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Induction or escalation therapy for patients with multiple sclerosis?
Emmanuelle Le Page, Gilles Edan
To cite this version:
Emmanuelle Le Page, Gilles Edan. Induction or escalation therapy for patients with multiple sclerosis?.
Revue Neurologique, Elsevier Masson, 2018, 174 (6), pp.449-457. �10.1016/j.neurol.2018.04.004�. �hal-
01833126v2�
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Multiple sclerosis on behalf SFSEP
Induction or escalation therapy for patients with multiple sclerosis?
E. Le Page * , G. Edan
CIC-P02-03Inserm,INCR,Departmentofneurology,CHUdeRennes,2,rueHenri-le-Guilloux,35000Rennes,France
abstract
Theconceptofinductionfollowedbyalong-termmaintenancetreatmenthasattracted muchattentionforthetreatmentofmultiplesclerosisoverthe30pastyears.Itwasfirst demonstratedbythecombinationofinductiontherapywithmitoxantrone(six-monthly courses)followedbymaintenancetherapywithanimmunomodulatorytreatmentsuchas aninterferon-borglatirameracetate.Long-termobservationalstudiesconfirmedthatthis therapeuticregimenprovidesarapidreductionindiseaseactivityandsustaineddisease controluptoatleastfiveyearsin60%ofpatients.Abettertreatmentresponsewasobserved inpatientswithearlysignsofaggressivedisease,asshowninrandomisedstudies(usingsix- monthly 12mg/m2 of mitoxantrone intravenously at a cumulative dose of 72mg/m2, followedbyaninterferon-b)aswellasinlong-termobservationalstudies.Butthesafety profileofmitoxantronemakeitmoreparticularlysuitableforyoungpatientswithfrequent earlyrelapseswithincompleterecoveryandmultiplegadolinium-enhancingT1lesionsor spinalcordlesionsonmagneticresonanceimaging.Morerecentlyapproved,thesecond candidateforaninductionstrategyisalemtuzumab:phasesIIandIIIrandomisedstudies showedthesuperiorityofalemtuzumab12mgperdaygivenintravenouslyforonlyfivedays andrepeatedfor3daysoneyearlater,comparedwithinterferon-bthreetimesaweek.Like withmitoxantrone,resultssupportedtheconceptoflong-termbenefitafterashortinduc- tionratherthanescalation,inasubsetofpatientswithearlyveryactiveMS,withasustained controlofthediseaseforupto7yearsin60%ofpatientsinthephaseIIIextensionstudies andinalong-termobservationalstudy.Onthecontrary,whenalemtuzumabwasfirst studied later in the disease course, results were disappointing. However, the risk of developingmanageablebutpotentiallyseveresystemicautoimmunediseaseswithinthe yearsfollowingthelastcourseofalemtuzumabmakeit,likemitoxantrone,moresuitable forpatientswithearlyaggressiveMS.Morerecently,cladribineanoralimmunosuppressant, showedinterestingresultsinaphaseIIIstudyextensionsuggestingitspotentialinduction effect,sinceaftertwocyclesoftreatment(5daysrepeated1monthlater)atoneyearof interval,theremainedlowupto4yearsoffollow-up,intheabsenceofanynewtreatment.
However,todayotherimmunosuppressivedrugshaveprovedtobestronglyandrapidly efficaciousintreatinghighlyactiveMSpatientsbutthroughamechanismofcontinuous immunosuppression (i.e., natalizumab and ocrelizumab). Indeed, disease activity can reappearrapidlyafterstoppingthesedrugs,sometimesassociatedwithareboundofthe
* Correspondingauthor.Servicedeneurologie,CHUPontchaillou,35033Rennescedex,France.
E-mailaddress:emmanuelle.lepage@chu-rennes.fr(E.LePage).
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1. Definitions of escalation and induction
Theconceptofinductiontreatmentfollowedbyalong-term maintenancetreatmentcombiningdifferentdrugswasfirst demonstrated in oncology. For example, in acute lympho- blasticleukaemia,theuseofinductionregimensassociating bonemarrowtransplantationandcombinationsofcytotoxic drugshasraisedevent-freesurvivalratesover80%afterfive yearsinyoungpatients,whilethisconditionwaspreviously rapidly fatal [1]. InMS,intheory two oppositeschemes of therapeuticstrategiesusingthedifferentdisease-modifying drugs(DMD)availablecanbediscussed[2–4]:theescalating approachandtheinductiontherapy.Aninductiontherapyis associated with a more aggressive effect on the immune systemthat seemstohave morerelevant short-andlong- lastingbeneficialeffects.Thisoldconceptisprobablycloseto the emerging concept of ‘‘Pulsed immune reconstitution therapy’’(PIRT)forthetreatmentofMS[5].
1.1. Escalatingtreatment
Escalating treatmentmeans tostartwiththesafest DMDs.
Iftheyfailed,theescalationtomoreaggressivesecond-line and then third-line DMDs is warranted. The escalating approachseesasfirst-linetreatmentglatirameracetateand beta-interferons,teriflunomid,dimethylfumarate,andeven- tually fingolimod. Second-line DMDs, i.e. natalizumab and ocrelizumab are responsible for a selective continuous immunosuppression. Third-line DMDs i.e. mitoxantrone andalemtuzumabarerespectivelynon-selectiveandselective PIRT.Finally,moreintensiveimmunosuppressionwithauto- logous bone marrow transplantation and high dose cyclo- phosphamidecanbeconsideredaslastlineofrescuetherapy.
