Outcomes and Cost-Effectiveness of Autologous Hematopoietic Cell Transplant for Multiple Sclerosis

  • Anastasie M. Dunn-Pirio
  • Benjamin M. HeymanEmail author
  • Dan S. Kaufman
  • Revere P. Kinkel
Multiple Sclerosis and Related Disorders (J Graves, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Multiple Sclerosis and Related Disorders


Purpose of review

This review presents a critical appraisal of the use of autologous hematopoietic cell transplant (AHCT) for the treatment of multiple sclerosis. We present the reader with a brief review on the AHCT procedure, its immunomodulatory mechanism of action in MS, the most recent evidence in support of its use in patients with relapsing-remitting multiple sclerosis (RRMS), as well as its cost considerations.

Recent findings

The first meta-analysis of clinical trials of AHCT for patients with MS demonstrated durable 5-year progression-free survival rates and low treatment-related mortality. Recently, the first randomized controlled phase III clinical trial demonstrated AHCT to be superior to best available therapy for a subset of patients with RRMS. This led to the American society for transplant and cellular therapies (ASTCT) to recommend AHCT “for patients with relapsing forms of MS who have prognostic factors that indicate a high risk of future disability.”


AHCT should be considered for patients with RRMS with evidence of clinical activity who have failed 2 lines of therapy or at least one highly active disease-modifying therapy.


Multiple sclerosis Autologous stem cell transplant Outcomes Cost-effectiveness 


Authors’ Contributions

Drs. Dunn-Pirio and Heyman co-first authored the manuscript, both conceiving the idea for work, and equally contributed to writing the manuscript. Drs. Kaufman and Kinkel conceived the idea for work, helped write the manuscript, provided critical feedback, edited, and contributed to the final manuscript.

Compliance with Ethical Standards

Conflict of Interest

Dan S. Kaufman reports grants and personal fees from Fate Therapeutics, for work unrelated to the topic of this manuscript. Revere P. Kinkel reports honararia for scientific consultation and/or educational programs sponsored by the company from Biogen, Genzyme/Sanofi and Genetech/Roche outside the submitted work.

