Switching between treatments is an opportunity for patients with multiple sclerosis (MS) to ameliorate disease control or safety. The aim of this study was to investigate the impact of switching from fingolimod (FTY) or natalizumab (NTZ) to ocrelizumab (OCR) on disease activity.
Methods:
We retrospectively enrolled 165 patients treated with OCR from 11 MS centres. We assessed the association of demographic and clinical characteristics on relapse rate (RR) and activity on magnetic resonance imaging (MRI) during wash-out and after 6 months of treatment with OCR through univariable and multivariable negative binomial regression models.
Results:
We registered a total of 35 relapses during the wash-out period. Previous treatment with FTY, relapses in the previous year, and relapsing-remitting course were associated with higher RR. In the first 6 months of OCR, 12 patients had clinical or MRI disease activity. Higher Expanded Disability Status Scale (EDSS) and higher lymphocyte count at OCR start were associated with a reduced probability of relapse.
Discussion and Conclusion:
This study confirms that withdrawal from sequestering agents as FTY increases the risk of relapses in the wash-out period. Nevertheless, starting OCR before achieving complete immune reconstitution could limit its effectiveness in the first 6 months probably because trapped lymphocytes escape the CD20-mediated depletion.
HauserSLBar-OrAComiG, et al. Ocrelizumab versus interferon Beta-1a in relapsing multiple sclerosis. N Engl J Med2017; 376: 221–234.
2.
MyhrKMTorkildsenØLossiusA, et al. B cell depletion in the treatment of multiple sclerosis. Expert Opin Biol Ther2019; 19(3): 261–227.
3.
RahmanzadehRWeberMSBrückW, et al. B-cells in multiple sclerosis therapy-a comprehensive review. Acta Neurol Scand2018; 137(6): 544–556.
4.
HauserSLBelachewSKapposL.Ocrelizumab in primary progressive and relapsing multiple sclerosis. N Engl J Med2017; 376: 1694.
5.
MandalaSHajduRBergstromJ, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science2002; 296(5566): 346–349.
6.
CalabresiPARadueEWGoodinD, et al. Safety and efficacy of fingolimod in patients with relapsing–remitting multiple sclerosis (FREEDOMS II): A double-blind, randomized, placebo controlled, phase 3 trial. Lancet Neurol2014; 13(6): 545–556.
7.
FrauJSormaniMPSignoriA, et al. Clinical activity after fingolimod cessation: Disease reactivation or rebound? i-MuST study group. Eur J Neurol2018; 25(10): 1270–1275.
8.
WillisMPearsonOIllesZ, et al. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm2017; 4(2): e320.
9.
Bernard-ValnetRPignoletBBiottiD, et al. Unexpected high multiple sclerosis activity after switching from fingolimod to alemtuzumab. Mult Scler Relat Disord2018; 25: 216–218.
10.
FrauJ.Outcomes after fingolimod to alemtuzumab treatment shift in relapsing–remitting MS patients: A multicentre cohort study. J Neurol2019; 266(10): 2440–2446.
11.
ComiG.Treatment of multiple sclerosis: Role of natalizumab. Neurol Sci2009; 30: S155–158.
12.
ProsperiniLKinkelRPMiravalleAA, et al. Post-natalizumab disease reactivation in multiple sclerosis: Systematic review and meta-analysis. Ther Adv Neurol Disord2019; 12: 1756286419837809.
13.
PfeufferSSchmidtRStraetenFA, et al. Efficacy and safety of alemtuzumab versus fingolimod in RRMS after natalizumab cessation. J Neurol2019; 266(1): 165–173.
14.
ThompsonAJBanwellBLBarkhofF, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol2018; Feb17(2): 162–173.
15.
SaccàFLanzilloRSignoriA, et al. Determinants of therapy switch in multiple sclerosis treatment-naïve patients: A real-life study. Mult Scler2019; 25(9): 1263–1272.
