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21.08.2018 | Original Article

Allogeneic haematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X-linked adrenoleukodystrophy

verfasst von: Nils Waldhüter, Wolfgang Köhler, Philipp G. Hemmati, Christian Jehn, Rudolf Peceny, Giang L. Vuong, Renate Arnold, Jörn-Sven Kühl

Erschienen in: Journal of Inherited Metabolic Disease

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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 haematopoietic stem cell transplantation (HSCT) from matched donors after myeloablative conditioning with busulfan and cyclophosphamide. All patients engrafted and 11 survived (estimated survival 73 ± 11%), eight with stable cognition and seven 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 ten 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.
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Literatur
Zurück zum Zitat Aubourg P, Blanche S, Jambaqué I et al (1990) Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med 322:1860–1866CrossRefPubMed Aubourg P, Blanche S, Jambaqué I et al (1990) Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med 322:1860–1866CrossRefPubMed
Zurück zum Zitat Ben-Barouch S, Cohen O, Vidal L, Avivi I, Ram R (2016) Busulfan fludarabine vs busulfan cyclophosphamide as a preparative regimen before allogeneic hematopoietic cell transplantation: systematic review and meta-analysis. Bone Marrow Transplant 51:232–240CrossRefPubMed Ben-Barouch S, Cohen O, Vidal L, Avivi I, Ram R (2016) Busulfan fludarabine vs busulfan cyclophosphamide as a preparative regimen before allogeneic hematopoietic cell transplantation: systematic review and meta-analysis. Bone Marrow Transplant 51:232–240CrossRefPubMed
Zurück zum Zitat Bertz H, Potthoff K, Mertelsmann R, Finke J (1997) Busulfan/cyclophosphamide in volunteer unrelated donor (VUD) BMT: excellent feasibility and low incidence of treatment-related toxicity. Bone Marrow Transplant 19:1169–1173CrossRefPubMed Bertz H, Potthoff K, Mertelsmann R, Finke J (1997) Busulfan/cyclophosphamide in volunteer unrelated donor (VUD) BMT: excellent feasibility and low incidence of treatment-related toxicity. Bone Marrow Transplant 19:1169–1173CrossRefPubMed
Zurück zum Zitat Capotondo A, Milazzo R, Politi LS et al (2012) Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation. Proc Natl Acad Sci U S A 109:15018–15023CrossRefPubMedPubMedCentral Capotondo A, Milazzo R, Politi LS et al (2012) Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation. Proc Natl Acad Sci U S A 109:15018–15023CrossRefPubMedPubMedCentral
Zurück zum Zitat de Beer M, Engelen M, van Geel BM (2014) Frequent occurrence of cerebral demyelination in adrenomyeloneuropathy. Neurology 83:2227–2231CrossRefPubMed de Beer M, Engelen M, van Geel BM (2014) Frequent occurrence of cerebral demyelination in adrenomyeloneuropathy. Neurology 83:2227–2231CrossRefPubMed
Zurück zum Zitat Filipovich AH, Weisdorf D, Pavletic S et al (2005) National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11:945–956CrossRefPubMed Filipovich AH, Weisdorf D, Pavletic S et al (2005) National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11:945–956CrossRefPubMed
Zurück zum Zitat Fitzpatrick AS, Loughrey CM, Johnston P et al (2008) Haematopoietic stem-cell transplant for adult cerebral adrenoleukodystrophy. Eur J Neurol 15:e21–e22CrossRefPubMed Fitzpatrick AS, Loughrey CM, Johnston P et al (2008) Haematopoietic stem-cell transplant for adult cerebral adrenoleukodystrophy. Eur J Neurol 15:e21–e22CrossRefPubMed
Zurück zum Zitat Gong Y, Sasidharan N, Laheji F et al (2017) Microglial dysfunction as a key pathological change in adrenomyeloneuropathy. Ann Neurol 82(5):813–827CrossRefPubMedPubMedCentral Gong Y, Sasidharan N, Laheji F et al (2017) Microglial dysfunction as a key pathological change in adrenomyeloneuropathy. Ann Neurol 82(5):813–827CrossRefPubMedPubMedCentral