Anastasie M. Dunn-Pirio and Benjamin M. Heyman each declare no potential conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Browne P, Chandraratna D, Angood C, Tremlett H, Baker C, Taylor BV, et al. Atlas of multiple sclerosis 2013: a growing global problem with widespread inequity. Neurology. 2014;83(11):1022–4.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Wallin MT, Culpepper WJ, Campbell JD, Nelson LM, Langer-Gould A, Marrie RA, et al. The prevalence of MS in the United States: a population-based estimate using health claims data. Neurology. 2019;92(10):e1029–e40.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Koch-Henriksen N, Sorensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 2010;9(5):520–32.PubMedGoogle Scholar
  4. 4.
    Alonso A, Hernan MA. Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology. 2008;71(2):129–35.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Scalfari A, Neuhaus A, Daumer M, Ebers GC, Muraro PA. Age and disability accumulation in multiple sclerosis. Neurology. 2011;77(13):1246–52.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Koch M, Kingwell E, Rieckmann P, Tremlett H. The natural history of primary progressive multiple sclerosis. Neurology. 2009;73(23):1996–2002.PubMedGoogle Scholar
  7. 7.
    Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132(Pt 5):1175–89.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Reich DS, Lucchinetti CF, Calabresi PA. Multiple Sclerosis. N Engl J Med. 2018;378(2):169–80.PubMedGoogle Scholar
  9. 9.
    Meinl E, Krumbholz M, Derfuss T, Junker A, Hohlfeld R. Compartmentalization of inflammation in the CNS: a major mechanism driving progressive multiple sclerosis. J Neurol Sci. 2008;274(1–2):42–4.PubMedGoogle Scholar
  10. 10.
    De Angelis F, John NA, Brownlee WJ. Disease-modifying therapies for multiple sclerosis. BMJ. 2018;363:k4674.PubMedGoogle Scholar
  11. 11.
    Oksenberg JR, Baranzini SE. Multiple sclerosis genetics--is the glass half full, or half empty? Nat Rev Neurol. 2010;6(8):429–37.PubMedGoogle Scholar
  12. 12.
    Grigoriadis N, van Pesch V, Paradig MSG. A basic overview of multiple sclerosis immunopathology. Eur J Neurol. 2015;22(Suppl 2):3–13.PubMedGoogle Scholar
  13. 13.
    Mc GJ Jr, Russell PS, Atkins L, Webster EW. Treatment of terminal leukemic relapse by total-body irradiation and intravenous infusion of stored autologous bone marrow obtained during remission. N Engl J Med. 1959;260(14):675–83.Google Scholar
  14. 14.
    Kurnick NB, Montano A, Gerdes JC, Feder BH. Preliminary observations on the treatment of postirradiation hematopoietic depression in man by the infusion of stored autogenous bone marrow. Ann Intern Med. 1958;49(5):973–86.PubMedGoogle Scholar
  15. 15.
    Re A, Michieli M, Casari S, Allione B, Cattaneo C, Rupolo M, et al. High-dose therapy and autologous peripheral blood stem cell transplantation as salvage treatment for AIDS-related lymphoma: long-term results of the Italian cooperative group on AIDS and tumors (GICAT) study with analysis of prognostic factors. Blood. 2009;114(7):1306–13.PubMedGoogle Scholar
  16. 16.
    Varma A, Biritxinaga L, Saliba RM, Stich M, Jauch SF, Afrough A, et al. Impact of hepatitis B Core antibody Seropositivity on the outcome of autologous hematopoietic stem cell transplantation for multiple myeloma. Biol Blood Marrow Transplant. 2017;23(4):581–7.PubMedGoogle Scholar
  17. 17.
    Giralt S, Costa L, Schriber J, Dipersio J, Maziarz R, McCarty J, et al. Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations. Biol Blood Marrow Transplant. 2014;20(3):295–308.PubMedGoogle Scholar
  18. 18.
    Bolwell BJ, Pohlman B, Rybicki L, Sobecks R, Dean R, Curtis J, et al. Patients mobilizing large numbers of CD34+ cells ('super mobilizers') have improved survival in autologous stem cell transplantation for lymphoid malignancies. Bone Marrow Transplant. 2007;40(5):437–41.PubMedGoogle Scholar
  19. 19.
    Duong HK, Savani BN, Copelan E, Devine S, Costa LJ, Wingard JR, et al. Peripheral blood progenitor cell mobilization for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2014;20(9):1262–73.PubMedGoogle Scholar
