Alemtuzumab use in clinical practice : recommendations from European multiple sclerosis experts

THERAPY IN PRACTICE Alem uzumab Use in Clinical P ac ice: Recommenda ions om Eu opean Mul iple Scle osis Expe s Thomas Be ge 1 •I ina Elo aa a 2 •S en F ed ikson 3 •Ch is McGuigan 4 • Lucia Moiola 5 •Kjell-Mo en Myh 6 •Celia O eja-Gue a a 7 •Igo S olia o 8 • Uwe K. Ze l 9 Published online: 23 No embe 2016 ÓThe Au ho (s) 2016. This a icle is published wi h open access a Sp inge link.com Abs ac Alem uzumab (Lem ada TM ) is a humanized monoclonal an ibody app o ed in mo e han 50 coun ies. Wi hin he Eu opean Union, alem uzumab is indica ed o he ea men o adul pa ien s wi h elapsing- emi ing mul iple scle osis (RRMS) wi h ac i e disease de ined by clinical o imaging ea u es; in he USA, he indica ion s a es ha alem uzumab should gene ally be ese ed o he ea men o pa ien s wi h elapsing o ms o mul iple scle osis who ha e had an inadequa e esponse o wo o mo e disease-modi ying he apies (DMTs). In clinical i- als, alem uzumab demons a ed e icacy in ea men -naı ¨ e pa ien s wi h ac i e RRMS and hose elapsing on p io DMTs, wi h a consis en and manageable sa e y and ol- e abili y p o ile. The Eu opean Union indica ion p o ides physicians wi h signi ican lexibili y ega ding ea men decisions, a o ding he oppo uni y o indi idualized ea men . Thus, alem uzumab may be an app op ia e ea men choice ac oss a b oad ange o pa ien s wi h RRMS, including, o example, ea men -naı ¨ e pa ien s wi h ac i e disease, pa ien s wi h highly ac i e disease, o o pa ien s elapsing on p io DMTs. The e a e se e al p ac icali ies o conside when using alem uzumab, including he unique dosing egimen, adminis e ed ia in a enous in usion on 5 consecu i e days a baseline and on 3 consecu i e days 12 mon hs la e , and as-needed e ea men (3 consecu i e days a leas 12 mon hs a e he las cou se) in cases o disease ecu ence. Addi ionally, ou ine mon hly moni o ing is equi ed o up o 48 mon hs a e he las in usion o p omp ly iden i y po en ially se ious au oimmune ad e se e en s. Gi en hese consid- e a ions, i is bene icial o gain insigh in o how alem- uzumab is being used in he eal-wo ld clinical se ing. He e, we epo ecommenda ions om Eu opean mul iple scle osis expe s ega ding bes p ac ices o alem uzumab ea men , including managemen o ad e se e en s and compliance wi h ongoing sa e y moni o ing equi emen s. &Thomas Be ge [email p o ec ed] 1 Clinical Depa men o Neu ology, Medical Uni e si y o Innsb uck, Innsb uck, Aus ia 2 Depa men o Neu ology and Rehabili a ion, Uni e si y o Tampe e Medical School and Tampe e Uni e si y Hospi al, Tampe e, Finland 3 Depa men o Clinical Neu oscience, Ka olinska Ins i u e, S ockholm, Sweden 4 S Vincen ’s Uni e si y Hospi al, Dublin, I eland 5 San Ra aele Scien i ic Ins i u e, Milan, I aly 6 Haukeland Uni e si y Hospi al and Uni e si y o Be gen, Be gen, No way 7 Hospi al Clı ´nico San Ca los, Mad id, Spain 8 Ins i u e o he Human B ain, Russian Academy o Sciences, S . Pe e sbu g, Russia 9 Depa men o Neu ology, Neu oimmunological Sec ion, Uni e si y o Ros ock, Ros ock, Ge many CNS D ugs (2017) 31:33–50 DOI 10.1007/s40263-016-0394-8 Key Poin s In he Eu opean Union (EU), alem uzumab is indica ed o adul pa ien s wi h elapsing- emi ing mul iple scle osis, wi h ac i e disease de ined by clinical o imaging ea u es. I can be conside ed as an ini ial he apeu ic o ea men -naı ¨ e pa ien s wi h ac i e disease and o pa ien s elapsing on p io disease-modi ying he apy. Heal hca e p o ide s should adhe e o he alem uzumab EU label, which gi es a b oad de ini ion o pa ien eligibili y o ea men ; alem uzumab is no sui able o pa ien s wi h inac i e elapsing- emi ing mul iple scle osis, hose s able on cu en he apy, o pa ien s wi h p og essi e mul iple scle osis. The Risk Managemen P og am in he EU and o he coun ies in addi ion o he Risk E alua ion and Mi iga ion S a egy in he USA a e c i ical o ensu e ea ly de ec ion o po en ial ad e se e en s a ising du ing and a e alem uzumab ea men and o ensu e compliance wi h moni o ing equi emen s. Da a om an ongoing ex ension s udy, om eal- wo ld s udies, and om pos -ma ke ing sa e y da a will also be impo an o es ablish long- e m sa e y o alem uzumab ea men . 