Rituximab monitoring and redosing in pediatric neuromyelitis …nn.neurology.org/content/nnn/3/1/e188.full.pdf · rituximab) or the date of final CD19 repopulation (for patients who

Margherita NosadiniMD

Gulay Alper MDCatherine J Riney MD

PhDLeslie A Benson MDShekeeb S Mohammad

FRACPSudarshini Ramanathan

FRACPMelinda Nolan FRACPRichard Appleton MDRichard J Leventer

FRACP PhDKumaran Deiva MD

PhDFabienne Brilot PhDMark P Gorman MDAmy T Waldman MDBrenda Banwell MDRussell C Dale MRCP

PhD

Correspondence toProf Dalerusselldalehealthnswgovau

Supplemental dataat Neurologyorgnn

Rituximab monitoring and redosing inpediatric neuromyelitis optica spectrumdisorder

ABSTRACT

Objective To study rituximab in pediatric neuromyelitis optica (NMO)NMO spectrum disorders(NMOSD) and the relationship between rituximab B cell repopulation and relapses in order toimprove rituximab monitoring and redosing

Methods Multicenter retrospective study of 16 children with NMONMOSD receiving$2 rituximabcourses According to CD19 counts events during rituximab were categorized as ldquorepopulationrdquoldquodepletionrdquo or ldquodepletion failurerdquo relapses (repopulation threshold CD19 $10 3 106 cellsL)

Results The 16 patients (14 girls mean age 96 years range 18ndash153) had a mean of 61 events(range 1ndash11) during a mean follow-up of 61 years (range 16ndash136) and received a total of 76rituximab courses (mean 47 range 2ndash9) in 426-year cohort treatment Before rituximab 625had received azathioprine mycophenolate mofetil or cyclophosphamide Mean time from rituximabto last documented B cell depletion and first repopulation was 45 and 68 months respectivelywith large interpatient variability Earliest repopulations occurred with the lowest doses Significantreduction between pre- and post-rituximab annualized relapse rate (ARR) was observed (p5 0003)During rituximab 6 patientswere relapse-free although21 relapses occurred in 10 patients includ-ing 13 ldquorepopulationrdquo 3 ldquodepletionrdquo and 4 ldquodepletion failurerdquo relapses Of the 13 ldquorepopulationrdquorelapses 4 had CD19 10ndash50 3 106 cellsL 10 had inadequate monitoring (1 CD19 in the 4months before relapses) and 5 had delayed redosing after repopulation detection

Conclusion Rituximab is effective in relapse prevention but B cell repopulation creates a risk ofrelapse Redosing before B cell repopulation could reduce the relapse risk further

Classification of evidence This study provides Class IV evidence that rituximab significantly reducesARR in pediatricNMONMOSD This study also demonstrates a relationship betweenBcell repopulationand relapses Neurol Neuroimmunol Neuroinflamm 20163e188 doi 101212NXI0000000000000188

GLOSSARYAQP45 aquaporin-4 ARR5 annualized relapse rate EDSS 5 Expanded Disability Status Scale IVIg 5 IV immunoglobulinMS 5 multiple sclerosis MOG 5 myelin oligodendrocyte glycoprotein NMO 5 neuromyelitis optica NMOSD 5 NMO spec-trum disorders ON 5 optic neuritis TM 5 transverse myelitis

Neuromyelitis optica (NMO) is an autoimmune inflammatory demyelinating disease of theCNS1 Although previously considered a multiple sclerosis (MS) variant IgG autoantibodytargeting aquaporin-4 (AQP4) channel (NMO-IgG) has clearly demonstrated that NMO is aseparate entity2 NMO lesions are characterized by humoral inflammatory response and astro-cytic cell death with AQP4 loss followed by inflammatory demyelination and axonal damage3