Recentlyapproved,daclizumabandcladribinemaycomplete this therapeutic panel,probably assecond-line treatments.
The advantage of escalation scheme is to allow many patients to have a satisfying control of the disease while receivingrelativelysafedrugsandneverescalatingtomore aggressivetherapy.Butthedisadvantageistoexposesome patientstotheriskoflosingpreciousyearsspentreceivinga treatmentthatwasnotpotentenoughandpotentiallyleading tosustainedaccumulationofdisability.Thenthekeytothe successoftheescalationstrategyistodefineupfrontwiththe patienttheexactsuboptimalresponsethresholdatwhichthe next-leveltherapeuticoptionshouldbeintroduced,without crossingthelineofirreversiblefurthersequelae.
1.2. Inductiontreatment
Inductiontreatmentmeanstostartwithastrongimmune- intervention.Theadvantageistofacilitateanearlierachie- vementof‘‘noevidenceofdiseaseactivity’’,whichisthegold standardforMStreatmentinsomeschoolsofthoughts.But the disadvantage is the risk to expose some patients needlessly toserioussideeffectsthatarewellknownwith thestrongestimmunosuppressiveagentsforMS.Thenthekey to thesuccess ofinduction strategyis touse immunosup- pressantsfortheminimumamountoftimeneededtogain adequate controlover disease activity, i.e., tostart with a strong immunossuppression followed by a maintenance therapy with safer drugs for a de-escalation. Considering thepotentialserioussideeffectsoftheimmunosuppressive therapeutic candidates for an induction, this strategy has generally been reserved for patients with very active or aggressivediseaseatonset.Inthesepatients,itisrecognised that the risk of early disability is high and that once neurological function islost it cannot berestored. Insuch patients, this disease-inherent risk can be considered to outweightheriskofpotentialserioussideeffectsofpowerful immunosuppressant drugs. The aim of this strategy is to prevent early structural damage related to inflammatory- mediated demyelination and axonal loss. This induction treatmentstrategymaybeausefulandconservativewayto usethesehighlyeffectivetherapieswhileminimisingexpo- sureandthesubsequentsafetyrisks.
2. Patients candidates for an induction strategy
Over the past two decades, important epidemiological, radiological and therapeutic studies provided evidence for theconceptofearlytreatmentinpatientswithadiagnosisof MS,whichissharedbyConsensusGroups.ThegoalofDMDsis topreventaccumulationofsustainedneurologicaldisability and inparticulartopreventfromtheriskoftransition toa secondaryprogressive(SP)MS.Today,theprognosticfactors associated witha highrisk oflong-term disabilityarewell established and there is strong evidence that it is mostly definedintheearlyphaseofthedisease.Itnowseemsclear thatpatientswhoexperiencefrequentrelapsesintheearliest stagesofdiseaseandthosewhoaccumulatealargenumberof T2focal lesionsvisibleon MRI,withparticular concernfor spinalcordlesions,becomedisabledmorequicklythanthose inflammatoryprocess,whichisthecontraryofamechanismofinductionthatisassociated
witharemnanteffect.Takingintoaccountadvantagesanddisadvantagesofthedifferent DMDs,whichenrichedthetodaytherapeuticarsenalforMS,weproposeinthispapersome algorithmssummarizingourreflexionaboutusinganescalationstrategyoraninduction strategyaccordingtodiseasecourseandactivity.
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whodonot[6–8].ThisiswellillustratedbytheconceptofMS asatwostagediseasewithafirstphasedependingoffocal CNSinflammatorylesionsandasecondphaseindependent from focal CNS inflammatory lesions but driven by a neurodegenerative process [6]. Because the target of all approvedDMDsis thefocal inflammation,whichpredomi- natesatthebeginningofthediseasecourse,itislogicalto concentrateallthetherapeuticeffortsintheearly(first)phase ofthedisease.Indeed, if somepositiveeffectwas recently describedinprogressiveformsofMSwithocrelizumaband siponimod [9,10], results should be interpreted cautiously because whenconsidering patients without anyclinical or radiologicalsignofinflammation,currentDMDsmightnotbe expected to be as effective while the focal inflammatory processislessrelevantandtheiractionontheneurodegene- rativeprocessuncertain.Thisisprobablybecausetheimmune derangement characterising MS increases over time and probably alsoshift froma peripheralimmune-pathological profiletoacentralnervoussystemcompartmentalisedprofile inlateMS[11].Havingsaidthat,shouldweconsiderthatthe initialtreatmentofearlyactiveRRMSshouldbewithapotent inductiontherapyratherthanstandardimmunomodulation thenescalationformostpatientswithearlyRRMS,moving fromtheconceptof‘‘earliertreatmentbetterforRRMS’’tothe conceptof‘‘earliermaximallyefficacioustreatmentbetterfor RRMS’’?No,thisapproachshouldbeconsideredforaselected groupofRRMSpatientshavingnegativeprognosticfactors[4]:
pure relapsing MS, young, highly active with2 relapses within the previous12 months,severerelapse resulting in EDSS score4, worsening EDSS score due to relapses (increase of2points within the previous12 months,2 additionalgadolinium-enhancinglesions)(re´farticledrugs).