1 In oduc ion Alem uzumab is a humanized monoclonal an ibody app o ed in mo e han 50 coun ies [1], including he Eu opean Union (EU) o he ea men o adul pa ien s wi h ac i e elapsing- emi ing mul iple scle osis (RRMS) de ined by clinical o imaging ea u es, and he USA o he ea men o elapsing o ms o mul iple scle osis (MS) [2,3]. In he USA, he indica ion o alem uzumab s a es ha i should gene ally be ese ed o pa ien s who ha e expe ienced an inadequa e esponse o wo o mo e dis- ease-modi ying he apies (DMTs) [3]. Alem uzumab selec i ely a ge s CD52, a p o ein exp essed a high le els on he su ace o T and B lym- phocy es bu a lowe le els on na u al kille cells and o he cell ypes in ol ed in inna e immuni y, leading o a selec i e deple ion o ci cula ing T and B cells [4,5], he eby dec easing in lamma o y MS disease ac i i y. Following ea men wi h alem uzumab, T and B lympho- cy es epopula e in a dis inc i e pa e n o e ime ha esul s in a ebalancing o he immune sys em o e a pe iod o 3–12 mon hs [5,6]. This mechanism allows o a unique dosing egimen o 12-mg in a enous in usions on 5 consecu i e days a baseline and on 3 consecu i e days 12 mon hs la e and may also accoun o he obse ed du able e icacy in he absence o con inuous ea men , wi h mos pa ien s only equi ing hese wo ini ial ea men cou ses [2,7,8]. The sa e y and e icacy o alem uzumab ha e been assessed in phase II and III clinical ials in ea men -naı ¨ e pa ien s (CAMMS223 [NCT00050778]; CARE-MS I [NCT0053034 8]), in pa ien s wi h ac i e disease despi e ea men wi h ano he DMT (CARE-MS II [NCT00548405]) (Table 1), and in ex ension (NCT00930553) and long- e m ollow-up s udies (NCT02255656) ha include pa ien s om he phase II, III, and IV ials. The phase II and III s udies all included an ac i e compa a o a m in which pa ien s we e ea ed wi h subcu a- neous (SC) in e e on b-1a (IFNb-1a), a DMT wi h an es ab- lished e icacy ac oss s anda d endpoin s in RRMS [9–13]. In CAMMS223 and CARE-MS II, wo doses (12 and 24 mg/day) o alem uzumab we e e alua ed; howe e , discussion o da a in his a icle will be es ic ed o he 12-mg dose as his is he app o ed and comme cially a ailable dose [2,9,12]. 2 Clinical T ial Expe ience wi h Alem uzumab 2.1 E icacy Da a om Clinical T ials As discussed, in he h ee pi o al clinical ials, SC IFNb- 1a was included as an ac i e compa a o (Table 1); he e- o e, all subsequen compa isons ela e o ou comes o alem uzumab s. SC IFNb-1a. Ac oss he CAMMS223 and CARE-MS I and II ials, alem uzumab signi ican ly educed he annualized elapse a e (AAR) (co-p ima y endpoin ) and was also associa ed wi h signi ican educ- ions in 6-mon h con i med disabili y wo sening (CDW, co-p ima y endpoin ) in CAMMS223 [9] and CARE-MS II [12], and a non-signi ican 30% educ ion in CARE-MS I [11]. In addi ion, in a ecen analysis o da a om he CAMMS223 s udy, alem uzumab had g ea e e icacy han SC IFNb-1a a mon h 36 in each o he unc ional sys ems ha make up he Expanded Disabili y S a us Scale (EDSS) sco e, wi h he g ea es e ec s being obse ed in he sen- so y, py amidal, and ce ebella sys ems, which a e hough o d i e CDW in RRMS [16]. Ac oss all ials, alem- uzumab also demons a ed imp o emen s in se e al magne ic esonance imaging (MRI) ou comes (lesion ol- ume/load, and b ain a ophy) [9,11,12]. In CARE-MS I and II, alem uzumab- ea ed pa ien s demons a ed a educed a e o b ain a ophy, as de e - mined by median yea ly pe cen age change in b ain 34 T. Be ge e al. pa enchymal ac ion o e 2 yea s [11,17], eaching sig- ni icance in bo h CARE-MS I (42% educ ion, p 0.0001) and CARE-MS II (24% educ ion, p= 0.0121) compa ed wi h SC IFNb-1a a yea 2. Fu he mo e, du able e icacy (AAR, disabili y, and MRI ou comes, including lesions and b ain a ophy) was demons a ed h oughou he ex ension s udies [7,8,13,17–19], wi h he majo i y o pa ien s (68–94%) no equi ing e ea men wi h alem uzumab o ano he DMT [17,20]. Key e icacy ou comes om he clinical ial p og am ials a e summa ized in Table 2. 