RESEARCH OPEN ACCESS

Effect of switching from natalizumab tomoderate- vs high-efficacy DMT inclinical practiceCarrie M Hersh DO Haleigh Harris BA Devon Conway MD and Le H Hua MD

Neurology Clinical Practice December 2020 vol 10 no 6 e53-e65 doi101212CPJ0000000000000809

Correspondence

Carrie M Hersh

hershcccforg

AbstractObjectiveTo assess the real-world comparative effectiveness of switching fromnatalizumab (NTZ) to amoderate-efficacy (Mod) disease-modifyingtherapy (DMT) vs high-efficacy therapy (HET) in patients withmultiple sclerosis (MS)

MethodsPatients discontinuing NTZ at twoMS centers (n = 556) who switched toMod DMT (n = 270)vs HET (n = 130) were assessed using propensity score (PS) weighting PS model covariatesincluded demographics and baseline clinical andMRI characteristics All outcomes were reportedas Mod DMT vs HET

ResultsOf the patients included in the study 486 switched to Mod DMT (dimethyl fumarate n =130 fingolimod n = 140) vs 234 who switched to HET (ocrelizumab n = 106 rituximabn = 17 alemtuzumab n = 7) Within the first 6 months post-NTZ switchers to Mod DMTexperienced comparable relapses (odds ratio [OR] = 136 95 confidence interval [CI][072ndash166] p = 0724) although they had increased MRI activity on treatment (OR = 25995 CI [109ndash357] p = 0037) By 24 months post-NTZ there was no difference in theannualized relapse rate (OR = 144 95 CI [069ndash159] p = 0334) or time to first clinicalrelapse (HR = 212 95 CI [087ndash517] p = 0090) although switchers to Mod DMT hadhigher gadolinium-enhancing (GdE) lesions (OR = 362 95 CI [156ndash521] p = 0005)earlier time to first GdE lesion (HR = 667 95 CI [206ndash916] p = 0002) lower proportionwith the absence of disease activity (OR = 041 95 CI [021ndash071] p = 0004) and higherrisk of disability progression on T25FW (OR = 183 95 CI [106ndash302] p = 0043) and 9-HPT (OR = 181 95 CI [105ndash356] p = 0044)

ConclusionPatients switching from NTZ to Mod DMT vs HET were at relatively increased risk of diseaseactivity within the first 6 months of NTZ withdrawal that was sustained at 24 months yieldinggreater disability progression

Lou Ruvo Center for Brain Health (CMH HH LHH) Cleveland Clinic Las Vegas NV and Mellen Center for Multiple Sclerosis Treatment and Research (DC) Cleveland Clinic Cleveland OH

Funding information and disclosures are provided at the end of the article Full disclosure form information provided by the authors is available with the full text of this article atNeurologyorgcp

The Article Processing Charge was funded by the Cleveland Clinic

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy 2020 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology e53

Natalizumab (NTZ) is a high-efficacy disease-modifying ther-apy (DMT) for relapsing forms of multiple sclerosis (MS)1ndash3

In clinical practice long-term use of NTZ is limited by potentialsafety risks including progressive multifocal leukoencephal-opathy (PML)45 that can be reduced by switching to a differ-ent DMT However the transition between NTZ andalternative therapies poses additional risks because diseasereactivation can occur upon NTZ discontinuation in the formof relapses andor gadolinium-enhancing (GdE) lesions6ndash9

The risk of rebound disease-activity that is worse compared tothe pre-NTZ period-increases with longer NTZ washoutperiods gt 3 months1011 and by switching to an alternativetherapy with lower efficacy12 Many studies investigated theeffect of switching from NTZ to a different DMT in high-riskPML populations10ndash23 However consensus is still lacking inregard toDMT sequencing followingNTZ cessation A paucityof data is available that directly compare disease activity head tohead across different DMT switching paradigms

Real-world studies are therefore needed to investigate theeffects of various post-NTZ sequencing strategies on both earlyand longer-term MS disease activity and disability progressionPublished data demonstrated that patients de-escalating ther-apy from NTZ to a lower-efficacy DMT (eg glatiramer ace-tate interferon beta and teriflunomide) are at risk of reboundor breakthrough disease activity121820 However patients mayfare better by switching to a moderate DMT (Mod DMT) orhigh-efficacy therapy (HET)

We sought to fill an important knowledge gap by comparing theeffectiveness of switching fromNTZ to aModDMTvs anotherHET onMS outcomes in a clinical practice cohort at 6 monthsand 24 months using propensity score (PS)-adjusted meth-ods24 In the present study we definedModDMT as treatmentwith either fingolimod or dimethyl fumarate based on equiv-alent clinical and MRI outcome measures derived from variouscomparative effectiveness studies25ndash30 We defined HET astreatment switch to ocrelizumab rituximab or alemtuzumab

MethodsStandard protocol approvals registrationsand patient consentsThis study was approved by the Institutional Review Board atthe Cleveland Clinic

Patient populationWe conducted a retrospective observational study of patientswith MS treated at the Cleveland Clinic Lou Ruvo Center forBrain Health (LRCBH) and Cleveland Clinic Mellen Centerwho discontinued NTZ between December 2005 and January2018 and switched either to a Mod DMT or another HETPatients were identified through the TOUCHreg prescribingprogram database All patients included in the study werepreviously diagnosed with MS by a Cleveland Clinic MS spe-cialist at the LRCBH or the Mellen Center

Data collectionAll patients who switched from NTZ to a Mod DMT or HETand had 6-month and 24-month data available were identifiedBaseline and outcome data were collected from the electronicmedical record (EMR) To adequately capture baseline diseasecharacteristics important for determining treatment allocationbetween the two therapeutic paradigms we included covariatesderived from the EMR data in the 12 months before NTZexposure and within 6 months before NTZ discontinuationThese data were confirmed by anMS clinician before they wereincluded in the data set The study adjusted for NTZ washoutduration gt3 months to lower the risk of disease rebound asa potential confounder

