Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome

Saute, Jonas Alex Morales; Souza, Carolina Fischinger Moura de; Poswar, Fabiano de Oliveira; Donis, Karina Carvalho; Campos, Lillian Gonçalves; Deyl, Adriana Vanessa Santini; Burin, Maira Graeff; Vargas, Carmen Regla; Matte, Úrsula da Silveira; Giugliani, Roberto; Saraiva-Pereira, Maria Luiza; Vedolin, Leonardo; Gregianin, Lauro José; Jardim, Laura Bannach

doi:10.1590/0004-282x20160155

Cited by 12 publications

(26 citation statements)

References 33 publications

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“…4 Allogeneic transplantation has been shown to eventually halt disease progression in many patients, although some white-matter disease progression on MRI is commonly observed during the first 12 to 18 months after transplantation. 6,7,18 …”

Section: Discussionmentioning

confidence: 99%

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy

et al. 2017

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BACKGROUND In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation. METHODS We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2–3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion. RESULTS A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications. CONCLUSIONS Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety.

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Section: Discussionmentioning

confidence: 99%

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy

et al. 2017

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“…Recently, a multicenter-based retrospective study of long-term outcomes of HSCT in 14 patients with ACALD has been reported ( Kühl et al , 2017 ). 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 ).…”

Section: Introductionmentioning

confidence: 95%

“…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 ).…”

Section: Introductionmentioning

confidence: 99%

Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy

Matsukawa

Yamamoto

Honda

et al. 2020

Brain Communications

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Accumulated experience supports the efficacy of allogenic haematopoietic stem cell transplantation in arresting the progression of childhood-onset cerebral form of adrenoleukodystrophy in early stages. For adulthood-onset cerebral form of adrenoleukodystrophy, however, there have been only a few reports on haematopoietic stem cell transplantation and the clinical efficacy and safety of that for adulthood-onset cerebral form of adrenoleukodystrophy remain to be established. To evaluate the clinical efficacy and safety of haematopoietic stem cell transplantation, we conducted haematopoietic stem cell transplantation on 12 patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy in a single-institution-based prospective study. Through careful prospective follow-up of 45 male adrenoleukodystrophy patients, we aimed to enrol patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy at early stages. Indications for haematopoietic stem cell transplantation included cerebral form of adrenoleukodystrophy or cerebello-brainstem form of adrenoleukodystrophy with Loes scores up to 13, the presence of progressively enlarging white matter lesions and/or lesions with gadolinium enhancement on brain MRI. Clinical outcomes of haematopoietic stem cell transplantation were evaluated by the survival rate as well as by serial evaluation of clinical rating scale scores and neurological and MRI findings. Clinical courses of eight patients who did not undergo haematopoietic stem cell transplantation were also evaluated for comparison of the survival rate. All the patients who underwent haematopoietic stem cell transplantation survived to date with a median follow-up period of 28.6 months (4.2–125.3 months) without fatality. Neurological findings attributable to cerebral/cerebellar/brainstem lesions became stable or partially improved in all the patients. Gadolinium-enhanced brain lesions disappeared or became obscure within 3.5 months and the white matter lesions of MRI became stable or small. The median Loes scores before haematopoietic stem cell transplantation and at the last follow-up visit were 6.0 and 5.25, respectively. Of the eight patients who did not undergo haematopoietic stem cell transplantation, six patients died 69.1 months (median period; range 16.0–104.1 months) after the onset of the cerebral/cerebellar/brainstem lesions, confirming that the survival probability was significantly higher in patients with haematopoietic stem cell transplantation compared with that in patients without haematopoietic stem cell transplantation (P = 0.0089). The present study showed that haematopoietic stem cell transplantation was conducted safely and arrested the inflammatory demyelination in all the patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy when haematopoietic stem cell transplantation was conducted in the early stages. Further studies are warranted to optimize the procedures of haematopoietic stem cell transplantation for adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy.

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“…The results of the study by Saute et al bring back to light some issues that should be considered in the decision process of HSCT in IEM, as an early age, at the beginning of the symptomatic phase, as well as the use of stem cells from a related donor 3 .…”

mentioning

confidence: 98%

“…Two important issues should also be considered for the HSCT: 1) the graft-versus-host disease observed in 27% of patients (CALD-3, CALD-7, MLD-9) in Saute et al study 3 , a major complication that is related to higher mortality rates in a long term follow up after HSCT 8 ; and 2) the controversial use of ERT for HSCT MPS-IH as adjuvant therapy 7 .…”

mentioning

confidence: 99%

Neurological outcome in patients with inborn errors of metabolism submitted to hematopoietic stem cell transplantation. What should we expect?

Lange

2016

Arq. Neuro-Psiquiatr.

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Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome

Cited by 12 publications

References 33 publications

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy

Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy

Neurological outcome in patients with inborn errors of metabolism submitted to hematopoietic stem cell transplantation. What should we expect?

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