2.2 Sa e y Da a om Clinical T ials Alem uzumab has a consis en and manageable sa e y and ole abili y p o ile as demons a ed ac oss indi idual clin- ical ials [9,11,12]), en olling a o al o 1694 pa ien s. Fu he mo e, a simila sa e y and ole abili y p o ile was also documen ed wi h a long- e m ollow-up (up o 5 yea s) in he ex ension s udies [7,8,13]. Ne e heless, se e al ad e se e en s (AEs) o in e es ha e been epo ed (Table 3). The mos equen ly epo ed AEs in clinical ials we e in usion-associa ed eac ions (IARs), expe ienced by [90% o pa ien s, which peaked immedia ely ollowing he ini ial alem uzumab cou se and hen dec eased wi h subsequen cou ses [21,22]. Few (B3%) se ious IARs we e epo ed [9,11–13,21,23,24]. The incidence o in ec ions (which we e mainly mild o mode a e in se e i y) was g ea es du ing he i s mon h ollowing in usion in all h ee ials [25] bu was lowe in he CAMMS223 and CARE-MS ex ensions compa ed wi h he co e s udies, sugges ing a educ ion in in ec ion isk o e ime [11–13,15]. Thy oid disease was he mos common au oimmune e en ; howe e , 1% o pa ien s expe ienced se ious hy- oid AEs [2,9,13,26,27]. Immune h ombocy openic pu pu a (ITP) was iden i ied as a po en ial isk in he CAMMS223 s udy, ini ially epo ed in six pa ien s, including he a al index case in a pa ien ecei ing alem- uzumab 24 mg [9,28,29]. Ac oss all clinical ials, ITP incidence was 2% in pa ien s ecei ing alem uzumab 12 o 24 mg (1.6% in pa ien s ecei ing alem uzumab 12 mg) [11–13,29]. In esponse o he index case and o he au oimmune e en s, enhanced moni o ing and pa ien educa ion was Table 1 Alem uzumab clinical ial p og am CAMMS223 a [2,9,14] CARE-MS I [2,11,14] CARE-MS II a [2,12,14] Pa ien s wi h ac i e RRMS who we e ea men naı ¨ e Pa ien s wi h ac i e RRMS who elapsed on p io DMT S udy du a ion: 3 yea s S udy du a ion: 2 yea s S udy du a ion: 2 yea s SC IFNb-1a (44 lg TIW) N= 111 Alem uzumab (12 mg/day) N= 112 SC IFNb-1a (44 lg TIW) N= 187 Alem uzumab (12 mg/day) N= 376 SC IFNb-1a (44 lg TIW) N= 202 Alem uzumab (12 mg/day) N= 426 MRI c i e ia: diagnosis pe McDonald 2001 c i e ia, including b ain MRI; C1Gd ? lesion on any o B4 b ain scans du ing B3-mon h un-in pe iod (including baseline scan) MRI c i e ia: diagnosis pe McDonald 2005 c i e ia; b ain MRI scan demons a ing whi e ma e lesions a ibu able o MS (wi hin 5 yea s o sc eening) MRI c i e ia: diagnosis pe McDonald 2005 c i e ia; whi e ma e lesions a ibu able o MS and a leas one o he ollowing: C9T 2 lesions C3 mm, any axis; a Gd ? lesion C3 mm, any axis, wi h C1 b ain T 2 lesion; spinal co d lesion wi h C1 b ain T 2 lesion Ac i e MS: C2 elapses in he p io 2 yea s and C1Gd ? MRI lesion a sc eening Ac i e MS: C2 elapses in he p io 2 yea s, wi h C1 elapse occu ing in he yea p io o s udy en y Ac i e MS: C2 elapses in he p io 2 yea s, wi h C1 elapse occu ing in he yea p io o s udy en y and C1 elapse occu ing du ing p io ea men b Mean age: 32 yea s Mean age: 33 yea s Mean age: 35 yea s EDSS ange: 0.0–3.0 (mean 2.0) c EDSS ange: 0.0–3.0 (mean 2.0) d EDSS ange: 0.0–5.0 (mean 2.7) d Mean/median ime since i s MS episode: 1.4/ 1.3 yea s Mean/median ime since i s MS episode: 2.0/ 1.6 yea s Mean/median ime since i s MS episode: 4.5/ 3.8 yea s Re ea men c i e ia o CAMMS223 (Sano i Genzyme, da a on ile) and CARE-MS ex ensions [15]: C1 elapse o C2 new o enla ging T 2 and/ o Gd ? b ain o spinal lesions, C12 mon hs since he second alem uzumab cou se DMT disease-modi ying he apy, EDSS Expanded Disabili y S a us Scale, Gd ? gadolinium-enhancing, IFN in e e on, MRI magne ic esonance imaging, MS mul iple scle osis, RRMS elapsing- emi ing mul iple scle osis, SC subcu aneous, TIW h ee imes pe week a A 24-mg/day ea men a m was included in hese s udies b T ea men wi h IFNbo gla i ame ace a e o C6 mon hs c A sc eening and baseline isi s d A sc eening Recommenda ions o Alem uzumab Use in Clinical P ac ice 35 Table 2 O e iew o he key endpoin s om he alem uzumab clinical ial p og am CAMMS223 ex ension [13,20] CARE-MS I [8,11,17,18,33,34] CARE-MS I ex ension [8,17,18] CARE-MS II [7,12,17,19,35] CARE-MS II ex ension [7,19] 5-yea da a S udy du a ion: 2 yea s Yea 4 S udy du a ion: 2 yea s Yea 4 SC IFNb-1a 44 lg TIW Alem uzumab 12 mg/day SC IFNb-1a 44 lg TIW Alem uzumab 12 mg/day Alem uzumab 12 mg/day SC IFNb-1a 44 lg TIW Alem uzumab 12 mg/day Alem uzumab 12 mg/day Pa ien s en e ing s udy, N111 112 187 376 349 202 426 393 Clinical endpoin s ARR 0.35 0.12 0.39 0.18 0.14 0.52 0.26 0.23 ARR ela i e educ ion (alem