Demographics and clinical radiographic laboratory andpatient-reportedoutcome (PRO)measureswere collected fromthe EMR Follow-up assessments (eg clinician visits MRIfrequency and protocols) did not differ between the groupsClinical relapsesmdashidentified retrospectively in the patientsrsquochartsmdashwere designated by the treating neurologist and de-fined as new or worseningMS symptoms lasting greater than 24hours without a coexisting fever or illness The timed 25-footwalk (T25FW)31 and 9-hole peg test (9-HPT)32 were mea-sured by the treating health care providers as part of routineclinical practice The number of new T2-hyperintense and GdEbrain MRI lesions were manually counted by Cleveland Clinicneuroradiologists Neuroradiologic data at 6-month follow-upwere compared with brain MRIs 6 months before NTZ dis-continuation and 24-month neuroradiologic data were com-pared with brain MRIs within 12 months of initiating theswitched DMT To assess the patient experience PRO meas-ures such as the Patient Health Questionnaire-9 (PHQ-9)33

and Performance Scale34 were also collected We stored col-lated information in an encrypted database using a password-protected Excel Spreadsheet on secureClevelandClinic servers

Statistical analysisData were imported for analysis into R version 35235 Themajority of covariates incorporated into the PS model weremissing in lt10 of patients However some covariates (egbaseline MRI data and JC virus antibody status) were missingin gt10 of patients We used the same approach as in ourpreviously conducted studies to account for missingness pat-terns in the PS2527

Analyses were conducted in both an intention-to-treat (ITT)model andon-treatment (ldquoper protocolrdquo) as a sensitivity analysisfor those switching fromNTZ to their respective DMT strategy(Mod DMT or HET) by 6- and 24-month follow-up Theprimary outcome was the annualized relapse rate ratio (ARRratio Mod DMT vs HET) at 24 months The ARR was cal-culated by dividing the total number of relapses by the totalnumber of person-years at risk Secondary outcome measuresincluded the time to first relapse time to first GdE lesion andproportions with new T2-hyperintense lesions GdE lesionsMRI disease activity (a composite outcome measure defined asthe proportion of patients with new T2-hyperintense lesions

e54 Neurology Clinical Practice | Volume 10 Number 6 | December 2020 NeurologyorgCP

andor GdE lesions) absence of disease activity (a compositeoutcome measure defined as freedom from clinical relapses andMRI disease activity) and 20worsening on theT25FWand 9-HPT252632

The PS was built as a logistic regression model to calculate thelikeliness of switching from NTZ toMod DMT as opposed toHET using a priori selected covariates (table 1) A PS wascalculated for each patient and subsequently used in an AverageTreatment effect on the Treated (ATT) weighting model toderive a sample of patients who were similar at baseline exceptfor their allocated treatment paradigm This approach reducedthe effect of indication bias on our comparisons of NTZ switchto Mod DMT vs HET while still retaining information from allpatients Owing to different sample sizes across the twocohorts a PS matching technique was not used because a largeselection of patients would have remained unmatched conse-quently introducing another selection bias into the PSmodel24

Before deriving conclusions on treatment effect differencesbetween our groups of interest we selected PS weighting onthe basis of a more complete balance across the variables in-cluded in our PS model between the two cohorts

Similar to previous studies2527 the strength of the PSmodel wasassessed by how well it balanced the two groups as determinedby comparing the standardized differences across the means ofthe covariates before and after PS adjustment In this study wedetermined excellent covariate balance as achieving an absolutestandardized difference of lt10 on the means of the covariatesacross the two therapeutic strategies Before ATT weightingunadjusted outcome measures were estimated using Pearson χ2

tests for categorical data and t tests for continuous data AfterATT weighting conditional logistic regression models wereused to calculate odds ratio (OR) estimates for binary outcomesand Cox proportional hazards models and Kaplan-Meier sur-vival curves to obtain survival end points The ARR was ana-lyzed using a Poisson regressionmodel Odds and hazards ratioswere measured as those who switched from NTZ to a ModDMT compared with patients who switched to HET Theprimary outcome measure (ARR ratio) was based on a two-tailed test of statistical significance with α = 005 Assuming 80power with a total sample size of 400 patients the minimumdetectable effect size was determined to be 026

Data availabilityAnonymized data can be shared at the request of qualifiedinvestigators for purposes of replicating procedures and results

ResultsBaseline characteristicsIn the original cohort 556 patients from the Cleveland ClinicLRCBH and the Mellen Center discontinued NTZ betweenDecember 2005 and January 2018 (figure 1) The majority ofpatients withdrew from NTZ due to increased PML risks (n= 305 549) Of those who had 24-month follow-up dataavailable for review a total of 270 patients switched to Mod

DMT (fingolimod n = 140 dimethyl fumarate n = 130) and130 patients transitioned to HET (ocrelizumab n = 104rituximab n = 18 and alemtuzumab n = 18)

Demographics and baseline disease characteristics are pre-sented in table 1 The majority of patients in our cohort hadrelapsing-remitting MS at the time of natalizumab exposure(Mod DMT = 959 HET = 952) A higher proportion ofpatients discontinuing NTZ due to increased PML risksswitched to Mod DMT (727) compared with HET (601)(p = 0019) which was consistent with the increased pro-portion of patients who switched to Mod DMT (626) vsHET (470) due to JC virus antibody seropositivity at anytime (p = 0027) The mean washout duration between groupswas similar and relatively short (Mod DMT = 14 monthsHET = 18 months p = 0340) reducing the risk of diseasereactivation that otherwise would have posed an additionalconfounder Duration ofNTZ treatment did not differ betweenour cohorts As expected the proportion with baseline diseaseactivity measured via relapses and newT2 andor GdE lesionsbefore starting NTZ was numerically higher compared withdisease activity while on NTZ (table 1)

Propensity score modelThe PS model was built using demographics and baselineclinical radiographic laboratory and PRO characteristicssummarized in table 1 Missing covariate data did not consid-erably change the overall balance of covariates after PSweighting The model correctly assigned higher PS to the ModDMT group compared with the HET group (figure e-1 linkslwwcomCPJA162) given that the logistic regression modelwas calculated to determine the likelihood of switching fromNTZ to the former treatment paradigm Before ATT weight-ing the treatment groups were not balanced well with at leasthalf of the covariates falling outside of the 10 absolute stan-dardized difference range Furthermore the absolute value ofthe standardized difference of the linear PS comparing ModDMT with HET was 912 which was considerably greaterthan the 50 standard previously recommended by Rubin36