From the Neuroimmunology Group (M Nosadini SSM SR FB RCD) Institute for Neuroscience and Muscle Research ChildrenrsquosHospital at Westmead University of Sydney Australia Paediatric Neurology Unit (M Nosadini) Department of Paediatrics University of PaduaItaly Clinical Neuroimmunology Program (GA) Division of Child Neurology Department of Pediatrics Childrenrsquos Hospital of PittsburghUniversity of Pittsburgh PA Neurology Department (CJR) Lady Cilento Childrenrsquos Hospital University of Queensland Australia PediatricMultiple Sclerosis and Related Diseases Program (LAB MPG) Boston Childrenrsquos Hospital Boston MA Department of Neurology (SR)Westmead Hospital Sydney Australia Neurology Department (M Nolan) Starship Childrenrsquos Health Auckland New Zealand The Roald DahlEEG Unit (RA) Pediatric Neurosciences Foundation Alder Hey Childrenrsquos Hospital Liverpool UK Department of Neurology (RJL)Murdoch Childrens Research Institute and University of Melbourne Department of Paediatrics (RJL) Royal Childrenrsquos Hospital MelbourneVictoria Australia Assistance Publique-Hopitaux de Paris (KD) Hocircpitaux Universitaires Paris-Sud National Referral Center for Neuro-Inflammatory Diseases in Children (KD) Pediatric Neurology Department and Universiteacute Paris-Sud (KD) Inserm U1012 Le Kremlin-BicecirctreFrance and Childrenrsquos Hospital of Philadelphia (ATW BB) University of Pennsylvania Philadelphia

Funding information and disclosures are provided at the end of the article Go to Neurologyorgnn for full disclosure forms The Article ProcessingCharge was paid by the authors

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 downloading and sharing the work provided it is properly cited The work cannot be changed in any way or used commercially

Neurologyorgnn copy 2016 American Academy of Neurology 1

ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited

The course of NMO is characterized by ahigh relapse rate with accumulation ofneurologic disability potentially causingpermanent blindness and paralysis There-fore relapse prevention is crucial Differenti-ation from MS is important because someMS therapies fail to control or may aggravateNMO4ndash6 Even though the optimal thera-peutic regimen has not been establishedacute NMO attacks are mainly treatedwith corticosteroids plasma exchange andIV immunoglobulin (IVIg) azathioprinemethotrexate mycophenolate mofetil ritux-imab mitoxantrone cyclophosphamide andtocilizumab have been used to preventrelapses7

Rituximab is an anti-CD20 chimericmonoclonal antibody that depletes B cellsthat is used in severe autoimmune andinflammatory CNS disorders despite the riskof infections as recently demonstrated in alarge pediatric study8 One prospective and3 retrospective adult NMO studies demon-strated reduced annualized relapse rate(ARR) and significantly improved ExpandedDisability Status Scale (EDSS) score with rit-uximab9ndash12 Pediatric data are more limitedand retrospective13ndash16 No study specificallyaddresses optimal rituximab monitoring andredosing to prevent relapses and reduce dis-ability To clarify these aspects we retrospec-tively studied 16 children with NMO whoreceived $2 rituximab courses in order toestablish rituximab efficacy the time fromrituximab to B cell repopulation and therelationship between B cell repopulationand relapses

METHODS Patients We identified 16 patients with NMO

who received $2 rituximab courses (18 years at first dose)

from 9 international pediatric neuroimmunology centers

NMO was defined according to the revised Wingerchuk cri-

teria for NMO17 and NMO spectrum disorders (NMOSD)18

In 13 of 16 patients diagnosis of definite NMO was met based

on the presence of both optic neuritis (ON) and transverse

myelitis (TM)19 The remaining 3 children had NMOSD (1

had a single attack of isolated TM 1 had an attack of TM and

brainstem manifestations and 1 had recurrent ON) and these

patients were all NMO-IgG positive Regarding serologic

status 15 of 16 patients were positive for NMO-IgG or

AQP4 antibodies 12 were tested and positive for NMO-

IgG using immunofluorescence and 3 were tested and

positive for both NMO-IgG (using immunofluorescence)

and anti-AQP4 antibodies (using cell-based assay) One

patient was negative for NMO-IgG but positive for antindash

myelin oligodendrocyte glycoprotein (MOG) antibodies

using cell-based assay (not tested for anti-AQP4 antibodies)

