Skip to main content

Advertisement

SpringerLink
Log in

Mitoxantrone versus cyclophosphamide in secondary-progressive multiple sclerosis

A comparative study

  • ORIGINAL CONTRIBUTION
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Fifty secondary progressive multiple sclerosis (SPMS) patients who had lost one or more EDSS points in the prior two years were selected to receive either cyclophosphamide (25 patients, 13 females, 12 males, F/M = 1.08; mean age: 42.4 years; mean disease duration: 13.3 years; mean EDSS at study entry: 5.7) or mitoxantrone (25 patients, 14 females, 11 males, F/M = 1.27; mean age: 38.2 years; mean disease duration: 11.5 years; mean EDSS at study entry: 5.5). SPMS patients were treated for two years with clinical evaluation (relapse rate, disability progression) every three months and radiological imaging (conventional magnetic resonance imaging) before therapy initiation and at the end of the first and second years of therapy. Safety profile and costs of the two therapeutic protocols were also analysed. In terms of clinical and radiological measures the drugs exerted a quite identical effect on both, and produced a significant reduction in both relapse rate (mitoxantrone Mito): p = 0.001, cyclophosphamide (Cy): p = 0.003) and disability progression (Mito: p = 0.01; Cy: p = 0.01). Subgroups of mitoxantrone- and cyclophosphamide-responding patients were identified (14/25 and 17/25, respectively) and were characterized by a significantly shorter duration of the secondary progressive phase of the disease. In these subgroups, the improvement in the EDSS score at the end of therapy was highly significant (p<0.0001 for Mito, p = 0.0004 for Cy). The safety profiles of both drugs were acceptable; however, the Cy-based therapy protocol was significantly less expensive. We conclude that Cy should be considered as a therapeutic option in rapidly deteriorating SPMS patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Millefiorini E, Gasperini C, Pozzilli C, et al. Randomized, placebo controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome J Neurol 1997;244:154–159

    Article  Google Scholar 

  2. Edan G, Miller D, Clanet M, et al. Therapeutic effect of mitoxantrone combined with methylperdisolone in multiple sclerosis: a randomized multicentre study of active disease using MRI and clinical criteria J Neurol Neurosurg Psychiatry 1997; 62:112–118

    PubMed  CAS  Google Scholar 

  3. Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo controlled, double-blind, randomized, multicentre trial Lancet 2002;360:2018–2025

    Article  PubMed  Google Scholar 

  4. Goodin DS, Arnason BGW, Coyle PK, Frhman EM, Paty DW. The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology Neurology 2003;61:1332–1338

    PubMed  CAS  Google Scholar 

  5. Jeffery DR, Herndon R. Review of mitoxantrone in the treatment of multiple sclerosis Neurology 2004; 63:S19–S24

    PubMed  CAS  Google Scholar 

  6. La Mantia L, Milanese C, Mascoli N, D’Amico R, Weinstock-Guttman B. Cyclophosphamide for multiple sclerosis (Cochrane Review). The Cochrane Library, 2002; Issue 3. Art. No.: CD002819.

  7. Hauser SL, Dawson DM, Lehrich JR, Beal LM, Kevy SV, Propper RD, Weiner HL. Intensive immunosuppression in progressive multiple sclerosis. A randomized, three arm study of high dose cyclophosphamide, plasma exchange, and ACTHN Engl J Med 1983;308:173–180

    Article  PubMed  CAS  Google Scholar 

  8. The Canadian Cooperative Multiple Sclerosis Study Group. The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. Lancet 1991,337:441–446

    Google Scholar 

  9. Likosky WH, Fireman B, Elmore R. Intensive immunosuppression in chronic progressive multiple sclerosis : the Kaiser study J Neurol Neurosurg Psychiatry 1991; 54:1055–1060

    Article  PubMed  CAS  Google Scholar 

  10. Weiner HL, Mackin GA, Orav EJ, et al. and the Northeast Cooperative Multiple Sclerosis Treatment Group. Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: final report of the Northeast Cooperative Multiple Sclerosis Treatment Group Neurology 1993;43:910–918

    PubMed  CAS  Google Scholar 

  11. Weinstock-Guttman B, Kinkel RP, Cohen JA. Treatment of fulminant multiple sclerosis with intravenous cyclophosphamide Neurologists 1997;3:178–185