Therefore we determined that PS adjustment was warranted toaccount for indication bias before making conclusions on dif-ferences in treatment effects

PS weighting balanced the two treatment groups effectivelywith only 5 covariates obtaining absolute standardized differ-ences gt10 (figure e-2 linkslwwcomCPJA162) In a dou-ble robust approach PS weighting also produced a similarlinear PS distribution with a standardized difference of 172which was sufficiently within the 50 standard

Outcome estimates by 6-month follow-upTo estimate the effectiveness of switching fromNTZ to a ModDMT vs HET on early MS disease activity we compared in-flammatory disease outcomes (eg relapse MRI activity andabsence of disease activity) within 6 months of NTZ discon-tinuation Unadjusted and postweighting outcomes aresummarized in tables 2 and 3 By 6 months 117 of Mod

NeurologyorgCP Neurology Clinical Practice | Volume 10 Number 6 | December 2020 e55

Table 1 Baseline characteristics of NTZ switchers to Mod DMT vs HETa

Moderate efficacy n = 270 High efficacy n = 130

p Valuen or mean or SD n or mean or SD

Demographics

Age at diagnosis (years SD) 333 90 321 96 0228

Age at NTZ discontinuation(years SD)

425 99 422 108 0778

Sex (female) 182 674 88 677 1000

Race 0079

White 224 862 92 754

Black 32 123 26 213

Other 4 16 4 33

Comorbidities

Tobacco smoking 72 267 29 223 0414

Asthma 27 100 17 131 0072

Cancer 11 41 1 08 0133

COPD 4 15 0 00 0391

Diabetes mellitus 24 89 8 62 0455

Hyperlipidemia 45 167 10 77 0022b

Hypertension 57 211 17 131 0072

Disease history

Disease duration (years SD) 171 86 151 89 0041b

Relapsing-remitting MS at disease onset 255 959 120 952 0422

Disease course at NTZ discontinuation 0021b

Relapsing-remitting 199 748 109 838

Primary progressive 2 08 3 23

Progressive relapsing 10 38 0 00

Secondary progressive 55 207 18 138

No of previous DMTs (number SD) 29 16 30 15 0443

Interferon 229 848 95 731 0037b

Glatiramer 115 426 55 423 1000

Fingolimod 10 37 23 177 lt0001b

Dimethyl fumarate 6 22 31 240 lt0001b

Teriflunomide 2 07 5 38 0070

Mitoxantrone 6 22 0 00 0203

Other immunosuppressive 30 111 10 59 0065

NTZ infusions mean (range) 35 (1ndash93) NA 28 (1ndash65) NA 0142

Reason for NTZ discontinuation

Breakthrough disease 40 148 24 185 0776

Intolerance 53 196 31 238 0504

NTZ risks (PML) 196 727 78 601 0019b

Continued

e56 Neurology Clinical Practice | Volume 10 Number 6 | December 2020 NeurologyorgCP

DMT-treated patients experienced a clinical relapse vs 87 ofHET-treated patients with a PS-adjusted OR = 136 (95confidence interval [CI] [072ndash166] p = 0724) In an ITTmodel MRI disease activity favored those who switched toHET (OR = 168 p = 0068) but did not reach statisticalsignificance In a sensitivity analysis including only patients ontreatment those treated with Mod DMT had higher MRI

disease activity (OR = 259 95 CI [109ndash387] p = 0037)GdE lesions (OR = 337 95 CI [145ndash468] p = 0007) andnew T2-hyperintense lesions (OR = 218 95 CI [110ndash401]p = 0029) Furthermore of those who had available clinical andMRI data by 6-month follow-up (ModDMT n = 238 HET n =109) patients switching from NTZ to Mod DMT had lowerlikelihood of achieving absence of disease activity (613)

Table 1 Baseline characteristics of NTZ switchers to Mod DMT vs HETa (continued)

Moderate efficacy n = 270 High efficacy n = 130

p Valuen or mean or SD n or mean or SD

DMT washout (mean SD) 14 55 18 45 0340

Labs

JCV antibody status at NTZdiscontinuation

Negative 68 358 59 504 0027b

Positive 119 626 55 470

Indeterminate 3 16 3 26

ALC at NTZ discontinuation(times109L mean SD)

32 11 32 10 0739

Disease activity

Relapse before NTZ initiation 103 401 56 483 0171

Relapse during NTZ treatment 13 48 7 54 1000

Brain MRI before NTZ initiation 229 848 100 769

GdE lesions 102 445 46 460 0901

New T2 lesions 85 371 45 469 0130

Brain MRI 6 months before NTZdiscontinuation

96 356 64 492

GdE lesions 3 32 0 00 0436

New T2 lesions 2 21 0 00 0663

Objective measures

T25FW (s SD) 91 90 73 39 0086

Ambulation assistance 0175

None 174 699 88 793

Unilateral 26 104 8 72

Bilateral 38 153 9 81

Wheelchair 11 44 6 54

9-HPT dominant (mean sec SD) 305 169 264 93 0099

Patient-reported outcomes

MS performance scale 150 77 145 85 0694

PHQ-9 score depressed 69 437 27 380 0512

Abbreviations 9-HPT = 9-hole peg test ALC = absolute lymphocyte count GdE = gadolinium enhancing HET = high-efficacy therapy JCV = JC virus Mod =moderate-efficacy DMT NTZ = natalizumab PHQ-9 = Patient Health Questionnaire-9 T25FW = timed 25-foot walk MS = multiple sclerosisNTZ discontinuation due to breakthrough disease is defined as NTZ cessation due to clinical relapses new MRI activity or progression of disabilityPHQ-9 score depressed defined as PHQ-9 score ge10a Unless otherwise specified in the table baseline disease characteristics defined as the time period within 12 months of NTZ initiationb Statistically significant p value (alpha = 005)

NeurologyorgCP Neurology Clinical Practice | Volume 10 Number 6 | December 2020 e57

compared with those who switched to HET (807) (OR =042 95 CI [023ndash076] p = 0004)