(patient 7)

Data collection Data were retrospectively collected by the

main investigator (RCD) through telephone interviews to

the physicians using a structured questionnaire created for this

study Information recorded included demographics clinical

characteristics of disease immune therapies received besides

rituximab rituximab regimen CD19 count measurements

and outcome Data collection focused on the relationship

between rituximab administration (timing dose number of

courses adverse reactions) CD19 counts and relapses

First-line immune therapy was defined as corticosteroids

IVIg and plasma exchange whereas second-line immune

therapy included rituximab cyclophosphamide azathioprine

and mycophenolate mofetil Disease duration pre-rituximab

was defined as the time between onset (first event) and

initiation of rituximab treatment Rituximab treatment

duration was defined as the time between rituximab

initiation and last follow-up (for patients with ongoing

rituximab) or the date of final CD19 repopulation (for

patients who stopped rituximab)

CD19 values and relationship to relapses The threshold forB cell repopulation was defined as CD19 count $10 3 106

cellsL as previously proposed1620 In order to study the B cell

status during relapses we used the CD19 count closest to the

clinical event (mean 46 days before or after the event median 1

range 0ndash22) We categorized a relapse as a ldquorepopulationrdquo relapse

when it was associated with B cell repopulation $10 3 106

cellsL as a ldquodepletionrdquo relapse when it occurred despite B cell

depletion 10 3 106 cellsL or as a ldquodepletion failurerdquo relapse

when it occurred following a rituximab course failing to deplete B

cells despite conventional rituximab doses and adequate CD19

monitoring In order to examine the timing of CD19 repopula-

tion we used data only from rituximab courses with evidence of

both B cell depletion and subsequent repopulation (31 courses

from 13 patients)

Therapeutic efficacy We used ARR as a clinical indicator of

therapeutic efficacy by comparing the ARR pre-rituximab and

during rituximab ARR was calculated only when a time span of

$6 months was available12 One relapse (patient 13) occurred 14

days after the first rituximab course and was considered to occur

before treatment effect because B cell depletion may take up to

1 month after rituximab administration21 Pre- and post-rituximab

ARR were compared using the Wilcoxon 2-sample test (only

patients with both pre- and post-rituximab ARR were included)

EDSS score was calculated retrospectively to assess the neurologic

outcome at the last follow-up We used Spearman correlation

coefficient (nonparametric) for correlating relapse number with

EDSS score at last follow-up

Research questions and classification of evidence Our pri-

mary research objectives were to determine the efficacy of ritux-

imab using ARR and to determine the relationship of relapses

to B cell repopulation Given the retrospective nature of our study

and lack of a control group our study represents Class IV

evidence

Standard protocol approvals registrations and patientconsents Patient data were acquired after local ethical approval

or using preexisting approved studies to collect deidentified clin-

ical data

2 Neurology Neuroimmunology amp Neuroinflammation


RESULTS Demographics Sixteen children (14 girls)with NMO or NMOSD treated with $2 rituximabcourses were included in our study (mean age 96years median 109 range 18ndash153) The patient racewas white (n 5 8) black or African American (n 5

5) Native Pacific Islander (n 5 1) mixed white andNative Pacific Islander (n 5 1) and mixed AfricanAsian and white (n 5 1)

Clinical presentation and disease course Disease onsetwas between 2000 and 2012 Ten patients had ONandor TM at onset (ON n 5 4 TM n 5 4 bothON and TM n 5 2) The other presentations werebrainstem disease only (n 5 3) TM and brainstemdisease (n 5 2) and ON and brainstem disease (n 5

1) The mean total duration of disease (time fromonset to last follow-up) was 61 years (median 51range 16ndash136) In the 16 children 98 total eventsoccurred (mean 61 median 5 range 1ndash11) most ofwhich (71 of 98) were monosymptomatic attacks