Furthermore, an interesting algorithm proposed by the MAGNIMSgroupcan beusedtoidentify patientsat riskof disability worsening according to clinical and radiological markers of MS activity recorded during the first year of treatment with a first-line DMD [12]. This algorithm was determinedonthebasisof1280naı¨vepatients,treatedforat leastoneyearwithaninterferon-betaandfollowedfortwo additionalyears.Thepercentageofpatientswithincreased EDSSscoreduringthetwofollowingyears wereof22%for patientshavingonerelapse or3newT2lesions(score1) duringthefirstyearand29%forpatientshavingonerelapse and3newT2lesions(score2)duringthefirstyear.These results provide a useful daily life tool for monitoring the responsetoafirst-linetreatmentandthepotentialneedto switchtoanotherDMD.Takingintoaccounttheseconside- rations,somestrategicpropositionsaresummarizedforusing DMDsinFigs.1and2:howtostartaccordingtoclinicaland radiologicalactivityduringthe12previousmonthsandhowto switchusingthescoreofSormani[12]duringafirstyearof exposuretoafirst-linetherapy:intypicalRRMSpatients,start withafirst-linetherapy;inhighlyactiveMSpatients,start with a second-line therapy preferring natalizumab and ocrelizumab in JCvirus negative patientsfor a continuous immunosuppression,orwithmitoxantroneandalemtuzumab inJCviruspositivepatientsforapulsedimmunereconstitu- tionwitharemnanteffecteventuallyfollowedbyamainte- nancetherapy.Aswitchtoanotherfirst-linetherapymightbe consideredfor patientshavinga score1of Sormaniand a
switchtoasecond-orthird-linetherapymightbeconsidered forpatientshavingascore2ofSormaniduringthefirstyearof afirst-lineDMDtherapy.
3. Three drugs can be considered to have an induction effect
Mitoxantronewasthefirstdrugstudiedinaninductionprotocol schemeinrelapsingMSandwasforalmost10yearstheonly immunosuppressanttobeapprovedinthisindicationinmost countries.Indeed,mitoxantronewaslicensedinOctober2000by theFoodandDrugAdministration(FDA)inworseningRR,SPand relapsing progressive MS patients and in several European countriesin2002,tobeadministeredeverythreemonths(12mg/
m2;maximumcumulativedose140mg/m2).Then,inOctober 2003theAgencefranc¸aisedese´curite´ sanitairepourlesproduits de sante´ (AFSSAPS)approved mitoxantrone for treatment of aggressiverelapsingMSgivenmonthlyfor6months(12mg/m2; maximumcumulativedose72mg/m2).Inconsequence,thereis long-termdatatosupportitsstrongrapidandsustainedefficacy intheindicationofrelapsingaggressiveMStakingintoaccount itssafetyprofilethatiswelldocumented[13–17].Inthe2000s, phases II and III studies [18–21] were designed to compare Fig.2–Whenandhowtoswitch?GA:glatirameracetate;
IFN-b:interferon-beta;DMF:dimethylfumarate;JCS: seronegativeforJCvirus;PIRT:pulsedimmune reconstitutiontherapy.
Fig.1–Startingadisease-modifyingdrug(DMD)inRRMS accordingtoclinicalandMRIactivityduringtheprevious 12months.GA:glatirameracetate;IFN-b:interferon-beta;
DMF:dimethylfumarate;JCS:seronegativeforJCvirus;
PIRT:pulsedimmunereconstitutiontherapy.
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alemtuzumabwithinterferon-beta3timesaweekinactiveMS patients,showingarapidstrongandsustainedactiononthe inflammatoryprocessanddecreasedriskofsustaineddisability worseningmorespecificallyinpatientswhowerenonrespon- ders toafirst-lineDMD.Alemtuzumab wasapprovedbythe FDA in November2011and in Europein September 2013in relapsingMS, givenatthe doseof 12mgper dayfor5days repeatedduringthreedays1yearlater.Butiflong-termfollow- upofpatientsconfirmedtheremnanteffectofthedrugwith sustainedefficacy,severeautoimmuneadverseeffectswerewell documented.Alemtuzumabmightthenbelikemitoxantronea good candidate for induction therapy in young early highly activerelapsingMSpatients.Morerecentlycladribine,anoral immunosuppressant, was approved in august 2017 by the EuropeanMedicinesAgency(EMA)inpatientswithveryactive relapsingMS,onthebasisoftwophaseIIIstudiesversusplacebo andtheir extensions [22,23]. Thedrug might alsobe a good candidatefor an induction therapeuticscheme becauseit is given at the dose of 3.5mg/kg as following: 5 days of oral treatmentthefirstmonthandthesecondmonth,followedby thesameschemethesecondyear,witharemnanteffectthe thirdandfourthyears.
Thesethreedrugsshowedaveryrapidsignificantcontrolof theinflammatoryprocess,morespecificallyinhighlyactive MSpatientsformitoxantroneandalemtuzumab,sustainedfor severalyearsafterashortadministration ofthetreatment, withmaintenancetherapy withasaferdruginthecaseof mitoxantrone,thereareindeedfewstudiesonthelong-term efficacyof induction strategies followed by amaintenance therapy [15–17]. Theseobservationssupport thehypothesis thatthesethreedrugscanbeclassifiedasPIRT.
On the contrary, natalizumab a highly selective strong approved immunosuppressive drug in MS [24], cannot be recommendedforinductionusebecauseitswithdrawalwas commonlyfollowedwithinfewmonthsbythereoccurrenceof disease activity [25,26]. The anti-CD20 ocrelizumab is not eitheragoodcandidateforaninductionstrategy sincethe treatmenthastobeadministeredevery6months[27]toavoid thereoccurrenceofdiseaseactivity.