uzumab s. SC IFNb-1a), % 66 (p 0.0001) 55 (p 0.0001) 49 (p 0.0001) Relapse- ee pa ien s, a % 4168 5978(p 0.0001) 87 47 65 (p 0.0001) 79 Pa ien s wi h 6-mon h CDW, a % 38 16 11 8 17 (yea s 0-4) 21 13 24 (yea s 0-4) CDW ela i e isk educ ion (alem uzumab s. SC IFNb-1a), % 69 (p= 0.0005) 30 (p= 0.22) b 42 (p= 0.0084) Pa ien s wi h 6-mon h CDI, a % N/A N/A 27 c 23 (p= 0.5192) c 30 (yea s 0–4) 13 29 (p= 0.0002) 41 (yea s 0–4) Mean change in EDSS sco e om baseline 0.46 -0.15 (p= 0.0056) -0.14 -0.14 (p= 0.97) -0.09 (yea s 0–4) 0.24 -0.17 (p 0.0001) 0.00 (yea s 0–4) MRI endpoin s Gd ? lesion ee, % 81 93 (p 0.0001) 87 78 91 (p 0.0001) 89 New/enla ging T 2 lesion ee, % 60 78 (p 0.0001) 71 48 76 (p 0.0001) 70 New T 1 hypoin ense lesion ee, % 82 93 (p= 0.0001) 85 74 93 (p 0.0001) 86 MRI ac i i y ee, d %5977(p 0.0001) 70 47 76 (p 0.0001) 70 B ain olume change Median BPF change, % (95% CI) –1.49 -0.87 (p 0.0001) (yea s 0–2) -1.134 c (yea s 0–4) –0.81 –0.62 (p= 0.0012) (yea s 0–2) -0.882 c (yea s 0–4) Reduc ion in a e o b ain olume loss, % 42 24 Disease- ee su i al Pa ien s wi h NEDA, e % 273960 143255 36 T. Be ge e al. Table 2 con inued CAMMS223 ex ension [13,20] CARE-MS I [8,11,17,18,33,34] CARE-MS I ex ension [8,17,18] CARE-MS II [7,12,17,19,35] CARE-MS II ex ension [7,19] 5-yea da a S udy du a ion: 2 yea s Yea 4 S udy du a ion: 2 yea s Yea 4 SC IFNb-1a 44 lg TIW Alem uzumab 12 mg/day SC IFNb-1a 44 lg TIW Alem uzumab 12 mg/day Alem uzumab 12 mg/day SC IFNb-1a 44 lg TIW Alem uzumab 12 mg/day Alem uzumab 12 mg/day Odds a io 1.75 (p= 0.006) 3.03 (p 0.0001) – Re ea men Pa ien s no equi ing e ea men , % N/A 94% N/A N/A 74 N/A N/A 68 ARR annualized elapse a e, BPF b ain pa enchymal ac ion, CI con idence in e al, CDI con i med disabili y imp o emen , CDW con i med disabili y wo sening, EDSS Expanded Disabili y S a us Scale, Gd ? gadolinium-enhancing, IFN in e e on, MRI magne ic esonance imaging, N/A no applicable, NEDA no e idence o disease ac i i y, SC subcu aneous, TIW h ee imes pe week a Kaplan–Meie es ima es b When CAMMS223 and CARE-MS I da a we e pooled, a signi ican educ ion in isk o 6-mon h CDW (50%, p= 0.0029), as well as ARR (56%, p 0.0001) was obse ed, when compa ed wi h SC IFNb-1a [36] c Sano i Genzyme, da a on ile d MRI ac i i y- ee was de ined as he absence o bo h Gd ? lesions and new o enla ging T 2 -hype in ense lesions; clinical disease ac i i y- ee was de ined as he absence bo h o elapses and 6-mon h CDW [8] e P e-speci ied e ia y endpoin in CARE-MS I and II. NEDA was de ined as pa ien s who we e MRI and clinically disease ee [8]. NEDA alues a e pe yea . Fo CARE-MS II, he denomina o o he pe cen age o pa ien s wi h each ype o e en is he o al numbe o pa ien s wi h MRIs pe o med a he gi en ime poin (Sano i Genzyme, da a on ile) Recommenda ions o Alem uzumab Use in Clinical P ac ice 37 in oduced o ongoing ials, which esul ed in ea ly iden i ica ion and managemen o ITP cases, as well as o he au oimmune e en s ( hy oid dys unc ion and glome uloneph opa hy) in he clinical ials and imp o ed pa ien ou comes. Subsequen ly, a Risk Managemen P o- g am (RMP) and a Risk E alua ion and Mi iga ion S a egy (REMS) [30] we e implemen ed o ensu e ea ly de ec ion o po en ial AEs in eal-wo ld clinical p ac ice. Ac oss he clinical de elopmen p og am, he e we e ou epo ed cases o immune neph opa hy, including one case o an i- glome ula basemen memb ane (an i-GBM) disease (in CAMMS223) epo ed 39 mon hs a e he second alem- uzumab cou se [13,31]. A single a al case o p og essi e mul i ocal leukoen- cephalopa hy (PML) has been epo ed in a pa ien who swi ched om na alizumab o alem uzumab. The PML diagnosis was no made un il a e he pa ien had ecei ed he i s cou se o alem uzumab; howe e , e ospec i e analysis o he MRI da a showed ha he onse o PML p eda ed alem uzumab ea men and, he e o e, was a ibu ed o na alizumab ea men (Sano i Genzyme, da a on ile). The e icacy and sa e y ou comes om he alem- uzumab clinical ials ha e also been ex ensi ely epo ed in he li e a u e; o u he in o ma ion, we e e he eade o hese publica ions [9,11–13,32]. 