(isolated ON n 5 29 isolated TM n 5 38isolated brainstem disease n 5 4) The remainingattacks were concurrent ON and TM (n 5 13) TMand brainstem disease (n 5 9) ON TM andbrainstem disease (n 5 2) ON and brainstemdisease (n 5 1) or other (n 5 2) Figure 1 illustratesthe clinical course of the 16 patients (clinical eventssecond-line immune therapies and rituximab courses)

Immune therapies before rituximab Before rituximab allpatients received IV methylprednisolone followed byoral prednisolone tapers 8 patients received plasmaexchange and 8 received IVIg Ten patients receivedother second-line immune treatments beforerituximab (figure 1 and table 1) mycophenolatemofetil (n 5 5 2 of 5 also received azathioprine)azathioprine (n 5 5 2 of 5 also receivedmycophenolate mofetil and 1 of 5 also receivedcyclophosphamide) and cyclophosphamide (n 5 31 of 3 also received azathioprine)

Figure 1 Clinical course of the 16 patients Clinical events second-line immune treatments and rituximab courses

AZA 5 azathioprine CYC 5 cyclophosphamide MMF 5 mycophenolate mofetil RTX 5 rituximab

Neurology Neuroimmunology amp Neuroinflammation 3


Rituximab administration A total of 76 rituximabcourses were administered in the 16 patients (mean47 median 45 range 2ndash9) (figure 1) The meantime between the first infusion of the first and lastrituximab courses was 298 months (median 235range 57ndash93) The protocols for administration (indescending order of frequency) were as follows 1000mg 3 2 infusions 2ndash4 weeks apart (n 5 31 courses)375 mgm2 3 4 weekly infusions (n 5 19 courses)375 mgm2 3 1 infusion (n 5 10 courses) 375mgm2 3 2 infusions 2 weeks apart (n 5 9 courses)750 mgm2 3 2 infusions 2 weeks apart (n 5 5courses) and 500 mgm2 3 2 infusions 2 weeks apart(n 5 2 courses) Rituximab was redosed at a mean of79 months (median 76 range 22ndash283) In somepatients it was redosed after a relapse in others afterdetection of B cell repopulation and in a minority atregular intervals regardless of B cell status At last avail-able follow-up rituximab was ongoing in 13 patientsRituximab was discontinued in the 3 remainingpatients because of difficulty coming to the hospital(patient 1) treatment failure (patient 2) and relapsefreedom for $2 years (patient 10)

Infusion reactions and adverse events Data on infusionreactions to rituximab and adverse events were

available in 14 of 16 patients Infusion reactionsoccurred in 6 of 14 children (dyspnea n 5 2 rashn 5 2 chest pain n 5 1 lightheadedness n 5 1tingling and stinging sensation in mouth and throatn 5 1) Other adverse reactions occurred in 3 of 14children including infections in 2 (skin infection n 5

1 mastoiditis n 5 1) and immunoglobulin deficiencywithout infectious complications in 1 (this patientreceived 4 rituximab courses of 750 mgm2 3 2)

Rituximab efficacy Six patients were relapse-freeduring rituximab treatment (patients 9 10 11 1314 and 15) (table 2 figure 1) In these 6 relapse-free patients the rate of use of other immunetherapies during rituximab (corticosteroids n 5 4IVIg n 5 2 plasma exchange n 5 0 second-lineimmune therapies n 5 0) was similar to the rate inthe other 10 patients (corticosteroids n 5 9 IVIgn 5 4 plasma exchange n 5 4 mycophenolatemofetil 1 cyclophosphamide n 5 1 azathioprinen 5 1) In the 10 relapsing patients a total of 21events occurred during rituximab treatment (mean21 median 15 range 1ndash5) (table 2) Relapsesoccurred a mean of 91 months (median 81 range12ndash278) after the last rituximab course (figure 2A)There was a statistically significant reduction between

Table 1 First-line and second-line immune treatments administered before rituximab