3.1. Mitoxantrone:thefirsttreatmenttodemonstratean inductionaction
Mitoxantrone, an anthracenedione, is a synthetic antineo- plasticagentfirstdiscoveredin1978.Ithasproventherapeutic efficacyinadvancedbreastcancer,non-Hodgkin’slymphoma, acutelymphoblasticleukemia,chronicmyeloidleukemiaand liverandovariancarcinomas[28–32].Soonafteritsintroduc- tionasacytotoxicagentincancerchemotherapy,itwasfound tobeimmunosuppressive.Wangetal.showedthatinvitro alloreactivitywasalmostcompletelyabrogatedbymitoxan- trone.Thedruginterferedonlywithlymphocytescapableof proliferatinginresponsetonewlypresentedantigenswithout affectingprecursorpopulations.Theeffectswereremarkably long-lasting[33,34].ThenthedrugwasstudiedinMSforits immunosuppressiveproperties.
3.1.1. Thepivotaltrial[13]
The French and British randomised controlled trial [9], evaluatedtheshort-termbenefitsofmitoxantronetreatment
forsixmonthsin42patientswithveryactiveRRorSPMS, definedasthe occurrenceoftwoor morerelapseswithout recoveryordisabilityprogressionbymorethantwopointsin the previoustwelvemonths,togetherwithMRIevidenceof active disease. Patients wererandomised to receive either mitoxantrone (20mg)and methylprednisolone(1g) intrave- nously every month or methylprednisolone alone oversix months.Theprimaryoutcomewastheproportionofpatients developingnewgadolinium-enhancingT1lesionsonmonthly MRI scans. In the mitoxantrone group, the proportion of patients without new enhancing lesions (90%)was signifi- cantlyhigherthaninthecontrolgroup(31%).Sixty-sixpercent ofpatientsinthemitoxantronegroupremainedrelapse-free duringthesix-monthtreatmentperiod,comparedto33%in thecontrolgroup.Indeed,atotalof31relapseswererecorded inthecontrolgroup,correspondingtoanannualisedrelapse rateof3.0,similartothatobservedbeforetreatment,whereas inthemitoxantronegroup,onlysevenrelapseswererecorded (annualised relapse rate of 0.7). Similarly, with respect to disability progression, twelve out of 21 patients in the mitoxantrone group improvedbyat leastonepoint onthe EDSS andonlyonedeteriorated. Incontrast,inthecontrol group,sixdeterioratedandonlythreeimproved.
3.1.2. Long-termefficacyofmitoxantrone
Anobservational5-yearfollow-upstudy[14].Followingthe successfulcompletionofthepivotaltrialdescribedabove,an observationalstudywas performedinRennes’sMScentre, evaluatingprospectivelyfor5yearsonehundredconsecutive highlyactiveRRMSpatients,usingtheFrenchregimen[9].
Themajorityofpatients(73%)were assignedtoamainte- nance treatment following induction with mitoxantrone.
In 21 patients, this consisted of quarterly boosters with mitoxantrone. Themajority of the remainder received an immunomodulatory treatment, principally aninterferon-b preparation, since glatiramer acetatewas notavailable in France for most of the recruitment period. In the year preceding treatment, the annualised relapse rate in the patientgroupwas3.29,andtheEDSSscorehadincreasedbya mean of 2.2 points. In addition, gadolinium-enhancing lesions were visible on MRI for84% of the sample.These patientsthuspresentedveryactivedisease.Inthefirstyear following the first administration of mitoxantrone, the annualised relapse rate declined to0.29 andwasreduced by 91%.This reductionwas maintained overthe five-year observation period, the annual relapse rate oscillating between0.3and0.4.Aroundone-thirdofpatientsremained freeofrelapsesforthefive-yearperiod,withamediantimeto firstrelapseof2.72year.Likewise,theproportionofpatients whose disabilitydeteriorated by atleast onepoint on the EDSS,confirmedatthreemonths,decreasedfrom88%inthe yearprecedingtreatmentto5%overthefirstyear.Overall, disability improvedor stabilised in59% ofpatientsthrou- ghout the five-year observation period.Potential determi- nants of a good treatment response were evaluated: the proportionofpatientswhosedisabilityworsenedatoneand two years was significantly lower (P<0.007) in patients whose EDSS score was4 when treatment was started.
Moreover, the fivepatientswhoworsened during the first year of treatment were significantly older (P<0.02) when
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treatmentwasstarted(41years)thanthosewhosedisability stabilisedorimproved(32years).Thetwentypatientswho converted to a secondary progressive course during the follow-upperiodweresignificantly(P<0.02)moredisabled (meanEDSSscore:4.8)atthestartoftreatmentthanthose whodidnot(meanEDSS score:3.9).Alltheseobservations indicatethatmitoxantroneismoreeffectiveinthelong-term whenstartedearlyinthedisease.