  20. 20.
    Anderlini P, Donato M, Lauppe MJ, Huh YO, Martin TG, Chan KW, et al. A comparative study of once-daily versus twice-daily filgrastim administration for the mobilization and collection of CD34+ peripheral blood progenitor cells in normal donors. Br J Haematol. 2000;109(4):770–2.PubMedGoogle Scholar
  21. 21.
    Arora S, Majhail NS, Liu H. Hematopoietic progenitor cell mobilization for autologous stem cell transplantation in multiple myeloma in contemporary era. Clin Lymphoma Myeloma Leuk. 2018.Google Scholar
  22. 22.
    Alegre A, Tomas JF, Martinez-Chamorro C, Gil-Fernandez JJ, Fernandez-Villalta MJ, Arranz R, et al. Comparison of peripheral blood progenitor cell mobilization in patients with multiple myeloma: high-dose cyclophosphamide plus GM-CSF vs G-CSF alone. Bone Marrow Transplant. 1997;20(3):211–7.PubMedGoogle Scholar
  23. 23.
    de la Rubia J, Blade J, Lahuerta JJ, Ribera JM, Martinez R, Alegre A, et al. Effect of chemotherapy with alkylating agents on the yield of CD34+ cells in patients with multiple myeloma. Results of the Spanish myeloma group (GEM) study. Haematologica. 2006;91(5):621–7.PubMedGoogle Scholar
  24. 24.
    Hiwase DK, Bollard G, Hiwase S, Bailey M, Muirhead J, Schwarer AP. Intermediate-dose CY and G-CSF more efficiently mobilize adequate numbers of PBSC for tandem autologous PBSC transplantation compared with low-dose CY in patients with multiple myeloma. Cytotherapy. 2007;9(6):539–47.PubMedGoogle Scholar
  25. 25.
    Openshaw H, Stuve O, Antel JP, Nash R, Lund BT, Weiner LP, et al. Multiple sclerosis flares associated with recombinant granulocyte colony-stimulating factor. Neurology. 2000;54(11):2147–50.PubMedGoogle Scholar
  26. 26.
    Snir O, Lavie G, Achiron A, Bank I, Ben-Aharon T, Sredni B, et al. G-CSF enhances the adhesion of encephalitogenic T cells to extracellular matrix components: a possible mechanism for exacerbation of multiple sclerosis. J Neuroimmunol. 2006;172(1–2):145–55.PubMedGoogle Scholar
  27. 27.
    Kyrcz-Krzemien S, Helbig G, Torba K, Koclega A, Krawczyk-Kulis M. Safety and efficacy of hematopoietic stem cells mobilization in patients with multiple sclerosis. Hematology. 2016;21(1):42–5.PubMedGoogle Scholar
  28. 28.
    Snowden JA, Saccardi R, Allez M, Ardizzone S, Arnold R, Cervera R, 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):770–90.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Oliveira MC, Labopin M, Henes J, Moore J, Del Papa N, Cras A, et al. Does ex vivo CD34+ positive selection influence outcome after autologous hematopoietic stem cell transplantation in systemic sclerosis patients? Bone Marrow Transplant. 2016;51(4):501–5.PubMedGoogle Scholar
  30. 30.
    Curro D, Mancardi G. Autologous hematopoietic stem cell transplantation in multiple sclerosis: 20 years of experience. Neurol Sci. 2016;37(6):857–65.PubMedGoogle Scholar
  31. 31.
    DeZern AE, Petri M, Drachman DB, Kerr D, Hammond ER, Kowalski J, et al. High-dose cyclophosphamide without stem cell rescue in 207 patients with aplastic anemia and other autoimmune diseases. Medicine (Baltimore). 2011;90(2):89–98.Google Scholar
  32. 32.
    Harrison DM, Gladstone DE, Hammond E, Cheng J, Jones RJ, Brodsky RA, et al. Treatment of relapsing-remitting multiple sclerosis with high-dose cyclophosphamide induction followed by glatiramer acetate maintenance. Mult Scler. 2012;18(2):202–9.PubMedGoogle Scholar
  33. 33.
    Burt RK, Burns W, Ruvolo P, Fischer A, Shiao C, Guimaraes A, et al. Syngeneic bone marrow transplantation eliminates V beta 8.2 T lymphocytes from the spinal cord of Lewis rats with experimental allergic encephalomyelitis. J Neurosci Res. 1995;41(4):526–31.PubMedGoogle Scholar
  34. 34.
    van Bekkum DW. Stem cell transplantation for autoimmune disorders. Preclinical experiments. Best Pract Res Clin Haematol. 2004;17(2):201–22.PubMedGoogle Scholar
  35. 35.
    van Gelder M, Kinwel-Bohre EP, van Bekkum DW. Treatment of experimental allergic encephalomyelitis in rats with total body irradiation and syngeneic BMT. Bone Marrow Transplant. 1993;11(3):233–41.PubMedGoogle Scholar