Patient SexAge at diseaseonset yr

First-line immune treatments before RTXSecond-line immunetreatments before RTX

Age at RTXinitiation yrIVMP OP PE IVIg MMF AZA CYC

1 F 725 1 (5 courses) 1 2 2 2 1 2 1292

2 M 183 1 (5 courses) 1 1 (1 cycle) 1 (1 course) 2 2 1 1333

3 F 1533 1 (2 courses) 1 1 (1 cycle) 2 2 2 2 1592

4 F 958 1 (2 courses) 1 2 1 (2 courses) 2 2 2 1025

5 F 808 1 (1 course) 1 2 1 (1 course) 2 2 2 817

6 F 1083 1 (8 courses) 1 2 2 2 1 1 1458

7 F 11 1 (1 course) 1 2 1 (2 courses) 2 2 2 1125

8 F 775 1 (8 courses) 1 1 (3 cycles) 2 1 1 2 1458

9 F 392 1 (6 courses) 1 2 1 (1 course) 1 1 2 1392

10 F 1242 1 (1 course) 1 2 2 2 2 2 1267

11 F 1175 1 (2 courses) 1 1 (1 cycle) 1 (1 course) 1 2 2 1258

12 F 1408 1 (2 courses) 1 1 (1 cycle) 2 1 2 2 1533

13 M 1117 1 (3 courses) 1 1 (1 cycle) 1 (8 courses) 1 2 2 1175

14 F 567 1 (7 courses) 1 2 1 (1 course) 2 1 2 1117

15 F 1133 1 (3 courses) 1 1 (15 cycles) 2 2 2 2 1367

16 F 1125 1 (4 courses) 1 1 (3 cycles) 2 2 2 1 14

Abbreviations AZA 5 azathioprine CYC 5 cyclophosphamide IVIg 5 IV immunoglobulin IVMP 5 IV methylprednisolone MMF 5 mycophenolate mofetilOP 5 oral prednisolone PE 5 plasma exchange RTX 5 rituximabWhen available the number of treatment courses and cycles is provided in parentheses Before rituximab all patients received IV methylprednisolone (total60 courses mean 37 courses per patient median 3 range 1ndash8) followed by oral prednisolone Plasma exchange was administered in 816 patients (total26 cycles mean 32 cycles per patient median 1 range 1ndash15 in data available there were mean 52 exchanges per cycle median 5 range 1ndash10) IVIg wasadministered in 816 patients (total 17 courses mean 21 courses per patient median 1 range 1ndash8)



pre- and post-rituximab ARR when first events wereincluded (p 5 0003) or excluded (p 5 0014) (table2) There was also a significant reduction in the ARRin the year after rituximab initiation compared to theyear before (p 5 0002)

CD19 count monitoring and repopulation on rituximab

During the total 426 years of cohort rituximab treat-ment a total of 196 CD19 counts were measured(mean 122 per patient median 9 range 1ndash36) Allpatients had documented B cell depletion after at least1 rituximab course In the 31 rituximab courses (in13 patients) with documented B cell depletion fol-lowed by repopulation the mean time from rituxi-mab administration to the last demonstrated depletedCD19 count was 45 months (median 51 range 09ndash87) and the mean time to the first demonstratedrepopulated CD19 count was 68 months (median67 range 27ndash122) The 2 shortest times to repo-pulation occurred 27 and 29 months after rituximab(375 mgm2 3 1 and 375 mgm2 3 2 respectively)in 2 different patients We observed notable interpa-tient variability in the time to B cell repopulation andsome intrapatient variability (figure 2B) The meantime to repopulation in the first rituximab courses(mean 74 months median 72 range 36ndash122

calculated in 8 courses) was similar to that in subse-quent courses (mean 67 months median 68 range27ndash112 calculated in 23 courses) Time to B cellrepopulation was faster in the younger patients (18courses in 5 patients with adequate data age range82ndash117 years at rituximab initiation) than in the olderpatients (12 courses in 7 patients age range 133ndash159years at rituximab initiation) (mean 59 vs 81 monthsmedian 56 vs 85 months) Where adequate data wereavailable (n 5 10 courses) once B cells repopulatedover the threshold of 10 3 106 cellsL B cell countsnever redepleted spontaneously In contrast accordingto available data (n 5 9 courses) only 22 of CD19counts 1ndash93 106 cellsL were followed by repopulatedCD19 values $10 3 106 cellsL within 1 month