3.1.3. Schemeofinductiontherapywithmitoxantrone, followedbyamaintenancetreatmentwithinterferon-b[15]
A French-Italian randomised controlled trial comparing induction with mitoxantrone followed by maintenance therapy withinterferon-b 1b tomonotherapy with interfe- ron-b1bincludedpatientswithRRMSwhohadexperiencedat leasttworelapseswithincompleterecoveryintheprevious year and who displayed gadolinium-enhancing lesions on MRI.Fifty-fivepatientswererandomisedtothemitoxantrone inductionregimenusedinthepreviousstudiesforsixmonths, followedbyathee-monthwash-out period andthen inter- feron-b 1b. The other study arm (54 patients) received interferon-b1bforthreeyearscombinedwithmethylpredni- solone 1g for the first six months. The clinical and demographic features of the patients at inclusion were comparableinthetwogroups.Patientsunderwentacomplete neurologicalexaminationeverythreemonthsandspin-echo MRIatinclusionandmonths9,24and36.Araterblindedto treatment assignment evaluated the MRI scans. Compared withtheinterferon-betagroup,inthemitoxantronegroupthe timetosustained1EDSSpointworseningwasdelayedby18 months(P<0.012).The3-yearriskofsustaineddisabilitywas reducedby65%(12%vs.34%).Thenumberofpatientsneeded to be treated with mitoxantrone before interferon-beta to avoidonesustaineddisabilityeventduringthe36monthswas six.ThemeanEDSSwasimproved by0.45pointatthelast observation in the mitoxantrone group (from 4.16 to 3.66;
P<0.007),and remained unchanged in the interferon-beta group(from3.86to3.76P=0.771).Whenconsideringthelevel ofdisabilityatscreening(EDSS4vs.EDSS>4),the3-year risksofsustainedworsening wererespectively3.9%,30.8%, 22.3% and 40.3% inpatients with baselineEDSS4 inthe mitoxantroneandinterferon-betagroups,andinpatientswith EDSS>4inthemitoxantroneandinterferon-betagroups.The studysuggestedthat thisinduction strategywithmitoxan- tronemaybemoreeffectiveinpatientswithalowerdisability.
Theproportionofpatients whoremained relapse-freewas increasedinthemitoxantronegroup(P<0.008).Frombaseline to the last observation in the mitoxantrone group, the annualisedrelapse ratewas lower(0.4 vs.1.1P<0.03)and the time to first relapse after treatment institution was delayed by 21 months compared with the interferon-beta group(P<0.001).Theproportionofpatientswhoremained freeofrelapsesthroughoutthefollow-upperiodwas53%in the induction group and 26% in the interferon-beta group (P<0.01).OnMRI,themeannumberofnewT2lesionswas significantlylowerinthemitoxantronegroupateachofthe timepoints, aswellasthemean number ofGd-enhancing lesionsatmonth9(P<0.012),andthepercentageofpatients withoutanyGd-enhancinglesionwashigherinthemitoxan- tronegroup(P<0.010).
3.1.4. Schemeofinductiontherapywithmitoxantrone, followedbyamaintenancetreatmentwithglatirameracetate [17]
InthissmallcontrolledstudyfortyRRMSpatientswith1–15 gadolinium-enhancing lesions on screening brain MRI and EDSS scores 0–6.5, were randomized to receiveshort-term inductiontherapywithmitoxantrone(threemonthly12mg/
m2 infusions) followed by 12 months of daily glatiramer acetate(GA)therapy20mg/daysubcutaneously(M-GA,n=21) ordailyGA20mg/dayfor15months(GA,n=19).MRIscans were performed at months 6, 9, 12 and 15. The primary measure of outcome was the incidence of adverse events;
secondary measures included number of Gd-enhanced lesions, confirmed relapses and EDSS changes.Except age, baselinedemographiccharacteristicswerewellmatchedin both treatmentarms. Bothtreatmentswere safeand well- tolerated.M-GAinductionproducedan89%greaterreduction [relative risk (RR)=0.11, P=0.0001] in the number of Gd- enhancing lesionsat months6and 9and a70% reduction (RR=0.30,P=0.0147)atmonths12and15versusGA alone.
Mean relapserateswere0.16and 0.32intheM-GA andGA groups,respectively.
3.1.5. Mitoxantronesafetyprofile[16]
From 2001, a French multicentre study was conducted prospectivelyinalargecohortofMSpatientsandannually updateduptoatleast5yearsafterinitiationofmitoxantrone therapyinordertodetermineitslong-termsafetyprofilein MS.Eighthundredandtwopatientsfrom12MScentres(308 RR,352SPand142PP)receivedmitoxantronemonthlyfor6 months(87%)orevery3months(13%).Patients underwent clinical andhematologic evaluationsbeforeeverymitoxan- trone infusionand every 6–12 monthsup to 5 years after mitoxantronestart.Echocardiogramswereperformedatthe startand endofmitoxantrone andupto5years after.The cohortwasfollowedfor5354patient-years(mean).Oneoutof 802 patients (0.1%) presented with acute congestive heart failure and 39 out of 794 patients (4.9%) presented with asymptomatic left ventricular ejection fraction reduction under 50% [persistent in 11 patients (28%), transient in 27 patients(69%),onthelastscanatyear5in1patient].Two casesoftherapy-relatedleukaemia(0.25%)weredetected20 monthsafterMITOXstart(onedeathandonewithmorethan 10 years confirmed remission). Of the 317 women treated before the age of 45, 17.3% developed a persistent age- dependantamenorrhea(5.4%before35-year-old,30.7%after 35-year-old).Thisistheonlyoneprospectivepublishedstudy ofalargecohortwithatleast5yearsoffollow-up.Itprovided goodinsightsintothelong-termsafetyprofileoftheuse of mitoxantrone according tothe French induction treatment protocolinMSpatients.
