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Treatment with alemtuzumab or rituximab after fingolimod withdrawal in relapsing–remitting multiple sclerosis is effective and safe

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Abstract

Background

It has been described that treating relapsing–remitting multiple sclerosis (RRMS) patients with alemtuzumab following fingolimod could be less effective due to the different dynamics of lymphocyte repopulation. Effectiveness and safety of alemtuzumab compared to rituximab after fingolimod withdrawal were analyzed.

Patients and methods

A follow-up of a cohort of RRMS patients treated with alemtuzumab or rituximab after fingolimod withdrawal was accomplished. Effectiveness, measured by the percentage of patients with no evidence of disease activity (NEDA), and the presence of side effects (SE) were registered.

Results

Fifty-five patients, 28 with alemtuzumab and 27 with rituximab, were analyzed. No differences in the washout period or in the baseline lymphocytes counts were observed. After a mean follow-up period of 28.8 months, the annualized relapsing rate was significantly reduced in the alemtuzumab group from 1.29 to 0.004 (p < 0.001) and in the rituximab group from 1.24 to 0.02 (p < 0.001), without differences. A significant reduction of the median EDSS from 2.8 to 2.0 in the alemtuzumab group and from 3.5 to 2.5 (p < 0.01) in the rituximab group was observed, without differences. Eighty-two per cent (n = 28) of patients in alemtuzumab group and 69.2% (n = 26) in rituximab group achieved NEDA criteria, without differences (p = 0.3). Symptoms related to the infusion were the most frequent SE in both groups. No serious SE were registered.

Conclusion

Treating RRMS patients with alemtuzumab or rituximab after fingolimod withdrawal is effective and safe, without significant differences between both groups in our series.

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References

  1. Duddy M, Bar-Or A (2006) B-cells in multiple sclerosis. Int MS J 13:84–90

    CAS  PubMed  Google Scholar 

  2. Lucchinetti C, Brück W, Parisi J et al (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47:707–717

    Article  CAS  Google Scholar 

  3. Faissner S, Gold R (2018) Efficacy and safety of the newer multiple sclerosis drugs approved since 2010. CNS Drugs 32:269–287. https://doi.org/10.1007/s40263-018-0488-6

    Article  CAS  PubMed  Google Scholar 

  4. Merkel B, Butzkueven H, Traboulsee AL et al (2017) Timing of high-efficacy therapy in relapsing-remitting multiple sclerosis: a systematic review. Autoimmun Rev 16:658–665. https://doi.org/10.1016/j.autrev.2017.04.010

    Article  PubMed  Google Scholar 

  5. Blinkenberg M, Sørensen PS (2017) Monoclonal antibodies for relapsing multiple sclerosis: a review of recently marketed and late-stage agents. CNS Drugs 31:357–371. https://doi.org/10.1007/s40263-017-0414-3

    Article  CAS  PubMed  Google Scholar 

  6. Rommer PS, Zettl UK (2018) Managing the side effects of multiple sclerosis therapy: pharmacotherapy options for patients. Expert Opin Pharmacother 19:483–498. https://doi.org/10.1080/14656566.2018.1446944

    Article  CAS  PubMed  Google Scholar 

  7. Sedal L, Winkel A, Laing J et al (2017) Current concepts in multiple sclerosis therapy. Degener Neurol Neuromuscul Dis 7:109–125. https://doi.org/10.2147/DNND.S109251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gholamzad M, Ebtekar M, Ardestani MS et al (2018) A comprehensive review on the treatment approaches of multiple sclerosis: currently and in the future. Inflamm Res. https://doi.org/10.1007/s00011-018-1185-0

    Article  PubMed  Google Scholar 

  9. Wingerchuk DM, Weinshenker BG (2016) Disease modifying therapies for relapsing multiple sclerosis. BMJ 354:i3518

    Article  PubMed  Google Scholar 

  10. Pardo G, Jones DE (2017) The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations. J Neurol 264:2351–2374. https://doi.org/10.1007/s00415-017-8594-9

    Article  PubMed  PubMed Central  Google Scholar 

  11. Grand F, Maison F, Yeung M, Morrow S et al (2018) Sequencing of high-efficacy disease-modifying therapies in multiple sclerosis: perspectives and approaches. Neural Regen Res 13:1871. https://doi.org/10.4103/1673-5374.239432