  36. 36.
    van Gelder M, van Bekkum DW. Treatment of relapsing experimental autoimmune encephalomyelitis in rats with allogeneic bone marrow transplantation from a resistant strain. Bone Marrow Transplant. 1995;16(3):343–51.PubMedGoogle Scholar
  37. 37.
    van Gelder M, van Bekkum DW. Effective treatment of relapsing experimental autoimmune encephalomyelitis with pseudoautologous bone marrow transplantation. Bone Marrow Transplant. 1996;18(6):1029–34.PubMedGoogle Scholar
  38. 38.
    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.PubMedGoogle Scholar
  39. 39.
    Majhail NS, Rizzo JD, Lee SJ, Aljurf M, Atsuta Y, Bonfim C, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Rev Bras Hematol Hemoter. 2012;34(2):109–33.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Marmont AM. Stem cell transplantation for severe autoimmune diseases: progress and problems. Haematologica. 1998;83(8):733–43.PubMedGoogle Scholar
  41. 41.
    Snowden JA, Patton WN, O'Donnell JL, Hannah EE, Hart DN. Prolonged remission of longstanding systemic lupus erythematosus after autologous bone marrow transplant for non-Hodgkin's lymphoma. Bone Marrow Transplant. 1997;19(12):1247–50.PubMedGoogle Scholar
  42. 42.
    Massey JC, Sutton IJ, Ma DDF, Moore JJ. Regenerating immunotolerance in multiple sclerosis with autologous hematopoietic stem cell transplant. Front Immunol. 2018;9:410.PubMedPubMedCentralGoogle Scholar
  43. 43.
    • Muraro PA, Robins H, Malhotra S, Howell M, Phippard D, Desmarais C, et al. T cell repertoire following autologous stem cell transplantation for multiple sclerosis. J Clin Invest. 2014;124(3):1168–72.One of the early study demonstrating the distinct effects that ASCT has on CD4+ and CD8+ T cell repertoires.PubMedGoogle Scholar
  44. 44.
    • Muraro PA, Douek DC, Packer A, Chung K, Guenaga FJ, Cassiani-Ingoni R, 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):805–16.First study to demonstrate that after treatment with ASCT there is an increase in the frequency of naïve CD4+ T cells, and the expanded T cell population is of thymic origin.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Abrahamsson SV, Angelini DF, Dubinsky AN, Morel E, Oh U, Jones JL, et al. Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis. Brain. 2013;136(Pt 9):2888–903.PubMedPubMedCentralGoogle Scholar
  46. 46.
    • Karnell FG, Lin D, Motley S, Duhen T, Lim N, Campbell DJ, et al. Reconstitution of immune cell populations in multiple sclerosis patients after autologous stem cell transplantation. Clin Exp Immunol. 2017;189(3):268–78.Comprehensive investigation using CyTOF mass cytometry to assess the reconstitution kinetics of immune cell subsets in the peripheral blood after ASCT.Google Scholar
  47. 47.
    Arruda LCM, de Azevedo JTC, de Oliveira GLV, Scortegagna GT, Rodrigues ES, Palma PVB, et al. Immunological correlates of favorable long-term clinical outcome in multiple sclerosis patients after autologous hematopoietic stem cell transplantation. Clin Immunol. 2016;169:47–57.PubMedGoogle Scholar
  48. 48.
    Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545–58.PubMedGoogle Scholar
  49. 49.
    Burman J, Fransson M, Totterman TH, Fagius J, Mangsbo SM, Loskog AS. T-cell responses after haematopoietic stem cell transplantation for aggressive relapsing-remitting multiple sclerosis. Immunology. 2013;140(2):211–9.PubMedPubMedCentralGoogle Scholar
  50. 50.
    • Darlington PJ, Touil T, Doucet JS, Gaucher D, Zeidan J, Gauchat D, et al. Diminished Th17 (not Th1) responses underlie multiple sclerosis disease abrogation after hematopoietic stem cell transplantation. Ann Neurol. 2013;73(3):341–54.Important analysis demonstrating that reduced TH17 response post ASCT are particularly important in the prevention of recurrent disease activity in MS patients following treatment with ASCT.PubMedGoogle Scholar
  51. 51.
    Darlington PJ, Stopnicki B, Touil T, Doucet JS, Fawaz L, Roberts ME, et al. Natural killer cells regulate Th17 cells after autologous hematopoietic stem cell transplantation for relapsing remitting multiple sclerosis. Front Immunol. 2018;9:834.Google Scholar