PardoGJonesDE.The sequence of disease-modifying therapies in relapsing multiple sclerosis: Safety and immunologic considerations. J Neurol2017; 264(12): 2351–2374.
18.
Naegelin RasenackMAndelovaMVon FeltenS, et al. Shortening the washout to 4 weeks when switching from natalizumab to fingolimod and risk of disease reactivation in multiple sclerosis. Mult Scler Relat Disord2018; 25: 14–20
19.
BergerBBaumgartnerARauerS, et al. Severe disease reactivation in four patients with relapsing-remitting multiple sclerosis after fingolimod cessation. J Neuroimmunol2015; 282: 118–122.
20.
HavlaJBPellkoferHLMeinlI, et al. Rebound of disease activity after withdrawal of fingolimod (FTY720) treatment. Arch Neurol2012; 69: 262–264.
21.
HatcherSEWaubantENourbakhshB, et al. Rebound syndrome in patients with multiple sclerosis after cessation of fingolimod treatment. JAMA Neurol2016; 73(7): 790–794.
22.
SongZYYamasakiRKawanoY, et al. Peripheral blood T cell dynamics predict relapse in multiple sclerosis patients on fingolimod. PLoS ONE2015; 10(4): e0124923.
23.
CavoneRFeliciLLapucciA, et al. Dysregulation of sphingosine 1 phosphate receptor-1 (S1P1) signaling and regulatory lymphocyte-dependent immunosuppression in a model of post-fingolimod MS rebound. Brain Behav Immun2015; 50: 78–86
24.
UygunogluUTutuncuMAltintasA, et al. Factors predictive of severe multiple sclerosis disease reactivation after fingolimod cessation. Neurologist2018; 23(1): 12–16.
25.
LevinSNEzumaCLevineL, et al. Switching from natalizumab to ocrelizumab in patients with multiple sclerosis. Mult Scler2020; 26(14): 1964–1965.
26.
SellnerJRommerPS.A review of the evidence for a natalizumab exit strategy for patients with multiple sclerosis. Autoimmun Rev2019; 18(3): 255–261.
27.
Grand’MaisonFYeungMMorrowSA, et al. Sequencing of disease-modifying therapies for relapsing-remitting multiple sclerosis: A theoretical approach to optimizing treatment. Curr Med Res Opin2018; 34(8): 1419–1430.
28.
SignorielloELanzilloRBrescia MorraV, et al. Lymphocytosis as a response biomarker of natalizumab therapeutic efficacy in multiple sclerosis. Mult Scler2016; 22(7): 921–925.
29.
KapposLRadueEWO’ConnorP, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med2010; 362: 387–401.
30.
GrutzkeBHuckeSGrossCC, et al. Fingolimod treatment promotes regulatory phenotype and function of B cells. Ann Clin Transl Neurol2015; 2(2): 119–130.
31.
GreenfieldALHauserSL.B-cell therapy for multiple sclerosis: Entering an era. Ann Neurol2018; 83(1): 13–26.
32.
SchmidtSSchultenT.Severe rebound after cessation of fingolimod treated with ocrelizumab with coincidental transient aggravation: Report of two cases. Ther Adv Neurol Disord2019; 12: 46818.
33.
GingeleSJacobusTLKonenFF, et al. Ocrelizumab depletes CD20⁺ T cells in multiple sclerosis patients. Cells2018; 8(1): 12.
34.
SabatinoJJJrWilsonMRCalabresiPA, et al. Anti-CD20 therapy depletes activated myelin-specific CD8+ T cells in multiple sclerosis. Proc Natl Acad Sci U S A2019; 116(51): 25800–25807.
35.
ZeccaC, et al. Treatment of multiple sclerosis with rituximab: A multicentric Italian–Swiss experience. Mult Scler2020; 26: 1519–1531.
36.
HolmoyTTorkildsenOZarnovickyS.Extensive multiple sclerosis reactivation after switching from fingolimod to rituximab. Case Rep Neurol Med2018; 2018: 5190794.