    Article  Google Scholar 

  12. Khatri B, Barkhof F, Comi G et al (2011) Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol 10:520–529. https://doi.org/10.1016/S1474-4422(11)70099-0

    Article  CAS  PubMed  Google Scholar 

  13. Bianco A, Patanella AK, Nociti V et al (2014) Second-line therapy with fingolimod for relapsing-remitting multiple sclerosis in clinical practice: the effect of previous exposure to natalizumab. Eur Neurol 73:57–65. https://doi.org/10.1159/000365968

    Article  CAS  PubMed  Google Scholar 

  14. Cohen JA, Barkhof F, Comi G et al (2010) Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 362:402–415. https://doi.org/10.1056/NEJMoa0907839

    Article  CAS  PubMed  Google Scholar 

  15. Hersh CM, Hara-Cleaver C, Rudick RA et al (2014) Experience with fingolimod in clinical practice. Int J Neurosci. https://doi.org/10.3109/00207454.2014.969839

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ayzenberg I, Hoepner R, Kleiter I (2016) Fingolimod for multiple sclerosis and emerging indications: appropriate patient selection, safety precautions, and special considerations. Ther Clin Risk Manag 12:261–272. https://doi.org/10.2147/TCRM.S65558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Coles AJ, Twyman CL, Arnold DL et al (2012) Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 380:1829–1839. https://doi.org/10.1016/S0140-6736(12)61768-1

    Article  CAS  Google Scholar 

  18. Cohen JA, Coles AJ, Arnold DL et al (2012) Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 380:1819–1828. https://doi.org/10.1016/S0140-6736(12)61769-3

    Article  CAS  Google Scholar 

  19. Havrdova E, Arnold DL, Cohen JA et al (2017) Alemtuzumab CARE-MS I 5-year follow-up: durable efficacy in the absence of continuous MS therapy. Neurology 89:1107–1116. https://doi.org/10.1212/WNL.0000000000004313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ziemssen T, Thomas K (2017) Alemtuzumab in the long-term treatment of relapsing-remitting multiple sclerosis: an update on the clinical trial evidence and data from the real world. Ther Adv Neurol Disord 10:343–359. https://doi.org/10.1177/1756285617722706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Brown JWL, Coles AJ (2013) Alemtuzumab: evidence for its potential in relapsing-remitting multiple sclerosis. Drug Des Dev Ther 7:131–138. https://doi.org/10.2147/DDDT.S32687

    Article  CAS  Google Scholar 

  22. Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E (2013) Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. PLoS One 8:e66308. https://doi.org/10.1371/journal.pone.0066308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Barra ME, Soni D, Vo KH et al (2016) Experience with long-term rituximab use in a multiple sclerosis clinic. Mult Scler J Exp Transl Clin. https://doi.org/10.1177/2055217316672100

    Article  PubMed  PubMed Central  Google Scholar 

  24. Alcalá C, Gascón F, Pérez-Miralles F et al (2018) Efficacy and safety of rituximab in relapsing and progressive multiple sclerosis: a hospital-based study. J Neurol 265:1690–1697. https://doi.org/10.1007/s00415-018-8899-3

    Article  CAS  PubMed  Google Scholar 

  25. Willis M, Pearson O, Illes Z et al (2017) An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 4:e320. https://doi.org/10.1212/NXI.0000000000000320

    Article  PubMed  PubMed Central  Google Scholar 

  26. Huhn K, Bayas A, Doerck S et al (2018) Alemtuzumab as rescue therapy in a cohort of 50 relapsing–remitting MS patients with breakthrough disease on fingolimod: a multi-center observational study. J Neurol 265:1521–1527. https://doi.org/10.1007/s00415-018-8871-2

    Article  CAS  PubMed  Google Scholar 

  27. Polman CH, Reingold SC, Banwell B et al (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69:292–302. https://doi.org/10.1002/ana.22366

    Article  PubMed  PubMed Central  Google Scholar 

  28. Coles AJ, Compston DAS, Selmaj KW et al (2008) Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 359:1786–1801. https://doi.org/10.1056/NEJMoa0802670

    Article  PubMed  Google Scholar 

  29. Coles AJ, Cohen JA, Fox EJ et al (2017) Alemtuzumab CARE-MS II 5-year follow-up. Neurology 89:1117–1126. https://doi.org/10.1212/WNL.0000000000004354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vidal-Jordana A, Tintoré M, Tur C et al (2015) Significant clinical worsening after natalizumab withdrawal: predictive factors. Mult Scler 21:780–785. https://doi.org/10.1177/1352458514549401