2.3 Addi ional Long-Te m Expe ience wi h Alem uzumab A long- e m, in es iga o -led, obse a ional coho s udy has also demons a ed he long- e m e icacy and sa e y o alem uzumab in pa ien s wi h ac i e RRMS [37]. In his s udy, 87 pa ien s (39% ha ing ecei ed a p io DMT) we e ollowed o up o 12 yea s (median ollow-up 7 yea s). The majo i y o pa ien s (68%) expe ienced an imp o e- men o s abiliza ion o disabili y (based upon 6-mon h CDW) compa ed wi h baseline. Re ea men was pe mi ed in he e en o a elapse wi h 52% o pa ien s ecei ing only he ini ial wo cou ses, wi h he emainde ecei ing h ee (36%), ou (8%), o i e (1%) cou ses. The emaining pa ien s (3%) ecei ed only a single ea men cou se [37]. 3 Use o Alem uzumab in a Real-Wo ld Clinical Se ing Real-wo ld da a indica e ha , in he majo i y o pa ien s wi h ac i e o highly ac i e RRMS, alem uzumab ea - men is associa ed wi h disease s abiliza ion [37,38]. The e is, howe e , some deba e ega ding which pa ien s would bene i mos om alem uzumab ea men . The ollowing sec ions o his a icle p esen he opinions and ecom- menda ions o Eu opean MS expe s wi h ega d o iden- i ying he mos app op ia e pa ien s o alem uzumab ea men and bes p ac ices o ea men and moni o ing. 3.1 Alem uzumab Indica ion The EU indica ion o alem uzumab s a es ha alem- uzumab is sui able o ‘‘adul pa ien s wi h RRMS wi h ac i e disease de ined by clinical o imaging ea u es’’ [2]. This ep esen s an appa en shi om p e ious egula o y labeling on he eligibili y o pa ien s o a pa icula DMT and po en ially allows physicians o use alem uzumab as a i s -line ea men choice in app op ia e pa ien s. EU indica ions o o he DMTs (e.g., ingolimod, na alizumab) a e mo e es ic i e, equi ing e idence o a speci ied le el o MRI ac i i y, in addi ion o clinical ac i i y be o e ea men ini ia ion. Fingolimod and na alizumab a e he e o e ecommended o use in pa ien s wi h highly ac i e disease who ha e b eak h ough disease ac i i y on a Table 3 Mos common AEs obse ed in clinical ials o alem uzumab 12 mg CAMMS223 [9,10] N= 108 CARE-MS I [11] N= 376 CARE-MS II [12] N= 435 AEs occu ing in [10% o pa ien s, n(%) In usion-associa ed eac ions 106 (98) 338 (90) 393 (90) In ec ion 71 (66) 253 (67) 334 (77) Uppe espi a o y ac 48 (44) 57 (15) 71 (16) U ina y ac 10 (9) 64 (17) 93 (21) Au oimmuni y Any au oimmune hy oid-associa ed e en 28 (26) 68 (18) 69 (16) Blood and lympha ic sys em diso de s NR 66 (18) 59 (14) Lymphopenia NR 26 (7) 23 (5) Leukopenia NR 11 (3) NR AEs ad e se e en s, NR no epo ed 38 T. Be ge e al. p e ious DMT (i.e., as a second-line he apy) o in hose wi h mo e apidly e ol ing se e e RRMS [39,40]. 3.2 Is The e a Requi emen o Speci ic Pa ien P o iles? The EU indica ion o alem uzumab may p o ide p e- sc ibing physicians wi h ce ain challenges when deciding which pa ien s a e mos sui able o ea men , al hough i also p o ides physicians wi h lexibili y, allowing hem o use hei own clinical expe ience and judgmen o make an in o med decision ega ding wha cons i u es ac i e disease and o p o ide indi idualized ea men choices in collab- o a ion wi h hei pa ien s. Clinical expe ience may be mo e aluable han igid ea men guidelines, which a emp o de ine speci ic pa ien p o iles o ea men eligibili y. Fu he mo e, de ining a single speci ic pa ien p o ile o alem uzumab may no be help ul as his may unin en ionally es ic he use o alem uzumab in ce ain pa ien s, pa icula ly gi en ha alem uzumab e icacy has been demons a ed in a b oad ange o pa ien s and ha subg oup analyses ha e shown ha he e ec s o alem- uzumab emain consis en ac oss mos demog aphic and disease cha ac e is ic subg oups [41–43]. The e o e, u he s udies a e equi ed o elucida e he a iabili y and du abili y o esponse in pa ien s ea ed wi h alem uzumab o iden i y eliable bioma ke s o clin- ical cha ac e is ics ha can assis in he managemen o MS and u he in o m ea men decisions. Recen ly, se e al g oups ha e in es iga ed he p ognos ic alue o pe iphe al CD4 ? lymphocy e cell coun eco e y as a po en ial bio- ma ke o iden i y pa ien s who migh bene i om e ea men wi h an addi ional cou se o alem uzumab, al hough he e idence is con lic ing in his ega d [44–46]. 