Thesestudiesusingamitoxantroneinductionregimenin patientswithveryaggressiveRRMSsuggestthatthiscanbe beneficialforreducingstronglydiseaseactivity,particularly whenfollowedbyamaintenancetherapywithasaferdisease- modifyingimmunomodulatorytreatment.Withthetreatment protocol recommended for use in France (six-monthly administrations ofmitoxantrone ivat acumulativedose of 72mg/m2), mitoxantroneisgenerallywell-toleratedbut the risk of leukaemia and of decrease of the left ventricular
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ejectionfraction justifytomonitorwhite blood cells count everythreemonthsandthecardiacfunctionbyechocardio- gram every year for 5 years after the last course of mitoxantrone.
3.2. Alemtuzumabasaninductiontreatmentinmultiple sclerosis
Firstlicensedfortreatmentofpatientswithchroniclympho- cyticleukaemia,alemtuzumab (initiallycalledCampath-1H) was assessed inMS from1991. Thishumanizedanti-CD52 monoclonalantibodyinducesanimmune-mediatedrapidand profounddepletionoflymphocytes,followedbydifferential recovery of lymphocyte subsets characterized by a rapid recovery ofanormalB-cellsnumber within 3months,but prolongedandsustainedsuppressionofCD4Tcells[35].First studiedinprogressiveactiveformsofMS,thedrugshoweda rapidandsustainedcontrolofthefocalinflammatorymarkers ofMSactivitybutfailedtostoptheprogressiveaccumulation ofdisability[36,37].Forthisreason,theideaofmovingtoan earlieruseofthetreatmentconductedtodesignphasesIIand IIIstudies[18–20]inthe2000stofocusonearlyhighlyactiveRR MSpatientswhowerenaı¨veorsuboptimalresponderstoa first-lineofDMD.Thethreestudieswerecontrolledcompared toreferenceDMDavailableatthattime,i.e.interferon-beta.
Thesethreelargeandwell-designedcontrolledtrialssupport itsuseasaninductiontreatmentinearlyhighlyactiveRRMS andmoreparticularlyinpatientswhofailedtorespondtoa first-lineofDMD.
3.2.1. ThephaseIIrandomisedtrialCAMMS223[18]
Threehundredandthirty-fourpreviouslyuntreatedearlyRR MSpatientswithEDSSscores3.0andadiseaseduration3 years were randomized to receive either subcutaneous interferon-beta-1a(atadoseof44mg)threetimesperweek orannualintravenous5daycyclesofalemtuzumab(atadose ofeither12mgor24mgperday)for36months.InSeptember 2005, alemtuzumab therapy was suspended after immune thrombocytopenicpurpuradevelopedinthreepatients,oneof whom died.Alemtuzumab significantlyreducedthe rateof sustainedaccumulationofdisabilityby71%,ascomparedwith interferon-beta-1a(9.0%vs.26.2%;P<0.001)andtheannua- lizedrateofrelapseby74%(0.10vs.0.36;P<0.001).Themean EDSSscoreimprovedby0.39pointinthealemtuzumabgroup andworsenedby0.38pointintheinterferon-beta-1a group (P<0.001).Inthealemtuzumabgroup,theT2lesionburden wasreduced,ascomparedwiththatintheinterferon-beta-1a group(P=0.005).Frommonth12tomonth36,brainvolume increased in the alemtuzumab group but decreased inthe interferon-beta-1agroup(P<0.02).
3.2.2. TheCARE-MS1phaseIIItrial[19]
Inthis2yearrandomisedtrial,581MSpatientsaged18–50 years with previously untreated RR MS were randomly allocated to receive intravenous alemtuzumab 12mg per daygivenfor5daysatbaselineandfor3daysat12months,or subcutaneousinterferon-beta-1a44mgthreetimesperweek.
Coprimaryendpointswererelapserateandtimeto6month sustained accumulation of disability in all patients who receivedatleastonedoseofstudydrug.Seventy-fiveoutof
187 (40%)patientsinthe interferon-beta-1a grouprelapsed (122events)comparedwith82outof376(22%)patientsinthe alemtuzumab group(119events;rateratio045;P<0.0001), corresponding toa549%improvementwithalemtuzumab.
Fifty-ninepercentofpatientsintheinterferon-beta-1agroup wererelapse-freeat2yearscomparedwith78%ofpatientsin the alemtuzumab group (P<0.0001). However, benefit in terms of disabilityendpoints notedin CAMMS223was not observedhere:20(11%)ofpatientsintheinterferon-beta-1a group had sustained accumulation of disability compared with30 (8%)inthealemtuzumab group(hazard ratio:0.70;
P<0.22).
3.2.3. TheCARE-MS2phaseIIItrial[20]
Inthis2yearrandomisedtrial,638patientswithRRMSandat leastonerelapseoninterferon-betaorglatirameracetatewere selected. Eligible participants were randomly stratified to receive either subcutaneous interferon-beta-1a 44mg three timesperweek,orintravenousalemtuzumab12mgor24mg perdayfor5daysatbaselineandfor3daysat12months.
