One strategy to mitigate progressive multifocal leukoencephalopathy (PML) risk is to switch to other highly effective disease-modifying therapies (DMTs). However, the optimal switch DMT following natalizumab (NTZ) discontinuation is yet to be determined.
Objective:
The objective of the study is to determine the most effective and tolerable DMTs to switch to following NTZ discontinuation due to John Cunningham virus (JCV) antibody positivity.
Methods:
This is a multicenter observational cohort study that included all stable relapsing-remitting multiple sclerosis (MS) patients who were treated with NTZ for at least 6 months before switching therapy due to JCV antibody positivity.
Results:
Of 321 patients, 255 switched from NTZ to rituximab/ocrelizumab, 52 to fingolimod, and 14 to alemtuzumab, with higher annualized relapse rate (ARR) in fingolimod switchers (0.193) compared with rituximab/ocrelizumab or alemtuzumab (0.028 and 0.032, respectively). Fingolimod switchers also had increased disability progression (p = 0.014) and a higher proportion developed magnetic resonance imaging (MRI) lesions compared with rituximab/ocrelizumab (62.9% vs. 13.0%, p < 0.001, and 66.6% vs. 24.0%, p < 0.001, respectively). Mean drug survival favored rituximab/ocrelizumab or alemtuzumab over fingolimod (p < 0.001).
Conclusion:
Our study shows superior effectiveness of rituximab/ocrelizumab and alemtuzumab compared with fingolimod in stable patients switching from NTZ due to JC virus antibody positivity.
CarrithersMDVisintinIKangSJ, et al. Differential adhesion molecule requirements for immune surveillance and inflammatory recruitment. Brain2000; 123(Pt. 6): 1092–1101.
2.
PolmanCHO’ConnorPWHavrdovaE, et al. A randomized placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med2006; 354: 899–910.
3.
RudickRAStuartWHCalabresiPA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med2006; 354: 911–923.
4.
HavrdovaEGalettaSHutchinsonM, et al. Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: A retrospective analysis of the natalizumab safety and efficacy in relapsing-remitting multiple sclerosis (AFFIRM) study. Lancet Neurol2009; 8(3): 254–260.
5.
PellegriniFBelachewSButzkuevenH, et al. Long term safety and efficacy of natalizumab and assessment of 2-year freedom from clinical disease activity in patients with multiple sclerosis in the TYSABRI® observational programme. Mult Scler2012; 18: 220–221.
6.
ButzkuevenHKapposLPellegriniF, et al. Efficacy and safety of natalizumab in multiple sclerosis: Interim observational programme results. J Neurol Neurosurg Psychiatry2014; 85(11): 1190–1197.
7.
BloomgrenGRichmanSHotermansC, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med2012; 366: 1870–1880.
8.
PlavinaTSubramanyamMBloomgrenG, et al. Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol2014; 76(6): 802–812.
9.
BaumgartnerAStichORauerS. Clinical and radiological disease reactivation after cessation of long-term therapy with natalizumab. Int J Neurosci2012; 122: 35–39.
10.
FoxRJCreeBACDe SezeJ, et al. MS disease activity in RESTORE: A randomized 24-week natalizumab treatment interruption study. Neurol2014; 82: 1491–1498.
EdwardsKKamathVO’ConnorJ. Abstract: Switching from natalizumab to teriflunomide in multiple sclerosis patients who have received natalizumab for more than 12 months (2014 CMSC ACTRIMS Annual Meeting), https://cmsc.confex.com/cmsc/2014/webprogram/Paper2464.html (accessed 8 February 2024).
13.
SempereAPMartín-MedinaPBerenguer-RuizL, et al. Switching from natalizumab to fingolimod: An observational study. Acta Neurol Scand2013; 128(2): e6–e10.
14.
LeursCEvan KempenZLDekkerI, et al. Switching natalizumab to fingolimod within 6 weeks reduces recurrence of disease activity in MS patients. Mult Scler2018; 24(11): 1453–1460.
15.
GugerMEnzingerCLeutmezerF, et al. Switching from natalizumab to fingolimod treatment in multiple sclerosis: Real life data from the Austrian MS treatment registry. Journal of Neurology2019; 266: 2672–2677.
16.
MancinelliCRScarpazzaCCordioliC, et al. Switching to ocrelizumab in RRMS patients at risk of PML previously treated with extended interval dosing of natalizumab. Mult Scler2021; 27(5): 790–794.
KlotzLGoldRHemmerB, et al. Diagnosis of multiple sclerosis 2010 revision of the McDonald criteria. Nervenartz2011; 82: 1302–1309.
19.
ThompsonABanwellBBarkhofF, et al. Diagnosis of multiple sclerosis 2017 revisions of the McDonald criteria. Lancet Neurol2018; 17: 162–173.
20.
SchumacherGABeebeGKiblerRF, et al. Problems of experimental trials of therapy in multiple sclerosis: Report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann N Y Acad Sci1965; 122: 552–568.
21.
PapathanasiouAHibbertATallantyreE, et al. Real-world annualized relapse rates from contemporary multiple sclerosis clinics in the UK: A retrospective multicentre cohort study. Neurol Sci2023; 44(10): 3629–3635.
22.
LublinFHäringDGanjgahiH, et al. How patients with multiple sclerosis acquire disability. Brain2022; 145: 3147–3161.
23.
PfeufferSRuckTPulR, et al. Impact of previous disease-modifying treatment on effectiveness and safety outcomes, among patients with multiple sclerosis treated with alemtuzumab. J Neurol Neurosurg Psychiatry2021; 92(9): 1007–1013.
24.
AlpingPFrisellTNovakovaL, et al. Rituximab versus fingolimod after natalizumab in multiple sclerosis patients. Ann Neurol2016; 79(6): 950–958.
25.
ZhuCKalincikTHorakovaD, et al. Comparison between dimethyl fumarate, fingolimod, and ocrelizumab after natalizumab cessation. JAMA Neurol2023; 80: 739–748.
26.
BigautKKremerLFabacherT, et al. Ocrelizumab versus fingolimod after natalizumab cessation in multiple sclerosis: An observational study. J Neurol2022; 269(6): 3295–3300.
27.
PfeufferSSchmidtRStraetenFA, et al. Efficacy and safety of alemtuzumab versus fingolimod in RRMS after natalizumab cessation. J Neurol2019; 266(1): 165–173.
28.
Santiago-SetienPBarquín-RegoCHernández-MartínezP, et al. Switch to ocrelizumab in MS patients treated with natalizumab in extended interval dosing at high risk of PML: A 96-week follow-up pilot study. Front Immunol2023; 14: 1086028.
29.
ZanghìAGalloAAvolioC, et al. Exit strategies in natalizumab-treated RRMS at high risk of progressive multifocal leukoencephalopathy: A multicentre comparison study. Neurotherapeutics2021; 18(2): 1166–1174.
30.
Bar-OrACalabresiPAArnoldD, et al. Rituximab in relapsing-remitting multiple sclerosis: A 72-week, open-label, phase I trial. Ann Neurol2008; 63(3): 395–400.
31.
VenetMLepineAMaaroufA, et al. Control of disease activity with large extended-interval dosing of rituximab/ocrelizumab in highly active pediatric multiple sclerosis. Mult Scler2024; 30(2): 261–265.
32.
ClaverieRPerrigueyMRicoA, et al. Efficacy of rituximab outlasts B-cell repopulation in multiple sclerosis: Time to rethink dosing. Neurol Neuroimmunol Neuroinflamm2023; 10(5): e200152.