Outcome estimates by 24-month follow-upTodetermine thedurability of treatment effect on inflammatorydisease activity and disability progression we assessed 24-month outcomes in NTZ switchers to Mod DMT vs HET(tables 2 and 3) By 24 months 133 of Mod DMT patientshad a clinical relapse vs 100 of HET patients Mod DMTpatients had 36 relapses over 1714 patient-years of treatmentwith ARR = 021 (95 CI = 007ndash039) HET patients had 13relapses over 1182 patient-years of treatment with ARR = 011(95 CI = 005ndash042) After PS weighting there was no dif-ference in the ARR (ARR ratio = 144 95CI [069ndash159] p =0334) The mean time to first relapse was 32 months for ModDMT compared with 44 months for HET Although survivaloutcomes favored HET no difference was found in time to firstrelapse between groups over the first 24 months of treatment(HR = 212 95 CI [087ndash517] p = 0090) (figure 2)

In an ITTmodel among all patients with availableMRI data by24-month follow-up (Mod DMT n = 252 HET n = 126)254 of patients on Mod DMT demonstrated MRI activity vs119 onHET (OR = 243 95 CI [108ndash393] p = 0039) Asensitivity analysis comparing only patients on treatmentshowed similar findings Furthermore patients treated withMod DMT had higher odds of GdE lesions (OR = 199 95CI [112ndash273] p = 0022) and new T2-hyperintense lesions(OR = 215 95 CI [118ndash301] p = 0011) with similarfindings in a sensitivity analysis only comparing patients ontreatment (tables 2 and 3) Patients who switched to ModDMT also experienced earlier time to first GdE lesion com-pared with HET (HR = 667 95 CI [206ndash916) p = 0002)(figure 3) An additional sensitivity analysis comparing

inflammatory disease outcomes stratified by reason fordiscontinuationmdashbreakthrough disease and safety risksmdashalsoshowed similar results to the entire cohort although compar-ative increased disease activity in the Mod DMT groupappeared to be driven by NTZ switchers due to breakthroughdisease (table 4)

Of patients with available on-treatment clinical and MRI out-come data by 24 months (Mod DMT n = 127 HET n = 92)NTZ switchers to Mod DMT had lower likelihood of absenceof disease activity (637) vs HET (804) (OR = 041 95CI [021ndash071] p = 0004) Using surrogate markers of dis-ability progression NTZ switchers to Mod DMT experiencedhigher odds of 20 worsening of the T25FW (OR = 183 95CI [106ndash302] p = 0043) and 20 worsening of the 9-HPT(OR = 181 95 CI [105ndash356] p = 0044) There were nocases of PML or other serious opportunistic infections reportedin either cohort

DiscussionNTZ is a high-efficacy DMT indicated for relapsing forms ofMS for which long-term use in clinical practice is limited bypotential safety risks including PML The risk is particularlyhigh in patients who (1) have a high anti-JC virus antibodyindex (2) had NTZ exposure longer than 24 months and (3)had previous exposure to immunosuppressive therapies45 Inthe current neurotherapeutic landscape of multiple availableDMTswith variousmechanisms of action and effectiveness andsafety profiles it is possible to lower these PML risks byswitching patients to another therapy However an additionalrisk of disease reactivation occurs upon NTZ interruptionAfter NTZ discontinuation the time to return of α4β1-integrinantigen saturation to values found in untreated patients likely

Figure 1 Study flow diagram

At 24-month follow-up 270 patients switched from NTZ to a Mod DMT (fingolimod and dimethyl fumarate) and 130 patients switched to HET (ocrelizumabrituximab and alemtuzumab) Themajority of patients discontinued NTZ due to increased PML risks of which a greater proportion switched to Mod DMT vsHET Low (efficacy) DMT glatiramer acetate interferon beta teriflunomide Other IS azathioprine mycophenolate mofetil cyclophosphamide pulsemethylprednisolone and pulse IVIG DMT = disease-modifying therapy HET = high-efficacy therapy IS = immunosuppressive therapy Mod = moderate-efficacy DMT NTZ = natalizumab PML = progressive multifocal leukoencephalopathy

e58 Neurology Clinical Practice | Volume 10 Number 6 | December 2020 NeurologyorgCP

vary across individuals and is predictive of the risk ofGdE lesionoccurrence and rebound disease83738

Consensus is currently lacking on DMT switching strategiesafter NTZ withdrawal and is primarily based on single-arminvestigations with variable outcomes a few small comparative

effectiveness studies or expert opinion Further observationalstudies are thus warranted to compare the effectiveness of post-NTZ sequencing strategies to guide decision making in clinicalpractice To fill this knowledge gap we conducted a real-worldPS-adjusted study comparing patients switching from NTZ toModDMTvsHET in a clinical practice cohortWe investigated

Table 2 Summary of unadjusted effectiveness outcomes of NTZ switchers to Mod DMT vs HET

Moderate efficacy n = 270 High efficacy n = 130

p Valuen or SD n or SD

6-month outcomes

Clinical relapse (no of patients) 31 117 11 87 0462

Relapses per patient (mean SD) 012 032 009 028 0364

MRI available for review(intention to treat)

219 811 107 823 0824

MRI activity (GdE + new T2 lesions) 47 215 12 112 0054

GdE lesions 37 169 11 103 0285

New T2 lesions 46 210 15 140 0127

MRI available for review (on treatment) 184 681 94 726 0133

MRI activity (GdE + new T2 lesions) 46 250 8 85 0039b

GdE lesions 30 163 2 21 0014b

New T2 lesions 39 214 8 85 0042b

Absence of disease activitya 146238 613 88109 807 0005b

24-month outcomes

Clinical relapse (no of patients) 36 133 13 100 0122

Relapses per patient (mean SD) 014 028 006 026 0364

MRI available for review(intention to treat)