CD19 count and relationship to relapses The 21 relapsesthat occurred in 10 children during rituximab treat-ment are detailed in table e-1 at Neurologyorgnn(adequate CD19 data in 20 of 21 relapses) Most ofthe events (13 of 20) occurred with B cellrepopulation and are defined as ldquorepopulationrdquorelapses In these 13 ldquorepopulationrdquo relapses themean CD19 value at relapse was 1923 3 106 cellsL (median 130 range 10ndash449) and in 4 of these 13events the CD19 count was 10ndash50 3 106 cellsL

Table 2 Duration of disease number of events and ARR pre- and post-rituximab

PatientDisease durationpre-RTX mo

Duration of RTXtreatment mo

No eventspre-RTX (includingfirst event)

No events duringRTX treatment

ARR pre-RTX includingfirst event (excludingfirst event)

ARR duringRTX

ARR in theyear beforeRTX

ARR in theyear afterRTX

1 675 22 5 1 089 (071) 054 1 1

2 137 23 5 5 044 (035) 261 1 0

3 4 26 2 1 mdash 046 mdash 1

4 8 173 2 2 300 (150) 139 mdash 1

5 13 275 1 2 mdash 087 mdash 0

6 45 46 9 2 240 (213) 052 3 1

7 32 31 2 1 mdash 039 mdash 1

8 823 26 10 1 146 (131) 046 3 0

9 1237 395 9 0 088 (078) 0 1 0

10 25 335 1 0 mdash 0 mdash 0

11 97 92 2 0 247 (124) 0 mdash 0

12 15 7 3 1 240 (160) 171 2 1

13 75 227 4 0 640 (480) 0 mdash 0

14 66 30 10 0 182 (164) 0 1 0

15 28 527 7 0 300 (257) 0 3 0

16 33 98 5 5 182 (145) 061 1 0

Mean 396 Mean 32 Mean 48 Mean 13 Mean 22 (15) Mean 06 Mean 17 Mean 04

Median 215 Median 267 Median 45 Median 1 Median 21 (15) Median 05 Median 1 Median 0

Range 13ndash137 Range 7ndash98 Range 1ndash10 Range 0ndash5 Range 04ndash64 (03ndash32) Range 0ndash26 Range 1ndash3 Range 0ndash1

Abbreviations ARR 5 annualized relapse rate RTX 5 rituximabThere was a statistically significant reduction between pre- and post-rituximab ARR when first events were included (p 5 0003) or excluded (p 5 0014)There was also a significant reduction in the ARR in the year before and after rituximab initiation (p 5 0002)



(10 16 37 and 40 3 106 cellsL) Of the 13ldquorepopulationrdquo relapses there was a lack of monitoring(defined as1 CD19 count in the 4 months precedingthe relapse) in 10 a delay in redosing (defined as$10 days between detection of repopulation andrituximab redosing) during which the relapseoccurred in 5 and there was no inadequatemonitoring or delayed redosing in 2

The remaining 7 clinical events occurred in 2 pa-tients 3 relapses in patient 2 (rituximab 750 mgm2 3

2 infusions 2 weeks apart) occurred despite B celldepletion and were defined as ldquodepletionrdquo relapseswhereas the 4 relapses in patient 16 (rituximab1000 mg3 2 infusions 4 weeks apart) occurred withdocumented persistent nondepleted CD19 counts(mean 62 CD19 countsrelapse median 6 range2ndash11) and were defined as ldquodepletion failurerdquo relap-ses Examples of relapse freedom after treatment andof ldquorepopulationrdquo ldquodepletionrdquo and ldquodepletion fail-urerdquo relapses are presented in figures 3 and e-1

