Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X‐linked adrenoleukodystrophy

Abstract

The adult cerebral form of X‐linked adrenoleukodystrophy (ACALD), an acute inflammatory demyelinating disease, results in a rapidly progressive neurodegeneration, typically leading to severe disability or death within a few years after onset. We have treated 15 men who had developed ACALD with allogeneic hematopoietic stem cell transplantation (HSCT) from matched donors after myeloablative conditioning with busulfan and cyclophosphamide. All patients engrafted and 11 survived (estimated survival 73 ± 11%), 8 with stable cognition and 7 of them with stable motor function (estimated event‐free survival 36 ± 17%). Death after transplantation occurred within the first year after HSCT and was caused either primarily by infection (N = 3) or due to disease progression triggered by infection (N = 1). Patients with minor myelopathic symptoms (N = 4) or with no or mild cerebral symptoms pre‐transplant (N = 7) had an excellent outcome. In contrast, no patient with major neurological symptoms associated with an extensive involvement of pyramidal tract fibres in the internal capsule (N = 5) survived without cognitive deterioration. Notably, early leukocyte recovery was associated with dismal outcome for yet unknown reasons. All 10 tested survivors showed a reduction of plasma hexacosanoic acid (C26:0) in the absence of Lorenzo's oil. Over time, the event‐free survival could be improved from 2 out of 8 patients (25%) before 2013 to 5 out of 7 patients (71%) thereafter. Therefore, allogeneic HSCT appears to be a suitable treatment option for carefully selected ACALD patients when transplanted from matched donors after myeloablative, busulfan‐based conditioning.

Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy

“…Moreover, neurological findings attributable to cerebral/cerebellar/brainstem lesions became stable or partially improved in all the 12 patients. Compared with the clinical outcomes in previous studies ( Hitomi et al , 2005 ; Fitzpatrick et al , 2008 ; Saute et al , 2016 ; Kühl et al , 2017 ; Waldhüter et al , 2019 ), the results described in the present report demonstrated outstanding clinical outcomes including arrest of disease progression of the clinical presentations and stabilization of the MRI findings as well as the safety associated with HSCT. The clinical courses of patients with ALD after HSCT were also better than those described in a natural history study ( Suzuki et al , 2005 ).…”

“…Of the 17 patients, however, three patients showed the progressive enlargement of cerebral lesions or appearance of new lesions >1 year after HSCT and eight patients died because of HSCT-related complications or disease progression ( Hitomi et al , 2005 ; Fitzpatrick et al , 2008 ; Saute et al , 2016 ; Kühl et al , 2017 ). Of the additional seven patients with ACALD recently reported in addition to the eight patients in the previous multicenter-based retrospective study, two patients died because of HSCT-related complications or disease progression ( Waldhüter et al , 2019 ). The source of stem cells was either cord blood or peripheral blood for 4 of the 10 patients who died ( Fitzpatrick et al , 2008 ; Saute et al , 2016 ; Kühl et al , 2017 ; Waldhüter et al , 2019 ), whereas the source of the stem cells in the present study was the bone marrow for all the patients.…”

“…Although the arrest of progressive cerebral lesions was observed in five patients, three patients showed the progression of brain MRI lesions >1 year after HSCT and eight patients died ( Hitomi et al , 2005 ; Fitzpatrick et al , 2008 ; Saute et al , 2016 ; Kühl et al , 2017 ). A single center-based retrospective study of additional seven ACALD patients in addition to the eight patients in the previous report ( Kühl et al , 2017 ) has also been reported ( Waldhüter et al , 2019 ). Of additional seven patients with ACALD, two patients died after HSCT.…”

“…In contrast to HSCT for CCALD, however, HSCT for ACALD has been conducted only on a few patients to date ( Hitomi et al , 2005 ; Fitzpatrick et al , 2008 ; Saute et al , 2016 ; Kühl et al , 2017 ; Waldhüter et al , 2019 ). Recently, a multicenter-based retrospective study of long-term outcomes of HSCT in 14 patients with ACALD has been reported ( Kühl et al , 2017 ).…”

Lipids in the Physiopathology of Hereditary Spastic Paraplegias

“…Approximately 20% of males with adrenomyeloneuropathy will also develop CALD later in life with the same poor prognosis as in children. The only available therapy for CALD is allogenic HSCT (Raymond et al, 2019;Waldhüter et al, 2019). If performed in patients with minimal brain lesions and no/minor clinical symptoms, it may arrest the progression of demyelinating lesions.…”