252 933 126 969 0244

MRI activity (GdE + new T2 lesions) 64 254 15 119 0012b

GdE lesions 44 175 11 87 0028b

New T2 lesions 72 286 19 151 0021b

MRI available for review (on treatment) 136 504 81 623 0011b

MRI activity (GdE + new T2 lesions) 26 191 8 99 0029b

GdE lesions 24 176 6 74 0013b

New T2 lesions 28 206 8 99 0010b

Absence of disease activitya 81127 637 7492 804 0006b

Measures of neurologic disability

T25FW (mean sec SD) 826 721 601 521 0032b

20 worsening of T25FW 113203 556 3894 402 0045b

9-HPT dominant (mean sec SD) 2493 1065 2136 1011 0039b

20 worsening of 9-HPT 103189 545 3783 446 0048b

Abbreviations 9-HPT = 9-hole peg test DMT = disease-modifying therapy GdE = gadolinium enhancing HET = highly effective therapy Mod = moderateT25FW = timed 25-foot walka Absence of disease activity defined as absence of clinical relapses + absence of MRI activity (GdE lesions andor new T2 lesions)b Statistically significant p value (alpha = 005)

NeurologyorgCP Neurology Clinical Practice | Volume 10 Number 6 | December 2020 e59

6-month time points to determine the early comparativeeffectiveness of NTZ switch to one of two treatment strategiesand 24-month time points to capture the durability of the newtreatmentrsquos effect

Overall disease activity remained low at 6-month and 24-month follow-up in both post-NTZ treatment arms relative tothe 12-month pre-NTZ period Numerically there was a signal

for increased disease activity post-NTZ across both groupsrelative to the time on treatment but it did not supersede that ofthe pre-NTZ period Therefore in our population patients didnot experience rebound diseasemdashputatively related to an im-mune reconstitution inflammatory syndromendashlike phenome-non39 Likely the low disease activity was related to twodifferent mechanisms in our study population (1) a shortwashout duration (mean lt2 months) across both treatment

Table 3 Unadjusted and adjusted effectiveness outcomes of NTZ switchers to Mod DMT vs HET

Unadjusted Propensity adjusted

Odds orhazards ratio 95 CI p Value

Odds orhazards ratio 95 CI p Value

6-month outcomes

Proportion with clinical relapse 132 066ndash203 0764 136 072ndash166 0724

MRI disease activity (intention-to-treat)

MRI activity (GdE + new T2 lesions) 172 092ndash285 0077 168 094ndash213 0068

GdE lesions 161 076ndash339 0281 163 083ndash269 0202

New T2 lesions 157 081ndash305 0200 158 084ndash291 0189

MRI disease activity (on-treatment)

MRI activity (GdE + new T2 lesions) 263 111ndash419 0032b 259 109ndash387 0037b

GdE lesions 335 142ndash485 0006b 337 145ndash468 0007b

New T2 lesions 214 108ndash412 0038b 218 110ndash401 0029b

Absence of disease activitya 052 034ndash082 0005b 042 023ndash076 0004b

24-month outcomes

Annualized relapse rate (ARR) ratio 143 072ndash196 0423 144 069ndash159 0334

Proportion with clinical relapse 140 068ndash288 0389 136 062ndash178 0711

Time to first relapse (months mean) 174 084ndash423 0126 212 087ndash517 0090

MRI disease activity (intent to treat)

MRI activity (GdE + new T2 lesions) 236 107ndash412 0038b 243 108ndash393 0039b

GdE lesions 189 108ndash324 0037b 199 112ndash273 0022b

New T2 lesions 202 109ndash303 0018b 215 118ndash301 0011b

MRI disease activity (on treatment)

MRI activity (GdE + new T2 lesions) 272 116ndash313 0032b 254 118ndash307 0021b

GdE lesions 359 149ndash548 0006b 362 156ndash521 0005b

New T2 lesions 214 108ndash412 0033b 223 117ndash388 0024b

Time to first GdE lesion (months mean) 523 212ndash864 0003b 667 206ndash916 0002b

Absence of disease activitya 055 028ndash077 0004b 041 021ndash071 0004b

Measures of neurologic disability

20 worsening of T25FW 178 103ndash321 0045b 183 106ndash302 0043b

20 worsening of 9-HPT 176 101ndash368 0047b 181 105ndash356 0044b

Abbreviations 9-HPT = 9-hole peg test CI = confidence interval DMT = disease-modifying therapy GdE = gadolinium enhancing HET = highly effectivetherapy Mod = moderate NTZ = natalizumab T25FW = timed 25-foot walka Absence of disease activity defined as absence of clinical relapses + absence of MRI activity (GdE lesions andor new T2 lesions)b Statistically significant p value (alpha = 005)

e60 Neurology Clinical Practice | Volume 10 Number 6 | December 2020 NeurologyorgCP

groups and (2) a form of inflammatory protection by switchingto an alternativeDMTof at leastmoderate efficacy The FrenchTYSEDMUS study (n = 4055) showed that 371 of patientswho discontinued NTZ experienced a relapse within 12months of drug interruption mainly occurring between 3 and 5months of NTZ cessation Similarly this study did not observerebound disease activity with a pre-NTZ ARR = 199 and post-NTZ ARR = 0659 On the other hand a smaller study in-vestigating the effects of NTZ interruption showed that thecumulative probability of rebound disease activity was 39 andmostly occurred between 3 and 9 months after NTZ cessationindependently of an alternative DMT6 These reported differ-ences in relapse rates and risk of rebound disease upon NTZcessation are likely related to variable use and sequencing ofDMTs across centers and the restrictive availability of NTZ inFrance to patients with very active disease

Various studies previously demonstrated the benefit ofswitching to an alternative DMT following NTZ discontinua-tion to reduce the risk of rebound disease In 1 study Villaverde-Gonzalez et al showed that 714 of patients remainedrelapse-free after switching from NTZ to one of the platformDMTs Furthermore 625 of patients experienced no radio-logic activity 12 months after NTZ cessation40 However thisstudy was limited by a small sample size and the use of lesseffective DMTs (eg glatiramer acetate and interferon beta)post-NTZ which are suspected to have limitations in

preventing rebound disease19ndash21 Patients switching to moreefficacious therapiesmay have better disease control1113ndash172223

For instance a large study (n = 536) showed that patientsswitching fromNTZ to fingolimod experienced only a small risein the relapse rate (ARR = 038) relative to the period while onNTZ (ARR = 026 p = 0002)41