    Article  Google Scholar 

  12. Gobbini MI, Smith ME, Richert ND, Frank JA, McFarland HF. Effect of open label pulse cyclophosphamide therapy on MRI meaures of disease activity in five patients with refractory relapsing-remitting multiple sclerosis J Neuroimmunol 1999;99:142–149

    Article  PubMed  CAS  Google Scholar 

  13. Khan OA, Zvartau-Hind M, Caon C, et al. Effect of monthly intravenous cyclophosphamide in rapidly deteriorating multiple sclerosis patients resistant to conventional therapy Mult Scler 2001;7:185–188

    Article  PubMed  CAS  Google Scholar 

  14. Hohol MJ, Olek MJ, Orav EJ, et al. Treatment of progressive multiple sclerosis with pulse cyclophosphamide/ methylprednisolone: response to therapy is linked to the duration of progressive disease Mult Scler 1999;5:403–409

    Article  PubMed  CAS  Google Scholar 

  15. Perini P, Gallo P. Cyclophosphamide is effective in stabilizing rapidly deteriorating secondary progressive multiple sclerosis J Neurol 2003;250:834–838

    Article  PubMed  CAS  Google Scholar 

  16. Weiner HL, Cohen JA. Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects Multiple Sclerosis 2001;8:142–154, 2002

    Google Scholar 

  17. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis Ann Neurol. 2001;50:121–7

    Article  PubMed  CAS  Google Scholar 

  18. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: Results of an international survey Neurology 1996;46:907–911

    PubMed  CAS  Google Scholar 

  19. Portaccio E, Zipoli V, Siracusa G, Piacentini S, Sorbi S, Amato MP. Safety and tolerability of cyclophosphamide ‘pulses’ in multiple sclerosis: a prospective study in a clinical cohort Mult Scler. 2003;9:446–50

    Article  PubMed  CAS  Google Scholar 

  20. de Bittencourt PR, Gomes-da-Silva MM. Multiple sclerosis: long-term remission after a high dose of cyclophosphamide Acta Neurol Scand. 2005;111:195–8

    Article  PubMed  Google Scholar 

  21. Smith D. Preliminary analysis of a trial of pulse cyclophosphamide in IFN-beta-resistant activeMS J Neurol Sci. 2004;223:73–9

    Article  PubMed  CAS  Google Scholar 

  22. Zephir H, de Seze J, Duhamel A, et al. Treatment of progressive forms of multiple sclerosis by cyclophosphamide: a cohort study of 490 patients J Neurol Sci. 2004;218:73–7

    Article  PubMed  CAS  Google Scholar 

  23. Zephir H, de Seze J, Dujardin K, et al. One-year cyclophosphamide treatment combined with methylprednisolone improves cognitive dysfunction in progressive forms of multiple sclerosis Mult Scler. 2005;11:360–3

    Article  PubMed  CAS  Google Scholar 

  24. Correale J, Rush C, Amengual A, Goicochea MT. Mitoxantrone as rescue therapy in worsening relapsing-remitting MS patients receiving IFN-beta J Neuroimmunol. 2005;162:173–83

    Article  PubMed  CAS  Google Scholar 

  25. Patti F, Reggio E, Palermo F, et al. Stabilization of rapidly worsening multiple sclerosis for 36 months in patients treated with interferon beta plus cyclophosphamide followed by interferon beta J Neurol. 2004;251:1502–6

    Article  PubMed  CAS  Google Scholar 

  26. Reggio E, Nicoletti A, Fiorilla T, Politi G, Reggio A, Patti F. The combination of cyclophosphamide plus interferon beta as rescue therapy could be used to treat relapsing-remitting multiple sclerosis patients Twenty-four months follow-up. J Neurol. 2005 Jun 6; [Epub ahead of print]

  27. Jeffery DR, Chepuri N, Durden D, Burdette J. A pilot trial of combination therapy with mitoxantrone and interferon beta-1b using monthly gadolinium-enhanced magnetic resonance imaging Mult Scler. 2005;11:296–301

    Article  PubMed  CAS  Google Scholar 

  28. Goffette S, van Pesch V, Vanoverschelde JL, Morandini E, Sindic CJ. Severe delayed heart failure in three multiple sclerosis patients previously treated with mitoxantrone.J Neurol. 2005 Apr 18; [Epub ahead of print]

