title: Long-term outcomes of allogeneic haematopoietic stem cell transplantation for adult cerebral X-linked adrenoleukodystrophy.
abstract: The adult cerebral inflammatory form of X-linked adrenoleukodystrophy is a rapidly progressive neurodegenerative disease, as devastating as childhood cerebral adrenoleukodystrophy. Allogeneic haematopoietic stem cell transplantation has been demonstrated to provide long-term neurological benefits for boys with the childhood cerebral form, but results in adults are sparse and inconclusive. We analysed data from 14 adult males with adult cerebral adrenoleukodystrophy treated with allogeneic haematopoietic stem cell transplantation on a compassionate basis in four European centres. All presented with cerebral demyelinating lesions and gadolinium enhancement. Median age at diagnosis of adult cerebral adrenoleukodystrophy was 33 years (range 21-48 years). In addition to cerebral inflammation, five patients had established severe motor disability from adrenomyeloneuropathy affecting only the spinal cord and peripheral nerves (Expanded Disability Status Scale score ≥ 6). Eight patients survived (estimated survival 57 ± 13%) with a median follow-up of 65 months (minimum 38 months). Death was directly transplant-/infection-related (n = 3), due to primary disease progression in advanced adult cerebral adrenoleukodystrophy (n = 1), or secondary disease progression (n = 2) after transient multi-organ failure or non-engraftment. Specific complications during stem cell transplantation included deterioration of motor and bladder functions (n = 12) as well as behavioural changes (n = 8). Arrest of progressive cerebral demyelination and prevention of severe loss of neurocognition was achieved in all eight survivors, but deterioration of motor function occurred in the majority (n = 5). Limited motor dysfunction (Expanded Disability Status Scale score < 6) prior to transplantation was associated with significantly improved survival [78 ± 14% (n = 9) versus 20 ± 18%(n = 5); P < 0.05] and maintenance of ambulation (Expanded Disability Status Scale score < 7) post-transplant (78% versus 0%; P = 0.021). In contrast, bilateral involvement of the internal capsule on brain MRI was associated with poorer survival [20 ± 18% (n = 5) versus 78 ± 14% (n = 9); P < 0.05]. This study is the first to support the feasibility, complications and potential long-term neurological benefit of allogeneic haematopoietic stem cell transplantation in adult cerebral adrenoleukodystrophy. Further studies are warranted to attempt to improve outcomes through patient selection and optimization of transplantation protocols.
authors.affiliation: Department of Pediatric Oncology/Hematology/SCT, Charité Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Jörn-Sven
authors.initials: JS
authors.lastname: Kühl
authors.affiliation: Department of Hematology, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France.
authors.forename: Felipe
authors.initials: F
authors.lastname: Suarez
authors.affiliation: Laboratory Medicine, STH NHS Foundation Trust, Northern General Hospital, Sheffield, S5 7AU, UK.
authors.forename: Godfrey T
authors.initials: GT
authors.lastname: Gillett
authors.affiliation: Department of Hematology, Oncology and Tumorimmunology, Charité Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Philipp G
authors.initials: PG
authors.lastname: Hemmati
authors.affiliation: Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Snowden
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stadler
authors.affiliation: Department of Hematology, Oncology and Tumorimmunology, Charité Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Giang L
authors.initials: GL
authors.lastname: Vuong
authors.affiliation: Department of Neuropediatrics and INSERM UMR1169, Hôpital Bicêtre, 78, avenue du Général Leclerc, 94270 Kremlin-Bicêtre, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Aubourg
authors.affiliation: Department of Pediatric Oncology/Hematology/SCT, Charité Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Köhler
authors.affiliation: Department of Hematology, Oncology and Tumorimmunology, Charité Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Arnold
mesh_terms: D000326:Adrenoleukodystrophy / Q000401:mortality / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D000328:Adult; D000359:Aftercare; D018450:Disease Progression; D005240:Feasibility Studies; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D011183:Postoperative Complications / Q000209:etiology* / Q000401:mortality / Q000503:physiopathology; D012720:Severity of Illness Index; D055815:Young Adult
keywords: X-linked adrenoleukodystrophy; adult cerebral form; brain MRI; haematopoietic stem cell transplantation; long-term outcome