Coprimaryendpointswererelapserateandtimeto6month sustained accumulation ofdisability, comparing alemtuzu- mab12mgandinterferon-beta-1ainallpatientswhoreceived atleastonedoseofstudydrug.Onehundredandfouroutof 202 (51%)patientsinthe interferon-beta-1a grouprelapsed (201events)comparedwith147outof426(35%)patientsinthe alemtuzumabgroup(236events;P<0.0001),correspondingto a49.4%improvementwithalemtuzumab.Ninety-four (47%) patientsintheinterferon-beta-1agroupwererelapse-freeat2 yearscomparedwith278(65%)patientsinthealemtuzumab group(P<0.0001).Forty(20%)patientsintheinterferon-beta- 1agrouphadsustainedaccumulationofdisabilitycompared with54(13%)inthealemtuzumabgroup(hazardratio:0.58;
P=0.008), corresponding to a 42% improvement in the alemtuzumabgroup.
3.2.4. Alemtuzumablong-termefficacyandsafetyinphasesII andIIItrialsextensions[38,39]
Patientswho completedthe corephasesII andIIIstudies wereeligibletoenrollinalong-termextensionstudyinwhich theycouldreceive retreatmentwithalemtuzumab, if they met specific disease activity criteria: 1 protocol-defined relapse, or2 new/enlarging T2 hyperintense or new gadolinium (Gd)-enhancingT1brain orspinal cordlesions onMRI.OtherDMTscouldbeadministeredattheinvestiga- tor’sdiscretion.FortheCARE-MSstudies,dataareavailable for6yearsoftreatment(2yearsofthecorestudyplus4years of the extension). For the CAMMS223 study, patients completing the3-yearcore studycouldenter anextended follow-upperiod(minimumadditional2years),andthenin 2010, they could enroll in the same extension study as patients from the CARE-MS studies, for a total available follow-up of10 years. Ifwe focuson long-term results in patientswhoreceived alemtuzumabwhilethey weresub- optimalresponderstoaDMD(CARE-MS2patients),393outof 435 entered the extension, and 344 remained on study throughYear6.Fifty-fivepercentofpatientsrequiredonly theinitialtwocoursesofalemtuzumabwith30%,12%,2%, and 1% receiving a third, fourth, fifth, or sixth course, respectively.Investigatorscitedrelapseasthemostcommon
Accepted
manuscritpt
reasonforretreatment.Relapsereductionwithalemtuzumab wasdurableoverthelong-termwithanannualrelapserateof 0.28forYears0–2and0.20forYears3–6,89%ofpatientsfree fromsustaineddisabilityworseningfrombaselineforYears 0–2and72%forYears3–6.Theproportionofpatientswith confirmeddisabilityimprovementincreasedfromYear2to Year 6, indicating that patients continued to experience improvementduringtheextensionstudy.Theproportionof patients who converted from RRMS to SP MS following alemtuzumabtreatmentwasestimatedto1.1%over6yearsin CARE-MS1and3.7%inCARE-MS2,usingadefinitionofSPMS recentlydevelopedbyLorscheideretal.basedondatafrom the MSBase registry (re´f [20,21]). While SPMS conversion amongthe MSBasecohortwas calculated at18% over 5.8 years’ follow-up[39]. MRI resultsconfirmed the sustained long-termcontrolofdiseaseactivitywith76%ofpatientsfree ofMRIactivityatYear2and69%atYear6,and91%ofpatients free of Gd-enhancing lesions at Year 2 and Years 3 6.
Interestingly,themedianyearlybrainvolumelossdecreased progressivelyover2yearsinalemtuzumab-treatedpatients andremainedlowinYears3–6(medianyearlybrainvolume lossfrom 0.07to 0.19%;inYears3–6)(re´f[32]).Themost frequentadverseeventassociatedwithalemtuzumabisthe injectionassociatedreaction(mostlymildtomoderateand manageableusingpretreatmentwithmethylprednisolone).
Infections were more frequent with alemtuzumab than interferon-beta,but the incidencedeclined from 63.2% in Year1andto43.4%inYear6inCARE-MS2.Ratesofserious infectionswerelowineachyear(<3%).Themostfrequent wereherpetic infectionsjustifyingthe nowrecommended preventionwithacyclovirduringthemonthfollowingthelast cycle and the more frequent opportunistic infections were listeriamonocytogenes(estimatedfrequency:0.26%),followed bycytomegalovirus(estimatedfrequency:0.13%).Therehave beennomedicallyconfirmedcasesofprogressivemultifocal leukoencephalopathy (PML) in MS without relevant pre- treatments (natalizumab-associated PML). For the autoim- munesideeffects,thepooledCARE-MSpatientswhoreceived alemtuzumab 12mg (n=811) presented a cumulative inci- denceofthyroid eventsof42%over6yearswith apeakof incidencewithin2yearsofthelastalemtuzumabtreatment course,aspontaneousresolutionfor20.7%ofcases,conven- tionaloralmedicationsfor79.0%,iodineablationfor9.0%and thyroidectomyfor8.5%.SeriousthyroidAEspeakedatYear3 (3.1%)andsubsequentlydeclined.Dataonidiopathicthrom- bopenicpurpura(ITP)showedacumulativeincidenceof2.0%
inpatientstreatedwithalemtuzumab12-mgdosesuccessfully treatedwithfirst-linetherapyinmostofthecases(corticoste- roids with or without intravenous immunoglobulin) and sometimesrequiring second-line therapywith rituximabor plenectomywithdurableremission.Fourcasesofautoimmune nephropathy were reported [two cases of membranous glomerulonephritis, one case was glomerulonephritis with anti-glomerularbasement membrane (GBM)antibodies,and one was anti-GBM disease], treated with plasmapheresis, cyclophosphamide, and steroids or angiotensin-converting enzymeinhibitorsanddiuretics.Thesesafetyprofileconside- rationsjustifyamonitoringofplateletscounts,renalfunction monthlyandthyroidfunctioneverythreemonthsfor4years afterthelastcourseofalemtuzumab.