  52. 52.
    • de Paula ASA, Malmegrim KC, Panepucci RA, Brum DS, Barreira AA, Carlos Dos Santos A, et al. Autologous haematopoietic stem cell transplantation reduces abnormalities in the expression of immune genes in multiple sclerosis. Clin Sci (Lond). 2015;128(2):111–20.First study to examine differential gene expression in T cell subsets pre and post ASCT.Google Scholar
  53. 53.
    Burt RK, Cohen BA, Russell E, Spero K, Joshi A, Oyama Y, et al. Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores. Blood. 2003;102(7):2373–8.PubMedGoogle Scholar
  54. 54.
    Samijn JP, te Boekhorst PA, Mondria T, van Doorn PA, Flach HZ, van der Meche FG, et al. Intense T cell depletion followed by autologous bone marrow transplantation for severe multiple sclerosis. J Neurol Neurosurg Psychiatry. 2006;77(1):46–50.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Atkins HL, Bowman M, Allan D, Anstee G, Arnold DL, Bar-Or A, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016;388(10044):576–85.Google Scholar
  56. 56.
    Bowen JD, Kraft GH, Wundes A, Guan Q, Maravilla KR, Gooley TA, et al. Autologous hematopoietic cell transplantation following high-dose immunosuppressive therapy for advanced multiple sclerosis: long-term results. Bone Marrow Transplant. 2012;47(7):946–51.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Muraro PA, Pasquini M, Atkins HL, Bowen JD, Farge D, Fassas A, et al. Long-term outcomes after autologous hematopoietic stem cell transplantation for multiple sclerosis. JAMA Neurol. 2017;74(4):459–69.PubMedPubMedCentralGoogle Scholar
  58. 58.
    • Mancardi GL, Sormani MP, Di Gioia M, Vuolo L, Gualandi F, Amato MP, 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):835–42.Study demonstrating the BEAM/ATG conditioning followed by autologous stem cell rescue can induce durable remissions for patients with RRMS.PubMedGoogle Scholar
  59. 59.
    Burman J, Iacobaeus E, Svenningsson A, Lycke J, Gunnarsson M, Nilsson P, et al. Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience. J Neurol Neurosurg Psychiatry. 2014;85(10):1116–21.Google Scholar
  60. 60.
    Mancardi GL, Sormani MP, Gualandi F, Saiz A, Carreras E, Merelli E, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial. Neurology. 2015;84(10):981–8.PubMedGoogle Scholar
  61. 61.
    Nash RA, Hutton GJ, Racke MK, Popat U, Devine SM, Steinmiller KC, et al. High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS. Neurology. 2017;88(9):842–52.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Shevchenko JL, Kuznetsov AN, Ionova TI, Melnichenko VY, Fedorenko DA, Kurbatova KA, et al. Long-term outcomes of autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis: physician's and patient's perspectives. Ann Hematol. 2015;94(7):1149–57.PubMedGoogle Scholar
  63. 63.
    • Burt RK, Balabanov R, Han X, Sharrack B, Morgan A, Quigley K, et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2015;313(3):275–84.Early clinical trial demonstrating the reduced intensity conditioning regimen, Cyclophosphamide/ATG, can improve neurological disability in patients with RRMS.Google Scholar
  64. 64.
    Curro D, Vuolo L, Gualandi F, Bacigalupo A, Roccatagliata L, Capello E, et al. Low intensity lympho-ablative regimen followed by autologous hematopoietic stem cell transplantation in severe forms of multiple sclerosis: a MRI-based clinical study. Mult Scler. 2015;21(11):1423–30.PubMedGoogle Scholar
  65. 65.
    •• Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC, et al. Effect of nonmyeloablative hematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis: a randomized clinical trial. JAMA. 2019;321(2):165–174. First randomized control clinical trial demonstrating the superiority of autologous hematopoetic stem cell transplant over standard disease modifying therapy for patients with relapsing-remitting multiple sclerosis.PubMedPubMedCentralGoogle Scholar
  66. 66.