Our PS analysis demonstrated no differences in clinical relapsesbetween NTZ switchers to Mod DMT vs HET although itnumerically favoredHETThemean time tofirst clinical relapse(3ndash5 months) observed in our patient population was consis-tent with the natural course of drug elimination and what waspreviously reported in a number of smaller studies638 Al-though there were no differences across early MRI diseaseactivity end points in an ITTmodel our sensitivity analysis on-treatment at 6-month follow-up and cumulative MRI diseaseactivity over 24 months demonstrated lower effectiveness inNTZ switchers to Mod DMT compared with HET Data inpatients switching from NTZ to other HET are scarce How-ever 1 comparative effectiveness study favored rituximab (n =114) over fingolimod (n = 142) in patients discontinuing NTZin relation to relapses (rituximab 18 fingolimod 176) andGdE lesions (09 vs 162) at 15 years22 These data areconsistent with those reported in the current investigationAnother small observational study (n = 16) investigatingpatients who switched from NTZ to alemtuzumab had norelapses MRI activity or increased EDSS scores23 These data

Figure 2 Kaplan-Meier plot of relapse-free status through 24-month follow-up

Kaplan-Meier survival analysis showeda twofold higher hazard of first clinical re-lapse in NTZ switchers to moderate- vshigh-efficacy DMT but did not reach statis-tical significance DMT = disease-modifyingtherapy

NeurologyorgCP Neurology Clinical Practice | Volume 10 Number 6 | December 2020 e61

collectively suggest that rituximab and alemtuzumab are fa-vorable options for post-NTZ therapy

In a subgroup comparative effectiveness analysis stratified byreason for NTZ discontinuation increased MRI activity in theMod DMT group was driven by patients who withdrew fromNTZ due to breakthrough disease A similar finding reportingon relapse rates was observed in a study by Jokubaitis et al14

that reported that 30 of patients with disease activity onNTZrelapsed within the first 6 months of transitioning onto fingo-limod (RR = 0001ndash013)

Other predictors of disease reactivation following NTZ with-drawal were described Independent predictors of time to firstclinical relapse inNTZ switchers to fingolimod in the Jokubaitiset al14 study were the number of clinical relapses within theprevious 6 months (HR = 159 p = 0002) and washout du-ration of 2ndash4 months compared with no washout at all (HR =210 p = 0041) A smaller French prospective study in-vestigating the effects of switching from NTZ to fingolimodsimilarly showed a lower risk of relapse (OR = 023 p = 0001)during a shorter washout period lt3 months and with lessdisease activity before NTZ initiation (p = 003)11

Approximately 20 of patients relapsed during the first 6months of fingolimod treatment in a previous study11 In

contrast our patient population experienced a lower risk ofclinical relapses within the first 6 months of therapy whenswitching fromNTZ toModDMT (117) and an even lowerrisk when transitioning onto another HET (87) This dif-ference was likely related to the shorter meanwashout period inour patient population (16months) vs amean of 43months inthe French study It is unlikely that the inclusion of dimethylfumarate in the Mod DMT cohort in our investigation yieldeda considerable difference in findings relative to other studiesreporting on the effectiveness of NTZ to fingolimod transitionHowever if the addition of dimethyl fumarate was a differentialfactor the anticipation would be for a greater number ofrelapses in our cohort (rather than fewer) given that no ob-servational studies to date have demonstrated superior effec-tiveness of dimethyl fumarate compared with fingolimodSimilarly another study showed that the ARR 1 year after NTZto dimethyl fumarate transition was lower in those witha washout duration le3 months vs gt3 months (rate ratio 04995 CI [026ndash090])15 Overall published studies collectivelydemonstrated that a washout period lt3 months between NTZand fingolimod or dimethyl fumarate is important in preventingdisease reactivation

In this study the treating providers likely started patients onNTZ they thought were at highest risk of disease activity Thusthe fact that individuals in the Mod group fared worse (despite

Figure 3 Kaplan-Meier plot of GdE lesionndashfree status through 24-month follow-up

Kaplan-Meier survival analysis showed earliertime to first GdE lesion in patients switchingfrom NTZ to moderate- vs high-efficacy DMTDMT = disease-modifying therapy

e62 Neurology Clinical Practice | Volume 10 Number 6 | December 2020 NeurologyorgCP

likely having less aggressive disease) would support the need totransition most patients to HET after NTZ The current in-vestigation was limited by various factors First our PS modelcould not adjust for unmeasured covariates or residual biasesTo reduce the risk of hidden bias we included a comprehensivelist of covariates believed to be important and representative ofthose factors essential in determining treatment allocation fol-lowing NTZ discontinuation Other limitations inherent inobservational studies included the retrospective nature of theinvestigation missing data (eg radiologic and objectivemeasures of disability progression) and the potential for recallbias in patient-reported relapses However the frequency ofestablished visits at our centers (on average every 3ndash6 months)

and the requirement for relapse confirmation by the treatingclinician before inclusion into the study accounted for the latterconcern We do not routinely assess EDSS scores duringfollow-up visits therefore surrogate measures of disabilityprogression including 20 worsening of the T25FW and 9-HPT were reported32 Our study is also limited in that it wasconducted at two tertiary referralMS centers which likely differin patient population and treatment practices compared withother community centers Despite these limitations thiscomprehensive real-world study provides clinical insights intothe comparative effectiveness of switching from NTZ to al-ternative treatment strategies that are increasingly used inroutine practice

Table 4 Unadjusted and adjusted effectiveness outcomes of NTZ switchers to Mod DMT vs HET by 24-month follow-upstratified by reason for NTZ discontinuation

Unadjusted Propensity adjusted

Odds orhazards ratio 95 CI p Value

Odds orhazards ratio 95 CI p Value

NTZ discontinuation due tobreakthrough diseaseb

Proportion with clinical relapse 164 089ndash492 0083 171 095ndash474 0061

MRI disease activity (intention-to-treat)

MRI activity (GdE + new T2 lesions) 179 098ndash523 0057 187 101ndash517 0049c

GdE lesions 183 099ndash544 0053 194 106ndash568 0043c

New T2 lesions 181 098ndash503 0055 189 102ndash524 0047c

MRI disease activity (on-treatment)