3.3 Pe sonal Expe ience wi h Alem uzumab in Rou ine Clinical P ac ice In he absence o speci ic pa ien p o iles and alida ed bioma ke s, pe sonal clinical expe ience will ine i ably in luence alem uzumab- ela ed ea men decisions. Col- lec i ely, we ha e ea ed 181 pa ien s wi h alem uzumab, ei he as a i s -line o as an escala ion he apy in pa ien s wi h b eak h ough disease ac i i y on a p e ious DMT (Table 4). Mos o ou pa ien s ini ia ed ea men wi h alem- uzumab owing o b eak h ough disease (i.e., ha ing only a pa ial esponse o, o no esponding o, o he he apies). In gene al, hese pa ien s had expe ienced one o mo e elapses wi hin he p e ious 12 mon hs and demons a ed ecen in lamma o y disease ac i i y (as e idenced ei he by gadolinium enhancemen (Gd ? ) o by an ob ious inc ease in T 2 lesion load) on a b ain MRI. Thus, alem- uzumab use in his g oup o pa ien s was consis en wi h a ea men escala ion pa adigm. The e was a consensus ha mo e a o able ea men ou comes a e ypically obse ed in hese pa ien s i alem uzumab ea men can be ini ia ed ea ly on in he disease cou se, pa icula ly in pa ien s who a e younge , ha e highly ac i e disease, and ha e low le els o disabili y a he s a o ea men . Ne e heless, in clinical p ac ice, we ha e also ound alem uzumab is e i- cacious in pa ien s wi h al eady accumula ing disabili y, pa icula ly when used as a escue he apy o s abilize disease and p e en u he disabili y wo sening i in lam- ma o y disease ac i i y (ei he clinically o on MRI) is s ill o e . We, he e o e, ecommend he use o alem uzumab in pa ien s wi h ac i e RRMS, ega dless o hei le el o disabili y. Howe e , 15% o ou pa ien s ep esen ed a e y impo an ea men g oup, namely hose who we e ea - men naı ¨ e bu who p esen ed wi h ea ly, highly ac i e disease. Compa ed wi h pa ien s ecei ing alem uzumab as an escala ion he apy, hese pa ien s we e gene ally younge and had a sho e , bu mo e ac i e disease cou se, usually wi h wo o mo e elapses in he p eceding 3–6 mon hs (clus e o elapses). We eel ha alem uzumab may ep esen an e ec i e ea men op ion in ea men - naı ¨ e pa ien s wi h apidly e ol ing MS (o a clinical elapse accompanied by an inc ease in he numbe o T 2 lesions and/o ongoing e idence o Gd ? T 1 lesions), and, as expe ience g ows and he a o able ou comes associa ed wi h ea ly in e en ion wi h alem uzumab become e iden , alem uzumab use in his pa ien popula ion will inc ease. In CARE-MS I, alem uzumab signi ican ly educed he a e o Table 4 Summa y o au ho expe iences wi h alem uzumab Na ional app o al/ eimbu semen pe iod Sep embe 2013–May 2015 Pa ien s ea ed, N181 Female, n(%) 129 (71) Age, mean ( ange), yea s 35 (17–66) Alem uzumab as: Fi s -line he apy, n(%) 27 (15) Escala ion he apy, n(%) 154 (85) Da a p o ided cou esy o he au ho s and ep esen s a summa y o he expe iences in Aus ia, Finland, Ge many, I eland, I aly, No way, and Spain Recommenda ions o Alem uzumab Use in Clinical P ac ice 39 b ain olume loss in ea men -naı ¨ e pa ien s wi h MS by 42% compa ed wi h SC IFNb-1a [34], and, gi en he co ela ion be ween b ain olume loss and disabili y and cogni i e wo sening [47,48], ea ly ea men wi h alem- uzumab may be mo e a o able han delaying ea men (discussed in Sec . 3.4). Indeed, we eel ha ini ia ing alem uzumab in ea men -naı ¨ e pa ien s may be ad an a- geous, as lymphocy e le els ha e no been a ec ed by use o p io DMTs. In ou expe ience, alem uzumab has a place in ou ine clinical p ac ice o he ea men o pa ien s elapsing on p io ea men s, as well as hose who a e ea men naı ¨ e. Pos poning ea men in a o o escala ing pa ien s h ough al e na i e DMTs, in e ec e aining alem uzumab as a las eso , is no ad ised, and we eel ha ini ia ing alem uzumab as soon as possible, pa icula ly in pa ien s wi h low le els o disabili y, will be associa ed wi h he mos a o able ou comes. 