Advertisement

Neurotherapeutics

, Volume 14, Issue 4, pp 888–893 | Cite as

Five Questions Answered: A Review of Autologous Hematopoietic Stem Cell Transplantation for the Treatment of Multiple Sclerosis

Review

Abstract

Multiple sclerosis (MS) is thought to be an autoimmune disease targeting the central nervous system leading to demyelination, and axonal and neuronal damage, resulting in progressive disability. More intensive therapies such as immunodepletion with hematopoietic stem-cell rescue are being used at a time prior to patients becoming irreversibly disabled. Over the last 15 years, there has been a shift away from using autologous hematopoietic stem-cell transplants (aHSCT) to treat patients with progressive MS, towards treating those with active inflammation and relapses. There is an increasing body of evidence that aHSCT improves all measured MS outcomes, including burden of disease on MRI, clinical relapses, accumulation of disability, and quality of life of patients with active MS not controlled with standard therapy. Importantly, the progression-free survival curves of these patients plateau after the first few years demonstrating the impact that aHSCT has in changing the natural history of MS, potentially freeing patients from the relentless accumulation of disability. Concurrently there has been a reduction in procedure-related mortality. The results of randomized trials will likely spur further development of this field.

Keywords

Multiple sclerosis Hematopoietic stem cell transplantation Immunoablation Chemotherapy Autoimmunity Immune reconstitution 

Notes

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

13311_2017_564_MOESM1_ESM.pdf (1.2 mb)
ESM 1 (PDF 1224 kb)