    Article  CAS  PubMed  Google Scholar 

  31. Miravalle A, Jensen R, Kinkel RP (2011) Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy. Arch Neurol 68:186–191. https://doi.org/10.1001/archneurol.2010.257

    Article  PubMed  Google Scholar 

  32. Havla J, Gerdes LA, Meinl I et al (2011) De-escalation from natalizumab in multiple sclerosis: recurrence of disease activity despite switching to glatiramer acetate. J Neurol 258:1665–1669. https://doi.org/10.1007/s00415-011-5996-y

    Article  CAS  PubMed  Google Scholar 

  33. Ghadiri M, Fitz-Gerald L, Rezk A et al (2017) Reconstitution of the peripheral immune repertoire following withdrawal of fingolimod. Mult Scler J 23:1225–1232. https://doi.org/10.1177/1352458517713147

    Article  CAS  Google Scholar 

  34. Sánchez P, Meca-Lallana V, Vivancos J (2018) Tumefactive multiple sclerosis lesions associated with fingolimod treatment: report of 5 cases. Mult Scler Relat Disord 25:95–98. https://doi.org/10.1016/j.msard.2018.07.001

    Article  PubMed  Google Scholar 

  35. Frau J, Sormani MP, Signori A et al (2018) Clinical activity after fingolimod cessation: disease reactivation or rebound? Eur J Neurol 25:1270–1275. https://doi.org/10.1111/ene.13694

    Article  CAS  PubMed  Google Scholar 

  36. Holmøy T, Torkildsen Ø, Zarnovicky S (2018) Extensive multiple sclerosis reactivation after switching from fingolimod to rituximab. Case Rep Neurol Med 2018:1–3. https://doi.org/10.1155/2018/5190794

    Article  Google Scholar 

  37. Mills EA, Mao-Draayer Y (2018) Aging and lymphocyte changes by immunomodulatory therapies impact PML risk in multiple sclerosis patients. Mult Scler J 24:1014–1022. https://doi.org/10.1177/1352458518775550

    Article  Google Scholar 

  38. Guarnera C, Bramanti P, Mazzon E (2017) Alemtuzumab: a review of efficacy and risks in the treatment of relapsing remitting multiple sclerosis. Ther Clin Risk Manag 13:871–879. https://doi.org/10.2147/TCRM.S134398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Šega-Jazbec S, Barun B, Horvat Ledinek A et al (2017) Management of infusion related reactions associated with alemtuzumab in patients with multiple sclerosis. Mult Scler Relat Disord 17:151–153. https://doi.org/10.1016/j.msard.2017.07.019

    Article  PubMed  Google Scholar 

  40. Rotondi M, Molteni M, Leporati P et al (2017) Autoimmune thyroid diseases in patients treated with alemtuzumab for multiple sclerosis: an example of selective anti-TSH-receptor immune response. Front Endocrinol (Lausanne) 8:254. https://doi.org/10.3389/fendo.2017.00254

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, La Fe Hospital, 106 Avenue Fernando Abril Martorell, 46026, Valencia, Spain

    Carmen Alcalá, Francisco Pérez-Miralles, S. Gil-Perotín & B. Casanova

  2. Department of Neurology, Clinic Hospital, Valencia, Spain

    F. Gascón & J. A. Domínguez

Authors
  1. Carmen Alcalá
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  2. F. Gascón
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  3. Francisco Pérez-Miralles
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  4. J. A. Domínguez
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  5. S. Gil-Perotín
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  6. B. Casanova
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Correspondence to Carmen Alcalá.

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The authors declare that they have no conflict of interest.

Ethical standard

All patients included in the study acceded to donate and signed a specific informed consent and all research was conducted following legal and ethical requirements at the Research Institute of the Hospital La Fe and was approved by its Institutional Review Board.

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Alcalá, C., Gascón, F., Pérez-Miralles, F. et al. Treatment with alemtuzumab or rituximab after fingolimod withdrawal in relapsing–remitting multiple sclerosis is effective and safe. J Neurol 266, 726–734 (2019). https://doi.org/10.1007/s00415-019-09195-2

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  • DOI: https://doi.org/10.1007/s00415-019-09195-2

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