    •• Fassas A, Anagnostopoulos A, Kazis A, Kapinas K, Sakellari I, Kimiskidis V, et al. Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study. Bone Marrow Transplant. 1997;20(8):631–8. First clinical trial of the use of autologous hematopoetic stem cell transplant for the treament of patients with multiple sclerosis.PubMedGoogle Scholar
  67. 67.
    •• Sormani MP, Muraro PA, Schiavetti I, Signori A, Laroni A, Saccardi R, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a meta-analysi. Neurology. 2017;88(22):2115–22. Meta-analysis demonstrating the efficacy of safety of autologous hematopoetic stem cell transplant for patients with relapsing-remitting multiple sclerosis.PubMedGoogle Scholar
  68. 68.
    • Cohen JA, Baldassari LE, Atkins HL, Bowen JD, Bredeson C, Carpenter PA, et al. Autologous hematopoietic cell transplantation for treatment-refractory relapsing multiple sclerosis: position statement from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2019;25:845–54.First position paper by ASBMT that recommended ASCT as standard of care for treatment-refractory relapsing MS with high risk of future disability.PubMedGoogle Scholar
  69. 69.
    • Nash RA, Hutton GJ, Racke MK, Popat U, Devine SM, Griffith LM, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report. JAMA Neurol. 2015;72(2):159–69.Clinical trial demonstrating that high intensity conditioning regimen followed with autologous stem cell rescue can induce durable remissions in patients with RRMS.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Lublin FD. New multiple sclerosis phenotypic classification. Eur Neurol. 2014;72(Suppl 1):1–5.PubMedGoogle Scholar
  71. 71.
    Casanova B, Jarque I, Gascon F, Hernandez-Boluda JC, Perez-Miralles F, de la Rubia J, et al. Autologous hematopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: comparison with secondary progressive multiple sclerosis. Neurol Sci. 2017;38(7):1213–21.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Saccardi R, Freedman MS, Sormani MP, Atkins H, Farge D, Griffith LM, et al. A prospective, randomized, controlled trial of autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: a position paper. Mult Scler. 2012;18(6):825–34.PubMedGoogle Scholar
  73. 73.
    Musella A, Gentile A, Rizzo FR, De Vito F, Fresegna D, Bullitta S, et al. Interplay between age and neuroinflammation in multiple sclerosis: effects on motor and cognitive functions. Front Aging Neurosci. 2018;10:238.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Schweitzer F, Laurent S, Fink GR, Barnett MH, Reddel S, Hartung HP, et al. Age and the risks of high-efficacy disease modifying drugs in multiple sclerosis. Curr Opin Neurol. 2019.Google Scholar
  75. 75.
    Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000;343(20):1430–8.PubMedGoogle Scholar
  76. 76.
    Scalfari A, Neuhaus A, Degenhardt A, Rice GP, Muraro PA, Daumer M, et al. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain. 2010;133(Pt 7):1914–29.PubMedPubMedCentralGoogle Scholar
  77. 77.
    • Saccardi R, Kozak T, Bocelli-Tyndall C, Fassas A, Kazis A, Havrdova E, et al. Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database. Mult Scler. 2006;12(6):814–23.Retrospective study demonstrating the intermediate conditioning regimens can induce durable remissions without treatment related mortality for patients with RRMS.PubMedGoogle Scholar
  78. 78.
    Marrie RA, Elliott L, Marriott J, Cossoy M, Blanchard J, Leung S, et al. Effect of comorbidity on mortality in multiple sclerosis. Neurology. 2015;85(3):240–7.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Martinez C, Jorge AS, Pereira A, Moreno M, Nunez J, Gayoso J, et al. Comorbidities, not age, are predictive of survival after autologous hematopoietic cell transplantation for relapsed/refractory Hodgkin’s lymphoma in patients older than 50 years. Ann Hematol. 2017;96(1):9–16.PubMedGoogle Scholar
  80. 80.
    Snowden JA, Sharrack B, Akil M, Kiely DG, Lobo A, Kazmi M, et al. Autologous haematopoietic stem cell transplantation (AHCT) for severe resistant autoimmune and inflammatory diseases - a guide for the generalist. Clin Med (Lond). 2018;18(4):329–34.PubMedPubMedCentralGoogle Scholar
  81. 81.