3.4 Alem uzumab Ea ly in Mul iple Scle osis The impo ance o ea ing MS ea ly in he disease cou se o p e en in lamma o y p ocesses ha lead o i e e sible b ain loss is well es ablished [49–52]. T adi ionally, he ea men pa adigm is one o escala ion he apy, du ing which d ugs wi h g ea e e icacy (o en wi h dis inc mechanisms o ac ion) bu wi h inc easing isk a e used as disease p og esses, wi h he mos e icacious d ugs (e.g., na alizumab, o en conside ed ollowing ailu e o one o mo e DMTs [53,54]) used as he las line o he apy. Howe e , da a om alem uzumab clinical s udies [9,11–13], coupled wi h i s indica ion in he EU [2], a o d physicians he oppo uni y o s a alem uzumab ea men in pa ien s wi h ac i e MS ea ly in he disease cou se o p e en po en ially a oidable CNS damage and p o ide he pa ien wi h he bes oppo uni y o a o able ea men ou comes. This may be pa icula ly impo an o pa ien s wi h ac i e MS wi h poo p ognos ic signs, o example, pa ien s p esen ing wi h mo o , ce ebella , o sphinc e in ol emen a onse o hose expe iencing equen elapses wi h poo eco e y du ing he ea ly yea s o hei disease [55,56]. The bene i s o ea ly in e en ion wi h o he DMTs ha e been widely epo ed; o example, in he pi o al 2-yea SC IFNb-1a s udy (PRISMS) and i s 2-yea ex ension (PRISMS-4), pa ien s who s a ed ea men ea ly had imp o ed clinical ou - comes compa ed wi h pa ien s whose ea men was delayed [57,58]. These obse a ions ha e been con i med in long- e m ollow-up s udies [59–61]. Ea ly in e en ion is hough o add ess he in lamma o y componen o he disease, he eby educing de elopmen o u he CNS pa hology [53,62]. Agg essi e he apy ea ly on in he disease cou se may p o oke an immunological ese and may, he e o e, a o ably a ec long- e m disease p o- g ession [53]. Howe e , he concep o ea ly ea men o ac i e dis- ease wi h an immunomodula o y d ug such as alem- uzumab, belie ed o ebalance he immune sys em, is no ye ully es ablished and would ep esen a signi ican change in mindse o some physicians. In some Eu opean specialis MS cen e s, pa ien s wi h highly ac i e o apidly e ol ing se e e RRMS a e al eady conside ed o i s -line ea men wi h ingolimod o na alizumab (bo h conside ed ypically second-line he apies in he EU), and, as no ed abo e, alem uzumab was used as a i s -line he apy in 15% o all alem uzumab- ea ed pa ien s in ou expe ience (Table 4). These obse a ions pe haps indica e ha MS ea men may be mo ing in o a new e a, away om he escala ion pa adigm and owa d mo e obus ea ly ea - men o ac i e disease. 3.5 Swi ching o Alem uzumab om P io Disease- Modi ying The apies The e icacy o alem uzumab in pa ien s wi h ac i e disease who had elapsed on p io DMTs is o pa icula clinical ele ance; in such cases, swi ching he apies should be conside ed u gen ly o b ing MS ac i i y unde con ol. As discussed b ie ly abo e (Sec . 2.1, Table 2), he CARE-MS II s udy demons a ed supe io e icacy wi h alem uzumab s. SC IFNb-1a in pa ien s wi h ac i e disease who had elapsed on p io DMTs [12]. The oppo uni y o swi ch he apies may be pa icula ly impo an o ce ain pa ien subg oups. Fo example, pa ien s ecei ing na alizumab he apy o o e 2 yea s and/o who a e posi i e o an i- John Cunningham i us (an i-JCV) an ibodies, as well as hose ha ing p e iously ecei ed o he immunosupp essi e medica ions, a e a inc eased isk o de eloping PML and may equi e an al e na i e DMT [63]. He e, oo, alem- uzumab may p o ide a ea men al e na i e op ion. Howe e , ansi ioning om one pa icula DMT o ano he can be complex, and a washou pe iod may be equi ed in ce ain ci cums ances. T ea men cessa ion guidelines and ecommended washou pe iods a e some- imes p o ided wi hin he espec i e label o each DMT (Table 5), al hough he e a e cu en ly no ecommenda- ions o ansi ioning o alem uzumab om hese indi- idual DMTs. Howe e , in he CARE-MS II ex ension, pa ien s who swi ched om SC IFNb-1a o alem uzumab we e no equi ed o unde go a washou pe iod. The e o e, i is o en unclea o which ea men ansi ions a washou pe iod is equi ed, how long i should be, o wha long- e m sa e y su eillance p ocedu es should be implemen ed [53]. Ne e heless, as wi h o he immunomodula o y he apies, concomi an ea men , including ini ia ion o alem- uzumab wi hin he washou pe iod o he p e ious DMT, 40 T. Be ge e al. is no ad isable, owing o he po en ial isk o ca y-o e PML om p e ious ea men and addi i e e ec s on he immune sys em [2]. Consequen ly, i is impo an o con- side he hal -li e as well as he mechanism o ac ion (MoA) o he p e ious DMT when ansi ioning o alem- uzumab [53]. Despi e he absence o speci ic guidance o swi ching o alem uzumab om he DMTs lis ed in Table 5, he e a e some conside a ions ha may help guide swi ching in clinical p ac ice. The p oposed MoA o ingolimod (p e- en ing lymphocy e eg ess om pe iphe al lymphoid o gans) esul s in low le els o ci cula ing