MRI activity (GdE + new T2 lesions) 274 118ndash632 0028c 268 110ndash633 0034c

GdE lesions 357 148ndash723 0005c 342 149ndash716 0006c

New T2 lesions 223 109ndash687 0034c 231 109ndash621 0027c

Absence of disease activitya 048 032ndash083 0004c 039 021ndash089 0003c

NTZ discontinuation due to safety risksb

Proportion with clinical relapse 138 063ndash393 0382 133 062ndash318 0823

MRI disease activity (intention-to-treat)

MRI activity (GdE + new T2 lesions) 166 094ndash533 0123 168 094ndash426 0131

GdE lesions 172 097ndash489 0092 173 097ndash454 0087

New T2 lesions 163 091ndash421 0134 165 095ndash472 0098

MRI disease activity (on-treatment)

MRI activity (GdE + new T2 lesions) 201 105ndash429 0043c 208 105ndash526 0043c

GdE lesions 245 112ndash587 0041c 247 114ndash601 0039c

New T2 lesions 216 107ndash503 0042c 221 108ndash458 0041c

Absence of disease activitya 061 032ndash089 0012c 062 033ndash085 0011c

Abbreviations CI = confidence interval DMT=disease-modifying therapy GdE = gadoliniumenhancing HET =high-efficacy therapyMod=moderate-efficacytherapy NTZ = natalizumaba Absence of disease activity defined as absence of clinical relapses + absence of MRI activity (GdE lesions andor new T2 lesions)b NTZ discontinuation due to breakthrough disease (Mod DMT n = 40 HET n = 24) NTZ discontinuation due to safety risks (Mod DMT n = 196 HET n = 78)c Statistically significant p value (alpha = 005)

NeurologyorgCP Neurology Clinical Practice | Volume 10 Number 6 | December 2020 e63

ConclusionThe current study provides real-world clinical insights intoDMT switching patterns following NTZ discontinuationPatients switching from NTZ to Mod DMT vs HET are atrelatively increased risk of disease activity within the first 6months of NTZ withdrawal which is sustained at 24 monthsyielding greater disability progression The current study alsodemonstrates that switching to a DMT of at least moderateefficacy following NTZ discontinuation is effective in reducingthe risk of rebound disease when restricting the washout periodto lt3 months particularly in those switching to HET Thusthese data suggest that an HET should be considered in theappropriate clinical setting when transitioning a patient off ofNTZ especially when due to breakthrough disease A largermulticenter study investigating the short- and long-term effectsof post-NTZDMT sequencing is planned to improve upon theexternal validity of the current findings

AcknowledgmentThe authors thank the patients treated at the Cleveland ClinicLouRuvoCenter for BrainHealth andClevelandClinicMellenCenter

Study fundingThis study received partial funding support from the Sheilaand Eric Samson Foundation

DisclosureCM Hersh has received speaking and consulting fees fromGenzyme Genentech EMD Serono Novartis and Biogen andhas received research support paid to her institution fromBiogen Genentech and PCORI H Harris reports no dis-closures D Conway has received research support paid to hisinstitution from Novartis and the National Multiple SclerosisSociety and has received personal compensation for consultingfromNovartis and Tanabe Laboratories LH Hua has receivedspeaking and consulting fees from Biogen Genzyme Gen-entech Novartis Celgene and EMD Serono Full disclosureform information provided by the authors is available with thefull text of this article at Neurologyorgcp

Publication historyReceived by Neurology Clinical Practice September 23 2019 Acceptedin final form December 9 2019

References1 Polman CHOrsquoConnor PW Havrdova E et al A randomized placebo-controlled trial

of natalizumab for relapsing multiple sclerosis N Engl J Med 2006354899ndash9102 Miller DH Soon D Fernando KT et al MRI outcomes in a placebo-controlled trial of

natalizumab in relapsing MS Neurology 2007681390ndash14013 Merkel B Butzkueven H Traboulsee AL Havrdova E Kalincik T Timing of high-

efficacy therapy in relapsing-remitting multiple sclerosis a systematic review Auto-immun Rev 201716658ndash665

4 Bloomgren G Richman S Hotermans C et al Risk of natalizumab-associated pro-gressive multifocal leukoencephalopathy N Engl J Med 20123661870ndash1880

5 Plavina T Subramanyam M Bloomgren G et al Anti-JC virus antibody levels inserum or plasma further define risk of natalizumab-associated progressive multifocalleukoencephalopathy Ann Neurol 201476802ndash812

6 Gueguen A Roux P Deschamps R et al Abnormal inflammatory activity returns after natali-zumab cessation in multiple sclerosis J Neurol Neurosurg Psychiatry 2014851038ndash1040

7 OrsquoConnor PW Goodman A Kappos L et al Disease activity return during natalizumabtreatment interruption in patients withmultiple sclerosis Neurology 2011761858ndash1865

8 Vellinga MM Castelijns JA Barkof F et al Postwithdrawal rebound increase in T2lesional activity in natalizumab-treated MS patients Neurology 2008701150ndash1151

9 Papeix C Vukusic S Casey R et al Risk of relapse after natalizumab withdrawalresults from the French TYSEDMUS cohort Neurol Neuroimmunol Neuroinflamm20163e297

10 Sellner J Rommer PS A review of the evidence for a natalizumab exit strategy forpatients with multiple sclerosis Autoimmun Rev 201918255ndash261

11 Cohen M Maillart E Tourbah A et al Switching from natalizumab to fingolimod inmultiple sclerosis a French prospective study JAMA Neurol 201471436ndash441

12 Fox RJ Cree BAC De Seze J et al MS disease activity in RESTORE a randomized24-week natalizumab interruption study Neurology 2014821491ndash1498

13 Kappos L Radue EW Comi G et al Switching from natalizumab to fingolimoda randomized placebo-controlled study in RRMS Neurology 20158529ndash39

14 Jokubaitis VG Li V Kalincik T et al Fingolimod after natalizumab and the risk ofshort-term relapse Neurology 2014821204ndash1211

15 Cohan SL Moses H Calkwood J et al Clinical outcomes in patients with relapsing-remitting multiple sclerosis who switch from natalizumab to delayed-release dimethylfumarate a multicenter retrospective observational study (STRATEGY) Mult SclerRelat Disord 20182227ndash34

16 Calabrese M Pitteri M Farina G et al Dimethyl fumarate a possible exit strategyfrom natalizumab treatment in patients with multiple sclerosis at risk for severeadverse events J Neurol Neurosurg Psychiatry 2017881073ndash1078