Outcome At a mean follow-up of 61 years fromdisease onset (median 51 years range 16ndash136)mean EDSS score was 24 (median 25 range 0ndash65) and no ongoing problems (EDSS 0) werereported in 5 patients There was a trend of worseEDSS scores at follow-up in the patients who hadmore relapses during the disease course but thiswas not statistically significant (r 5 049 p 5

0051) The most common neurologic problem atfollow-up was reduced visual acuity reported in 10of 16 cases in 6 of these 10 patients visual acuity wasseverely reduced (worse eye with maximal visualacuity corrected less than 20200) Pyramidal signsin the lower limbs were reported in 2 of 16 casesupper limb involvement in 0 of 16 and bowel orbladder impairment in 1 of 16

DISCUSSION We retrospectively studied 16 chil-dren with NMO treated with $2 rituximab courseswith the aim of optimizing rituximab monitoring and

Figure 2 Time to relapse and time to B cell repopulation after rituximab

(A) Relapses during rituximab (RTX) treatment according to the time from last rituximab course (total 21 relapses in 10 pa-tients) (B) Inter- and intraindividual variability in the time to B cell repopulation after rituximab in 9 patients To assess thevariability in the intraindividual time to repopulation these 9 patients were selected based on the availability of at least 2rituximab courses with evidence of a repopulated CD19 count after demonstrated depletion and the fact that the samedose regimen was administered (rituximab regimen specified for each patient next to the bar) The horizontal bars representthe range of intraindividual variability in the time to repopulation and the dots represent the actual measurements There issignificant variability between patients although the intrapatient variability appears to be less



Figure 3 Summary figure exemplifying 4 different types of response to rituximab treatment observed in our patients

Relapse freedom with rituximab (RTX) (A B) occurrence of relapses with a repopulated B cell count (ldquorepopulationrdquo relapses C D) occurrence of relapses with adepleted B cell count (ldquodepletionrdquo relapses E) occurrence of relapses in association with failure to reach B cell depletion (ldquodepletion failurerdquo relapses F) (A) Relapsefreedom (no relapses during rituximab) rituximab redosing after B cell repopulation (patient 14) (B) Relapse freedom (no relapses during rituximab) rituximabredosing before B cell repopulation (patient 10) (C) ldquoRepopulationrdquo relapses (relapses with B cell repopulation) repopulation was detected only at the time of therelapse (third and fourth relapses) subsequent rituximab courses were administered after the relapse (second and third rituximab courses) (patient 4) (D) ldquoRepo-pulationrdquo relapses (relapses with B cell repopulation) repopulation was noticed at CD19 count monitoring and rituximab was administered but clinical relapseoccurred a fewdays after rituximab before depletionwas achieved (second and third relapses) (patient 5) (E) ldquoDepletionrdquo relapses (relapses despite B cell depletion in

Continued



redosing to prevent relapses This represents the larg-est reported therapeutic study of pediatric NMO

Confirming published literature there was afemale predominance in our cohort and most ofthe clinical events were monosymptomatic TMON and brainstem events Our patients had a highrelapse rate and a long disease course before rituximabinitiation Fifteen of the 16 patients were NMO-IgGpositive although the single MOG-IgG-positivepatient had 2 events in the 3 months preceding ritux-imab initiation and 1 relapse during rituximabsuggesting a highly relapsing disease Althoughlong-term data regarding MOG-IgG-associated dis-ease are lacking early reports suggest that MOG-IgG-associated NMOSD is more reversible and lesssevere and carries less risk of permanent disabilitycompared to NMO-IgG-associated NMOSD1922

All patients received immunosuppressive therapiesbefore rituximab all received IV methylprednisoloneand oral steroids half received IVIg half receivedplasma exchange and 625 were given othersecond-line immune therapies before rituximab Rit-uximab was generally initiated after $2 eventsalthough it was started after the first event in 3 casesOverall our cohort likely represents a more severeend of the pediatric NMO spectrum