    • Rush CA, MacLean HJ, Freedman MS. Aggressive multiple sclerosis: proposed definition and treatment algorithm. Nat Rev Neurol. 2015;11(7):379–89.Important position paper defining the clinical entity of aggressive multiple sclerosis.PubMedGoogle Scholar
  82. 82.
    Lee H, Nakamura K, Narayanan S, Brown R, Chen J, Atkins HL, et al. Impact of immunoablation and autologous hematopoietic stem cell transplantation on gray and white matter atrophy in multiple sclerosis. Mult Scler. 2018;24(8):1055–66.PubMedGoogle Scholar
  83. 83.
    Adelman G, Rane SG, Villa KF. The cost burden of multiple sclerosis in the United States: a systematic review of the literature. J Med Econ. 2013;16(5):639–47.PubMedGoogle Scholar
  84. 84.
    Owens GM. Managed care aspects of managing multiple sclerosis. Am J Manag Care. 2013;19(16 Suppl):s307–12.PubMedGoogle Scholar
  85. 85.
    Carroll CA, Fairman KA, Lage MJ. Updated cost-of-care estimates for commercially insured patients with multiple sclerosis: retrospective observational analysis of medical and pharmacy claims data. BMC Health Serv Res. 2014;14:286.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Chen AY, Chonghasawat AO, Leadholm KL. Multiple sclerosis: frequency, cost, and economic burden in the United States. J Clin Neurosci. 2017;45:180–6.PubMedGoogle Scholar
  87. 87.
    Jones E, Pike J, Marshall T, Ye X. Quantifying the relationship between increased disability and health care resource utilization, quality of life, work productivity, health care costs in patients with multiple sclerosis in the US. BMC Health Serv Res. 2016;16:294.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Ernstsson O, Gyllensten H, Alexanderson K, Tinghog P, Friberg E, Norlund A. Cost of illness of multiple sclerosis - a systematic review. PLoS One. 2016;11(7):e0159129.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Hartung DM. Economics and cost-effectiveness of multiple sclerosis therapies in the USA. Neurotherapeutics. 2017;14(4):1018–26.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Broder MS, Quock TP, Chang E, Reddy SR, Agarwal-Hashmi R, Arai S, et al. The cost of hematopoietic stem-cell transplantation in the United States. Am Health Drug Benefits. 2017;10(7):366–74.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Majhail NS, Mau LW, Denzen EM, Arneson TJ. Costs of autologous and allogeneic hematopoietic cell transplantation in the United States: a study using a large national private claims database. Bone Marrow Transplant. 2013;48(2):294–300.PubMedGoogle Scholar
  92. 92.
    Saito AM, Cutler C, Zahrieh D, Soiffer RJ, Ho VT, Alyea EP, et al. Costs of allogeneic hematopoietic cell transplantation with high-dose regimens. Biol Blood Marrow Transplant. 2008;14(2):197–207.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Saito AM, Zahrieh D, Cutler C, Ho VT, Antin JH, Soiffer RJ, et al. Lower costs associated with hematopoietic cell transplantation using reduced intensity vs high-dose regimens for hematological malignancy. Bone Marrow Transplant. 2007;40(3):209–17.PubMedGoogle Scholar
  94. 94.
    •• Tappenden P, Saccardi R, Confavreux C, Sharrack B, Muraro PA, Mancardi GL, et al. Autologous haematopoietic stem cell transplantation for secondary progressive multiple sclerosis: an exploratory cost-effectiveness analysis. Bone Marrow Transplant. 2010;45(6):1014–21. First analysis performed to assess the cost-effectiveness of autologous hematopoetic stem cell transplant for the treatment of multiple sclerosis.PubMedGoogle Scholar
  95. 95.
    Noyes K, Bajorska A, Chappel A, Schwid SR, Mehta LR, Weinstock-Guttman B, et al. Cost-effectiveness of disease-modifying therapy for multiple sclerosis: a population-based study. Neurology. 2011;77(4):355–63.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Anastasie M. Dunn-Pirio
    • 1
  • Benjamin M. Heyman
    • 2
    Email author
  • Dan S. Kaufman
    • 2
  • Revere P. Kinkel
    • 1
  1. 1.Division of Neuroimmunology, Department of NeurosciencesUC San DiegoLa JollaUSA
  2. 2.Division of Regenerative Medicine, Department of Medicine, Moores Cancer CenterUC San DiegoLa JollaUSA

Personalised recommendations