3.3. Cladribineasaninductiontreatmentinmultiple sclerosis?
Intracellular accumulation ofthe active metabolite ofcla- dribine,2-chlorodeoxyadenosinetriphosphate,resultsinthe disruption of cellular metabolism, the inhibition of DNA synthesis andrepair, and subsequentapoptosis.Theaccu- mulation of the cladribine nucleotide produces rapid and sustained reductions in CD4+ and CD8+ cells and rapid, thoughmoretransient,effectsonCD19+Bcells,withrelative sparingofotherimmunecells.Ashortperiodofadministra- tion ofcladribine was associated withrapidand sustained effectonclinicalandMRImarkersofMSactivity[22,23].
3.3.1. TheCLARITYphaseIIItrial[22]
Inthis2-YearplacebocontrolledphaseIIItrial,1326RRMS patientswererandomizedtoreceivecladribinetablets(either 3.5mgor5.25mgperkilogramofbodyweight)givenintwoor four shortcoursesforthefirst48weeks,thenintwoshort coursesstartingatweek48andweek52(foratotalof8to20 daysperyear).Theprimaryendpointwastherateofrelapseat 96weeks.Resultswiththelicenseddoseof3.5mg/kgshoweda significantly lower annualized rate of relapse than in the placebogroup(0.14vs.0.33;P<0.001),ahigherrelapse-free rate (79.7% vs. 60.9%; P<0.001), a lower risk of 3-month sustained progression of disability (hazard ratio: 0.67; 95%
confidenceinterval[CI],0.48to0.93;P=0.02),andsignificant reductionsinthebrainlesioncountonMRI(P<0.001forall comparisons). The most frequent adverse events were lymphocytopenia(21.6%vs.1.8%)andherpeszoster(8patients vs.nopatients).
3.3.2. CLARITY2-yearExtensionstudy[23]
Atotalof806patientswereassignedtotreatment:patients from placebo recipients from CLARITY received cladribine 3.5mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5mg/kg or placebo, with blind maintained.
Results ofthe 2-yearextension study were crucialfor the developmentofcladribine,firstbecausetheywerereassuring intermofsafetyprofileandsecondbecauseefficacydatawere ofparticularinterest inthe groupofpatientswhoreceived cladribine 3.5mg/kg duringthe two first years and then a placebo during the third and fourth year, in favor of an induction action. Indeed, if lymphopenia was the most frequentadverseeffects,thefrequencyoflymphopeniagrade 3or4wasof11.4%duringthetwofirstyearsand5%duringthe extension, with recovery to grade 0–1 by study end. The occurrenceofopportunisticinfectionswasreassuring(nocase of progressive multifocal leukoencephalopathy) and the frequency ofherpeszosterinfections inthe 3.5mg/kgwas of2%.Thefrequencyofmalignancieswasof1.4%(similarto the general population). Moreover, the potential induction actionofthedrugwasdemonstratedinthegroupreceiving Cladribine3.5mg/kginCLARITYcorestudyandthenplacebo duringthethirdandfourthyear:efficacyimprovementswere maintainedinthesepatientswithapproximately75%relapse- free and 72.4% free of 3-month sustained progression of disability. In fact, cladribine tablets treatment for 2 years followed by 2 years’ placebo treatment produced durable clinicalbenefitssimilarto4yearsofcladribinetreatmentwith
Accepted
manuscritpt
alowriskofseverelymphopenia.Noclinicalimprovementin efficacy was apparent following further treatment with cladribinetabletsaftertheinitial2-yeartreatmentperiod.
4. Conclusion
Thecurrentchallengeintherapeuticstrategyistoidentifythe mosteffectivedrugandstrategyduringaspecificphaseofthe diseaseofeachsinglepatient.Bothescalatingandinduction strategiescanbesuccessfullyappliedonthebasisofclinical andradiologicaltools.Inductiontherapymeansperforminga strong immunossuppression followed by a maintenance therapy with a safe drug. Among FDA and EMA approved immunossuppressants,mitoxantrone,alemtuzumabandcla- dribine are 3candidates thatdeserves consideration for an induction strategy. However, natalizumab in JC negative patientsisabettercandidatefor anescalatingstrategy, like probably ocrelizumab but longer term data are needed.
Induction therapyisbeneficial for a selectedgroup ofearly aggressiveRRMS,havingnegativepredictivefactors.Monitor- ingoverthefirstfewyearssignificantlyrefinespredictionand facilitates selection ofthose requiringaggressive treatment.
MRIisakeyprognosticmarker.ThegoalofminimalMRIactivity over thefirstfew years afterclinical onsetisimportant for definingthetherapeuticstrategy.NewMRItechniques(brain andspinalcordimaging)shouldhelpustoidentifythoseRRMS patients,especiallyindividualswithoutanyrealdisability,who aremoreatriskofdevelopingdestructiveCNSlesionswithor withoutfirst-linetherapyandwhoarethereforemoreeligible foranearlyandmoreaggressivetreatmentstrategy...
Disclosure of interest
Theauthorsdeclarethattheyhavenocompetinginterest.
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