lymphocy es [69]. The e o e, i may be ad isable o wai un il lym- phocy e coun s begin o eco e be o e ini ia ing ea men wi h a DMT, such as alem uzumab, pa icula ly gi en ha he p oposed MoA o alem uzumab in MS equi es e ec- i e a ge ing o ci cula ing T and B cells, leading o hei deple ion and subsequen epopula ion [4,5,64]. Indeed, a ecen epo demons a ed clinical and MRI disease ac i i y in alem uzumab- ea ed pa ien s who had swi ched om ingolimod bu o whom a po en ially insu icien washou pe iod ollowing ingolimod cessa ion had been used, esul ing in lymphocy e coun s below no mal le els a he ime o alem uzumab ea men . The au ho s hypo hesized ha he seques a ion o lymphocy es in lymph nodes, owing o he mechanism o ac ion o in- golimod, coupled wi h an inadequa e washou pe iod (median 6 weeks, ange 4–10 weeks) may ha e educed he e ec i eness o alem uzumab [70]. By con as , he p oposed MoA o dime hyl uma a e (DMF) (ac i a ion o he nuclea ac o e y h oid 2- ela ed ac o 2) would gene ally no p edic any issues wi h apid ansi ion o ano he he apy, al hough DMF has also been shown o ha e a lymphopenic e ec in ce ain pa ien popula ions. Thus, as o ingolimod, a washou pe iod migh be ad isable when ansi ioning o alem uzumab [64,71]. Un o una ely, o bo h ingolimod and DMF, he ime pe iod o e which lymphocy es e u n o no mal is a iable and can ake many weeks, du ing which ime he pa ien is a isk o elapse [64]. Te i lunomide is also associa ed wi h a educ ion (*15%, mean wi hin no mal limi s) in lymphocy es and neu ophil coun s wi hin he i s 3 mon hs ollowing ea men ; mean lymphocy e and neu ophil coun s hen emain wi hin he no mal ange o whi e blood cell coun s (3.8–10.7 910 9 /L) du ing ea men [72]. Pa ien s ecei - ing e i lunomide ha e he oppo uni y o unde go an accele a ed elimina ion p ocedu e, which can educe plasma le els by [96% in 11 days [66,73], po en ially allowing he ini ia ion o alem uzumab ela i ely quickly a e s opping e i lunomide. By con as , na alizumab does no educe ci cula ing lymphocy e coun s, a he i blocks hei en y o he CNS esul ing in only mild lymphocy osis [64,74], and he e may be limi ed bene i in delaying ini ia ing ea men wi h ano he DMT ollowing na alizumab discon inua ion [64]. In ac , i has been sugges ed ha s a ing a new ea men immedia ely a e s opping na alizumab (i.e., no a washou pe iod) may be p e e able because he isk o de eloping PML, e en in an i-JCV an ibody-posi i e pa ien s, is lowe han he isk o a se e e elapse [75,76]. In CARE-MS II, pa ien s p e iously ea ed wi h na alizumab (3%) unde - wen a 6-mon h washou pe iod be o e s a ing alem- uzumab [12]. In eal-wo ld clinical se ings, and, in Table 5 Gene al guidance o he apy cessa ion o common DMTs In e e ons, gla i ame ace a e No speci ic guidance o cessa ion o he apy a No washou pe iod ecommended based upon he mechanism o ac ion [64] Te i lunomide An AEP is a ailable i apid emo al o e i lunomide om he ci cula ion is desi ed [65] AEP will educe plasma concen a ions o 0.02 mg/L in 11 days. Comple e elimina ion equi es 8 mon hs o 2 yea s in he absence o AEP [65,66] Dime hyl uma a e No speci ic guidance o cessa ion o he apy o equi emen o washou [67] Fingolimod A 6-week ea men - ee pe iod is equi ed o clea ingolimod om ci cula ion [39] Na alizumab A washou pe iod migh be app op ia e as he pha macodynamic e ec s o na alizumab las o app oxima ely 12 weeks ollowing he las dose [40] Daclizumab Washou pe iod o 4 weeks is ecommended b [68] Ri uximab/oc elizumab c Washou pe iod o 6 mon hs is ecommended b [68] AEP accele a ed elimina ion p ocedu e, DMTs disease-modi ying he apies, EU Eu opean Union, FACS luo escence-ac i a ed cell so ing, IFN in e e on, MS mul iple scle osis, SC subcu aneous a In CARE-MS II [12], no washou pe iod was equi ed o pa ien s swi ching om SC IFNb-1a o alem uzumab b Washou guidance is based on ci ed sou ces along wi h he expe opinion o he au ho s c Oc elizumab is no ye app o ed o he ea men o MS in he EU In all cases, he immune compe ence (including FACS analysis o B cells in he case o i uximab/oc elizumab) should be con i med be o e ini ia ing alem uzumab Recommenda ions o Alem uzumab Use in Clinical P ac ice 41 5. 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