  29. Voltz R, Starck M, Zingler V, Strupp M, Kolb HJ. Mitoxantrone therapy in multiple sclerosis and acute leukaemia: a case report out of 644 treated patients Mult Scler. 2004;10:472–4

    Article  PubMed  Google Scholar 

  30. Tanasescu R, Debouverie M, Pittion S, Anxionnat R, Vespignani H. Acute myeloid leukaemia induced by mitoxantrone in a multiple sclerosis patient J Neurol. 2004; 251:762–3

    Article  PubMed  Google Scholar 

  31. Cohen BA, Mikol DD. Mitoxantrone treatment of multiple sclerosis: safety considerations Neurology. 2004;63:S28–32

    PubMed  CAS  Google Scholar 

  32. Jeffery DR, Herndon R. Review of mitoxantrone in the treatment of multiple sclerosis Neurology. 2004;63:S19–24

    PubMed  CAS  Google Scholar 

  33. Rizvi SA, Zwibel H, Fox EJ. Mitoxantrone for multiple sclerosis in clinical practice Neurology. 2004;63:S25–7

    PubMed  CAS  Google Scholar 

  34. Scott LJ, Figgitt DP. Mitoxantrone: a review of its use in multiple sclerosis CNS Drugs. 2004;18:379–96

    Article  PubMed  CAS  Google Scholar 

  35. Hommes OR, Weiner HL. Clinical practice of immunosuppressive treatments in multiple sclerosis: results of a second international questionnaire J Neurol Sci. 2004;223:65–7

    Article  PubMed  CAS  Google Scholar 

  36. Smith DR, Balashov KE, Hafler DA, Khoury SJ, Weiner HL. Immune deviation following pulse cyclophosphamide/ methylprednisolone treatment of multiple sclerosis: increased interleukin-4 production and associated eosinophilia Ann Neurol 1997;42:313–318

    Article  PubMed  CAS  Google Scholar 

  37. Comabella M , Balashov K, Issazadeh S, Smith D, Weiner DS, Khoury SJ. Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophophamide therapy J Clin Invest 1998;102:671–678

    Article  PubMed  CAS  Google Scholar 

  38. Takashima H, Smith DR, Fakaura H, Khoury SJ, Hafler DA, Weiner HL. Pulse cyclophosphamide plus methylprednisolone induces myelin-antigen-specific IL-4-secreting T cells in multiple sclerosis patients Clin Immunol Immunopathol 1998;88:28–34

    Article  PubMed  CAS  Google Scholar 

  39. Wender M, Tokarz-Kupczyk E, Mularek O. Early results of the treatment of chronic progressive forms of multiple sclerosis with cyclophosphamide and ACTH (Article in Polish) Neurol Neurochir Pol 1988;22:399–403

    PubMed  CAS  Google Scholar 

  40. Weiner HL. Immunosuppressive treatment in multiple sclerosis J Neurol Sci. 2004;223:1–11

    Article  PubMed  CAS  Google Scholar 

  41. Gouthier SA, Weinwe HL. Cyclophosphamide therapy for MS The International MS Journal. 2005;12:52–58

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Multiple Sclerosis Centre of Veneto Region First Neurology Clinic, University Hospital of Padova, Via Giustiniani 5, 35128, Padova, Italy

    Paola Perini, Massimiliano Calabrese, Michela Tiberio, Federica Ranzato, Leontino Battistin & Paolo Gallo MD, PhD

  2. IRCCS San CamilloLido, di Venezia, Italy

    Leontino Battistin

Authors
  1. Paola Perini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Massimiliano Calabrese
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michela Tiberio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Federica Ranzato
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Leontino Battistin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paolo Gallo MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paolo Gallo MD, PhD.

Additional information

Received in revised form: 5 January 2006

Rights and permissions

Reprints and permissions

About this article

Cite this article

Perini, P., Calabrese, M., Tiberio, M. et al. Mitoxantrone versus cyclophosphamide in secondary-progressive multiple sclerosis. J Neurol 253, 1034–1040 (2006). https://doi.org/10.1007/s00415-006-0154-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-006-0154-7

Keywords

Search

Navigation