did not survive. Eight out of 10 patients who received myeloablative conditioning followed by bone marrow transplantation survived. There were a total of six deaths in the study. The deaths were attributed to the following causes: one death was due to primary disease progression without complications of HSCT, two deaths were due to secondary disease progression after life-threatening infection, one death was due to graft rejection, and three early patient deaths were attributed to transplantation-associated infection with non-engraftment or due to immobility due to advanced disease. Among the variables examined, survival was related to extent of baseline motor dysfunction. Limited AMN with EDSS < 6.0 was significantly associated with superior survival compared to advanced AMN with EDSS
≥ 6.0. Significant neurological and/or behavioral deterioration was seen in all but one patient during the transplantation and during early follow-up. This markedly improved or disappeared in all surviving patients between 6-12 months.
This analysis of 14 adult patients with cerebral ALD shows that HSCT can, at least in a subgroup of patients, prolong survival and preserve neurologic function by arresting inflammatory demyelination. Even though hematopoietic stem cell transplantation was associated with significant risks, including death and disease deterioration in the few months immediately following transplantation, given the devastating prognosis associated with this form of ALD, this is a potentially beneficial option that deserves to be studied further for carefully selected adults with cerebral ALD.