Zurück zum Zitat Hitomi T, Mezaki T, Tomimoto H et al (2005) Long-term effect of bone marrow transplantation in adult-onset adrenoleukodystrophy. Eur J Neurol 12:807–810CrossRefPubMed Hitomi T, Mezaki T, Tomimoto H et al (2005) Long-term effect of bone marrow transplantation in adult-onset adrenoleukodystrophy. Eur J Neurol 12:807–810CrossRefPubMed
Zurück zum Zitat Holtick U, Albrecht M, Chemnitz JM et al (2015) Comparison of bone marrow versus peripheral blood allogeneic hematopoietic stem cell transplantation for hematological malignancies in adults—a systematic review and meta-analysis. Crit Rev Oncol Hematol 94:179–188CrossRefPubMed Holtick U, Albrecht M, Chemnitz JM et al (2015) Comparison of bone marrow versus peripheral blood allogeneic hematopoietic stem cell transplantation for hematological malignancies in adults—a systematic review and meta-analysis. Crit Rev Oncol Hematol 94:179–188CrossRefPubMed
Zurück zum Zitat Hunter CA, Jones SA (2015) IL-6 as a keystone cytokine in health and disease. Nat Immunol 16:448–457CrossRefPubMed Hunter CA, Jones SA (2015) IL-6 as a keystone cytokine in health and disease. Nat Immunol 16:448–457CrossRefPubMed
Zurück zum Zitat Kemp S, Berger J, Aubourg P (2012) X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects. Biochim Biophys Acta 1822:1465–1474CrossRefPubMed Kemp S, Berger J, Aubourg P (2012) X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects. Biochim Biophys Acta 1822:1465–1474CrossRefPubMed
Zurück zum Zitat Köhler W (2010) Leukodystrophies with late disease onset: an update. Curr Opin Neurol 23(3):234–241CrossRefPubMed Köhler W (2010) Leukodystrophies with late disease onset: an update. Curr Opin Neurol 23(3):234–241CrossRefPubMed
Zurück zum Zitat Köhler W, Sokolowski P (1999) A new disease-specific scoring system for adult phenotypes of x-linked adrenoleukodystrophy. J Mol Neurosci 13:247–252CrossRef Köhler W, Sokolowski P (1999) A new disease-specific scoring system for adult phenotypes of x-linked adrenoleukodystrophy. J Mol Neurosci 13:247–252CrossRef
Zurück zum Zitat Kühl JS, Suarez F, Gillett GT et al (2017) Long-term outcomes of allogeneic haematopoietic stem cell transplantation for adult cerebral X-linked adrenoleukodystrophy. Brain 140:953–966CrossRefPubMed Kühl JS, Suarez F, Gillett GT et al (2017) Long-term outcomes of allogeneic haematopoietic stem cell transplantation for adult cerebral X-linked adrenoleukodystrophy. Brain 140:953–966CrossRefPubMed
Zurück zum Zitat Kühl JS, Kupper J, Baqué H et al (2018) Potential risks to stable long-term outcome of allogeneic hematopoietic stem cell transplantation for children with cerebral X-linked adrenoleukodystrophy. JAMA Network Open 1:e180769CrossRef Kühl JS, Kupper J, Baqué H et al (2018) Potential risks to stable long-term outcome of allogeneic hematopoietic stem cell transplantation for children with cerebral X-linked adrenoleukodystrophy. JAMA Network Open 1:e180769CrossRef
Zurück zum Zitat Loes DJ, Hite S, Moser H et al (1994) Adrenoleukodystrophy: a scoring method for brain MR observations. AJNR Am J Neuroradiol 15:1761–1766PubMed Loes DJ, Hite S, Moser H et al (1994) Adrenoleukodystrophy: a scoring method for brain MR observations. AJNR Am J Neuroradiol 15:1761–1766PubMed
Zurück zum Zitat López-Erauskin J, Galino J, Ruiz M et al (2013) Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy. Hum Mol Genet 22(16):3296–3305CrossRefPubMed López-Erauskin J, Galino J, Ruiz M et al (2013) Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy. Hum Mol Genet 22(16):3296–3305CrossRefPubMed
Zurück zum Zitat Miller WP, Rothman SM, Nascene D et al (2011) Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood 118:1971–1978CrossRefPubMed Miller WP, Rothman SM, Nascene D et al (2011) Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood 118:1971–1978CrossRefPubMed
Zurück zum Zitat Moser HW (1997) Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy. Brain 120(Pt 8):1485–1508CrossRefPubMed Moser HW (1997) Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy. Brain 120(Pt 8):1485–1508CrossRefPubMed