17 Zurawski J Flinn A Sklover L Sloane JA Relapse frequency in transitioning from natali-zumab to dimethyl fumarate assessment of risk factors J Neurol 20162631511ndash1517

18 Edwards KR Kamath V OrsquoConnor J Switching From Natalizumab to Teriflunomidein Multiple Sclerosis Patients Who Have Received Natalizumab for More Than 12Months Abstract presented at 2014 CMSC ACTRIMS Annual Meeting May 292014 Dallas TX Available at cmscconfexcomcmsc2014webprogramPa-per2464html Accessed July 16 2019

19 Gobbi C Meier DS Cotton F et al Interferon beta 1b following natalizumab discon-tinuation one year randomized prospective pilot trial BMC Neurol 201313101

20 Havla J Gerdes LA Meinl I et al De-escalation from natalizumab in multiple scle-rosis recurrence of disease activity despite switching to glatiramer acetate J Neurol20112581665ndash1669

21 Rossi S Motta C Studer V et al Effect of glatiramer acetate on disease reactivation inMS patients discontinuing natalizumab Eur J Neurol 20132087ndash94

22 Mancinelli CR Scarpazza C Santuccio G et al Dealing with highly active multiplesclerosis after natalizumab-associated PML could rituximab be of help Neurol Sci201839965ndash966

23 Malucchi S Capobianco M Lo Re M et al High-risk PML patients switching fromnatalizumab to alemtuzumab an observational study Neurol Ther 20176145ndash152

24 Rosenbaum R Rubin DB The central role of the propensity score in observationalstudies for causal effects Biometrika 19837041ndash55

25 Hersh CM Love TE Bandyopadhyay A et al Comparative efficacy and discontin-uation of dimethyl fumarate and fingolimod in clinical practice at 24-month follow-upMult Scler J Exp Transl Clin 201732055217317715485

26 Vollmer B Nair KV Sillau SH Corboy J Vollmer T Alvarez E Comparison offingolimod and dimethyl fumarate in the treatment of multiple sclerosis two-yearexperience Mult Scler J Exp Transl Clin 201732055217317725102

27 Vollmer B Ontaneda D Bandyopadhyay A et al Discontinuation and comparativeeffectiveness of dimethyl fumarate and fingolimod in 2 centers Neurol Clin Pract20188292ndash301

Appendix Authors

Name Location Contribution

Carrie MHersh DO MSc

Cleveland Clinic Lou RuvoCenter for Brain Health

Drafted and revised themanuscript for intellectualcontent and contributed tothe study concept designacquisition analysis andinterpretation of the data

Haleigh HarrisBA

Cleveland Clinic Lou RuvoCenter for Brain Health

Contributed to the dataacquisition

Appendix (continued)

Name Location Contribution

DevonConway MD

Cleveland Clinic MellenCenter

Contributed to the studyconcept interpretation ofthe data and revision of themanuscript

Le H Hua MD Cleveland Clinic Lou RuvoCenter for Brain Health

Contributed to the studyconcept interpretation ofthe data and revision of themanuscript

e64 Neurology Clinical Practice | Volume 10 Number 6 | December 2020 NeurologyorgCP

28 Fox RJ Chan A Zhang A et al Comparative effectiveness using a matching-adjustedindirect comparison between delayed-release dimethyl fumarate and fingolimod forthe treatment of multiple sclerosis Curr Med Res Opin 201733175ndash183

29 Prosperini L Lucchini M Haggiag S et al Fingolimod vs dimethyl fumarate inmultiple sclerosis A Real-World Propensity Score-Matched Study Neurology 201891e153ndashe161

30 Wicks P Rasouliyan L Katic B Nafees B Flood E Sasane R The real-world patientexperience of fingolimod and dimethyl fumarate for multiple sclerosis BMC ResNotes 20169434

31 Rudick RA Cutter G Reingold S The multiple sclerosis functional composite a newclinical outcome measure for multiple sclerosis trials Mult Scler 20068359ndash365

32 Kragt JJ van der Linden FA Nielsen JM Uitdehaag BM Polman CH Clinical impactof 20 worsening on timed 25-foot walk and 9-hole peg test in multiple sclerosisMult Scler 200612594ndash598

33 Kroenke K Spitzer RLWilliams JB The PHQ-9 validity of a brief depression severitymeasure J Gen Intern Med 200116606ndash613

34 Schwartz CE Vollmer T Lee H Reliability and validity of two self-report measures ofimpairment and disability for MS North American Research Consortium onMultipleSclerosis Outcomes Study Group Neurology 19995263ndash70

35 Team RC R A Language and Environment for Statistical Computing Vienna RFoundation for Statistical Computing 2014

36 Rubin DB Using propensity scores to help design observational studies applica-tion to the tobacco litigation Health Serv Outcomes Res Methodol 20012169ndash188

37 Plavina T Muralidharan KK Kuesters G et al Reversibility of the effects of natali-zumab on peripheral immune cell dynamics in MS patients Neurology 2017891584ndash1593

38 Cree B de Seze J Fox R et al Natalizumab effects during a 6 month dose in-terruption relationship of pharmacokinetic (PK) pharmacodynamic (PD) and MRImeasurement Neurology 201380S41003

39 Miravalle A Jensen R Kinkel RP Immune reconstitution inflammatory syndrome inpatients with multiple sclerosis following cessation of natalizumab therapy ArchNeurol 201168186ndash191

40 Villaverde-Gonzalez R Gracia Gil J Perez Sempere A et al Observational study ofswitching from natalizumab to immunomodulatory drugs Eur Neurol 201777130ndash136

41 Comi G Gold R Dahlke F et al Relapses in patients treated with fingolimod afterprevious exposure to natalizumab Mult Scler 201521786ndash790

NeurologyorgCP Neurology Clinical Practice | Volume 10 Number 6 | December 2020 e65

DOI 101212CPJ0000000000000809202010e53-e65 Published Online before print February 12 2020Neurol Clin Pract

Carrie M Hersh Haleigh Harris Devon Conway et al practice

Effect of switching from natalizumab to moderate- vs high-efficacy DMT in clinical

This information is current as of February 12 2020

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