References

  1. 1.
    Rush CA, MacLean HJ, Freedman MS. Aggressive multiple sclerosis: proposed definition and treatment algorithm. Nat Rev Neurol 2015;11(7):379–389.CrossRefPubMedGoogle Scholar
  2. 2.
    Burman J, Iacobaeus E, Svenningsson A, et al. Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience. J Neurol Neurosurg Psychiatry 2014;85(10):1116–1121.CrossRefPubMedGoogle Scholar
  3. 3.
    Muraro PA, Pasquini M, Atkins HL, et al. Long-term outcomes after autologous hematopoietic stem cell transplantation for multiple sclerosis. JAMA Neurol 2017;74(4):459–469.CrossRefPubMedGoogle Scholar
  4. 4.
    Burt RK, Balabanov R, Han X, et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA 2015;313(3):275–284.CrossRefPubMedGoogle Scholar
  5. 5.
    Atkins HL, Bowman M, Allan D, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet 2016;388(10044):576–585.CrossRefPubMedGoogle Scholar
  6. 6.
    Nash RA, Hutton GJ, Racke MK, et al. High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS. Neurology 2017;88(9):842–852.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Mancardi GL, Sormani MP, Gualandi F, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial. Neurology 2015;84(10):981–988.CrossRefPubMedGoogle Scholar
  8. 8.
    Muraro PA, Martin R, Mancardi GL, Nicholas R, Sormani MP, Saccardi R. Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis. Nat Rev Neurol 2017;13(7):391–405.CrossRefPubMedGoogle Scholar
  9. 9.
    Harrison DM, Gladstone DE, Hammond E, et al. Treatment of relapsing-remitting multiple sclerosis with high-dose cyclophosphamide induction followed by glatiramer acetate maintenance. Mult Scler 2012;18(2):202–209.CrossRefPubMedGoogle Scholar
  10. 10.
    Rice CM, Mallam EA, Whone AL, et al. Safety and feasibility of autologous bone marrow cellular therapy in relapsing-progressive multiple sclerosis. Clin Pharmacol Ther 2010;87(6):679–685.CrossRefPubMedGoogle Scholar
  11. 11.
    Egorin MJ, Kaplan RS, Salcman M, et al. Cyclophosphamide plasma and cerebrospinal fluid kinetics with and without dimethyl sulfoxide. Clin Pharmacol Ther 1982;32(1):122–128.CrossRefPubMedGoogle Scholar
  12. 12.
    Hassan M, Oberg G, Ehrsson H, et al. Pharmacokinetic and metabolic studies of high-dose busulphan in adults. Eur J Clin Pharmacol 1989;36(5):525–530.CrossRefPubMedGoogle Scholar
  13. 13.
    Atkins H. Hematopoietic stem cell transplants (HSCT) for multiple sclerosis (MS) in north America. Bone Marrow Transplant 2010;45:S4–S5.CrossRefGoogle Scholar
  14. 14.
    Nash R, Bowen J, McSweeney PA, et al. High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Blood 2003;102(7):2364–2372.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Openshaw H, Stuve O, Antel JP, et al. Multiple sclerosis flares associated with recombinant granulocyte colony-stimulating factor. Neurology 2000;54(11):2147–2150.CrossRefPubMedGoogle Scholar
  16. 16.
    DiPersio JF, Stadtmauer EA, Nademanee A, et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood 2009;113(23):5720–5726.PubMedGoogle Scholar
  17. 17.
    Slavin S, Nagler A, Varadi G, Or R. Graft vs autoimmunity following allogeneic non-myeloablative blood stem cell transplantation in a patient with chronic myelogenous leukemia and severe systemic psoriasis and psoriatic polyarthritis. Exp Hematol 2000;28(7):853–857.CrossRefPubMedGoogle Scholar
  18. 18.
    Lu J-Q, Joseph JT, Nash RA, et al. Neuroinflammation and demyelination in multiple sclerosis after allogeneic hematopoietic stem cell transplantation. Arch Neurol 2010;67(6):716–722.CrossRefPubMedGoogle Scholar
  19. 19.
    Berisso GA, Van Lint MT , Bacigalupo A, Marmont AM. Case report: adoptive autoimmune hyperthyroidism following allogeneic stem cell transplantation from an HLA-identical sibling with Graves’ disease. Bone Marrow Transplant 1999;23(10):1091–1092.CrossRefPubMedGoogle Scholar
  20. 20.
    Moore J, Brooks P, Milliken S, et al. A pilot randomized trial comparing CD34-selected versus unmanipulated hemopoietic stem cell transplantation for severe, refractory rheumatoid arthritis. Arthritis Rheum 2002;46(9):2301–2309.CrossRefPubMedGoogle Scholar
  21. 21.
    Fassas A, Anagnostopoulos A, Kazis A, et al. Autologous stem cell transplantation in progressive multiple sclerosis—an interim analysis of efficacy. J Clin Immunol 2000;20(1):24–30.CrossRefPubMedGoogle Scholar
  22. 22.
    Sun W, Popat U, Hutton G, et al. Characteristics of T-cell receptor repertoire and myelin-reactive T cells reconstituted from autologous haematopoietic stem-cell grafts in multiple sclerosis. Brain 2004;127(Pt 5):996–1008.CrossRefPubMedGoogle Scholar
  23. 23.
    Darlington PJ, Touil T, Doucet J-S, et al. Diminished Th17 (not Th1) responses underlie multiple sclerosis disease abrogation after hematopoietic stem cell transplantation. Ann Neurol 2013;73(3):341–354.CrossRefPubMedGoogle Scholar
  24. 24.
    Muraro PA, Robins H, Malhotra S, et al. T cell repertoire following autologous stem cell transplantation for multiple sclerosis. J Clin Invest 2014;124(3):1168–1172.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Muraro PA, Douek DC, Packer A, et al. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. J Exp Med 2005;201(5):805–816.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017;376(3):221–234.CrossRefPubMedGoogle Scholar
  27. 27.
    Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012;380(9856):1829–1839.CrossRefPubMedGoogle Scholar
  28. 28.
    Sormani MP, Muraro PA, Saccardi R, Mancardi G. NEDA status in highly active MS can be more easily obtained with autologous hematopoietic stem cell transplantation than other drugs. Mult Scler 2017;23(2):201–204.CrossRefPubMedGoogle Scholar
  29. 29.
    Snowden JA, Saccardi R, Allez M, et al. Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2012;47(6):770–790.CrossRefPubMedGoogle Scholar
  30. 30.
    Mancardi GL, Sormani MP, Di Gioia M, et al. Autologous haematopoietic stem cell transplantation with an intermediate intensity conditioning regimen in multiple sclerosis: the Italian multi-centre experience. Mult Scler 2012;18(6):835–842.CrossRefPubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2017

Authors and Affiliations

  1. 1.The Ottawa HospitalOttawaCanada

Personalised recommendations