Cerebral X-Linked Adrenoleukodystrophy: The University of Minnesota Hematopoietic Cell Transplantation Experience from 1991 to 2004.
Authors: Peters Charles , Charnas Lawrence R. , DeFor Todd , Shapiro Elsa G. , Grewal Satkiran S. , Orchard Paul J. , Abel Susan L. , Ramsay Norma K.C. , Dusenbery Kathryn E. , Loes Daniel J. , Lockman Lawrence A. , Krivit William 
Published: October 2019

Hematopoietic cell transplantation (HCT) is the only effective long-term treatment for cerebral X-linked adrenoleukodystrophy (X-ALD), a beta-oxidation disorder of very-long-chain fatty acids. The most common cerebral phenotype of X-ALD has a median onset of 7 years and is characterized by adrenal insufficiency, disability, dementia and typically death within months to several years after clinical onset. The international HCT experience from 1982 to 1999 for cerebral X-ALD clearly demonstrated that baseline neurologic and neuropsychological function, degree of disability, and neuroradiologic status predicted outcomes following HCT [Peters C. et al. BLOOD2004;104:881]. The estimated 5-year survival varied with the number of neurologic deficits and the MRI severity score before HCT: 0 or 1 neurologic deficits and MRI severity score less than 9 (n=25), 92% (95% CI, 81%–100%); all other patients (n=37), 45% (95% CI, 23%–67%; P<.01). From 1991 to 2004, 59 consecutive patients with cerebral X-ALD underwent HCT at the University of Minnesota at a median age of 9.1 years (range, 4.0–16.1) from related marrow donors (n=22), unrelated marrow donors (n=23), or unrelated umbilical cord blood donors (n=14). The diagnosis of X-ALD was made on the basis of disease manifestations in 38 boys (64%) rather than family history. The median baseline MRI score was 10 (range, 0.5–19.5). The median follow-up was 3.2 years (range, 0.5–12.3). The two most common conditioning regimens were 1) cyclophosphamide (60 mg/kg/dose IV x 2 days) and total body irradiation (1400 cGy in 7 fractions with complete sparing of the brain) [n=34] and 2) busulfan (1.6 mg/kg/dose every 12 hours IV x 8 doses) and cyclophosphamide (50 mg/kg/day IV x 4 days) [n=18]. Survival was analyzed based upon age at HCT (4–9 years vs. over 9 years, P=NS), donor type (related marrow, unrelated matched marrow, unrelated mismatched marrow and UCB, P=NS), reason for diagnosis (family history vs. disease manifestation, P=.08). Analysis of survival according to the baseline MRI severity score was highly significant (P<.01). Specifically, boys with an MRI severity score <6 [n=12] enjoyed 100% survival at 5 years compared to boys with an MRI severity score greater than or equal to 10 [n=29] whose survival at 5 years was only 35% (95% CI, 9–61%). The leading causes of death in patients with MRI severity score of 6 or greater were X-ALD progression (n=17), GvHD and infection (n=4 each). The University of Minnesota HCT experience for cerebral X-ALD confirms the outstanding results previously reported for patients transplanted at an early stage of disease. It re-emphasizes the importance of serial neuroradiologic monitoring of boys with the biochemical diagnosis of X-ALD and the recommendation that HCT be performed with the earliest evidence of cerebral involvement.