Zurück zum Zitat Moser HW, Mahmood A (2007) New insights about hematopoietic stem cell transplantation in adrenoleukodystrophy. Arch Neurol 64:631–632CrossRefPubMed Moser HW, Mahmood A (2007) New insights about hematopoietic stem cell transplantation in adrenoleukodystrophy. Arch Neurol 64:631–632CrossRefPubMed
Zurück zum Zitat Peters C, Charnas LR, Tan Y et al (2004) Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood 104:881–888CrossRefPubMed Peters C, Charnas LR, Tan Y et al (2004) Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood 104:881–888CrossRefPubMed
Zurück zum Zitat Przepiorka D, Weisdorf D, Martin P et al (1995) 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 15:825–828PubMed Przepiorka D, Weisdorf D, Martin P et al (1995) 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 15:825–828PubMed
Zurück zum Zitat Remberger M, Törlén J, Ringdén O et al (2015) Effect of total nucleated and CD34(+) cell dose on outcome after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 21:889–893CrossRefPubMed Remberger M, Törlén J, Ringdén O et al (2015) Effect of total nucleated and CD34(+) cell dose on outcome after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 21:889–893CrossRefPubMed
Zurück zum Zitat Semmler A, Köhler W, Jung HH, Weller M, Linnebank M (2008) Therapy of X-linked adrenoleukodystrophy. Expert Rev Neurother 8(9):1367–1379CrossRefPubMed Semmler A, Köhler W, Jung HH, Weller M, Linnebank M (2008) Therapy of X-linked adrenoleukodystrophy. Expert Rev Neurother 8(9):1367–1379CrossRefPubMed
Zurück zum Zitat Shapiro E, Krivit W, Lockman L et al (2000) Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy. Lancet 356:713–718CrossRefPubMed Shapiro E, Krivit W, Lockman L et al (2000) Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy. Lancet 356:713–718CrossRefPubMed
Zurück zum Zitat Socié G, Schmoor C, Bethge WA et al (2011) Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood 117:6375–6382CrossRefPubMed Socié G, Schmoor C, Bethge WA et al (2011) Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood 117:6375–6382CrossRefPubMed
Zurück zum Zitat Turk BR, Moser AB, Fatemi A (2017) Therapeutic strategies in adrenoleukodystrophy. Wien Med Wochenschr 167:219–226CrossRefPubMed Turk BR, Moser AB, Fatemi A (2017) Therapeutic strategies in adrenoleukodystrophy. Wien Med Wochenschr 167:219–226CrossRefPubMed
Zurück zum Zitat Tvedt TH, Lie SA, Reikvam H et al (2016) Pretransplant levels of CRP and interleukin-6 family cytokines; effects on outcome after allogeneic stem cell transplantation. Int J Mol Sci 17. pii: E1823 Tvedt TH, Lie SA, Reikvam H et al (2016) Pretransplant levels of CRP and interleukin-6 family cytokines; effects on outcome after allogeneic stem cell transplantation. Int J Mol Sci 17. pii: E1823
Zurück zum Zitat van Geel BM, Bezman L, Loes DJ, Moser HW, Raymond GV (2001) Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy. Ann Neurol 49:186–194CrossRefPubMed van Geel BM, Bezman L, Loes DJ, Moser HW, Raymond GV (2001) Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy. Ann Neurol 49:186–194CrossRefPubMed
Zurück zum Zitat Weber FD, Wiesinger C, Forss-Petter S et al (2014) X-linked adrenoleukodystrophy: very long-chain fatty acid metabolism is severely impaired in monocytes but not in lymphocytes. Hum Mol Genet 23:2542–2550CrossRefPubMed Weber FD, Wiesinger C, Forss-Petter S et al (2014) X-linked adrenoleukodystrophy: very long-chain fatty acid metabolism is severely impaired in monocytes but not in lymphocytes. Hum Mol Genet 23:2542–2550CrossRefPubMed
Metadaten
Titel
Allogeneic haematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X-linked adrenoleukodystrophy
verfasst von
Nils Waldhüter
Wolfgang Köhler
Philipp G. Hemmati
Christian Jehn
Rudolf Peceny
Giang L. Vuong
Renate Arnold
Jörn-Sven Kühl
Publikationsdatum
21.08.2018
Verlag
Springer Netherlands
Erschienen in
Journal of Inherited Metabolic Disease
Print ISSN: 0141-8955
Elektronische ISSN: 1573-2665
DOI
https://doi.org/10.1007/s10545-018-0241-9

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