In our cohort the protocols of rituximab induc-tion redosing and monitoring were heterogeneousreflecting the multicenter nature of our cohort andthe lack of guidelines and consensus opinion Ritux-imab was redosed at a mean of 79 months althoughwith considerable variability (range 22ndash283months) Redosing occurred for different reasonsincluding occurrence of relapses detection of B cellrepopulation or more rarely planned redosing (fig-ures 3 and e-1)

Rituximab treatment was relatively well toleratedwith no major complications in 426-year cohort treat-ment There was evidence of efficacy in our cohort 6of the patients were relapse-free during treatment(figures 3 A and B and e-1) There was a significantreduction in ARR using all measures although it isimportant to note that the ARR may decline duringthe course of disease regardless of treatment23 The useof other immune therapies was similar in the 6 relapse-free patients compared to the other patients suggestingthat the lack of relapses was not due to other concom-itant therapies administered with rituximab

The clinical events during rituximab occurred a meanof 91 months after the last rituximab course althoughthe timing of relapses was very widely distributed

We chose a CD19 count of 10 3 106 cellsL as athreshold for B cell repopulation as previously used1620

partly because absolute values (rather than percentages)would allow adequate comparison across centers Theobservation that 4 of the 13 ldquorepopulationrdquo relapsesin our cohort occurred during early repopulation(10ndash50 3 106 cellsL) confirms the clinical validity of10 3 106 cellsL as a threshold We also observed thatonce B cells repopulated beyond 10 3 106 cellsLCD19 counts continued to rise and there was no spon-taneous return to B cell redepletion

We confirmed a relationship between B cell repo-pulation and relapses Most relapses occurred withCD19 repopulation and only 1 patient had relapseswith depleted CD19 counts confirming that deple-tion appears to be protective in most patients In mostof the 13 ldquorepopulationrdquo relapses CD19 monitoringwas inadequate and B cell repopulation went unno-ticed until subsequent clinical relapse In 5 of theldquorepopulationrdquo relapses there was delayed rituximabredosing after detection of B cell repopulation andrelapses occurred while waiting to admit the patientfor redosing Furthermore B cell depletion can takeup to 1 month after rituximab administration21

allowing for a ldquowindow of vulnerabilityrdquo for relapses(as shown in figure 3D) The remaining 7 relapsesoccurred in 2 patients defined as ldquodepletionrdquo relapsein one patient (figure 3E) and ldquodepletion failurerdquorelapse in the other (figure 3F) Therefore only 1 ofthe 16 patients (patient 2) had relapses despite ade-quate monitoring and documented B cell depletionand can therefore be defined as having true rituximabfailure The reason for the different response to ritux-imab in these 2 patients with ldquodepletionrdquo and ldquodeple-tion failurerdquo relapses is not clear although someinvestigators have suggested that B cell activatingfactor of the tumor necrosis factor family may berelevant2024ndash26 Some studies in adult patients haveshown a relationship of anti-AQP4 antibodies withB cell status and clinical relapses112728 althoughothers have not found a convincing relationship20

Unfortunately longitudinal anti-AQP4 antibodieswere not available in our cohort

In light of the above considerations on the rela-tionship between B cell repopulation and relapsesunderstanding the timing of repopulation after ritux-imab is critical for preventing relapses The meantime for B cell repopulation in our cohort wasbetween 45 (mean time of last depletion) and 68months (mean time of first repopulation) after the lastrituximab course However repopulation as early as

Figure 3 legend continuedthe last 3 relapses) (patient 2) (F) ldquoDepletion failurerdquo relapses (relapses associated with failure to reach B cell depletion in the first second and thirdrituximab courses) In this patient B cell depletion was achieved in subsequent rituximab courses (total 9 courses same rituximab regimen used in all thecourses 1000 mg 3 2) The figure shows only the first 5 courses no relapses occurred subsequently



27 months post-rituximab and persistent B celldepletion up to 87 months were observed suggestinglarge interpatient variability in CD19 count effects(figure 2B) similar to other published data29 Incontrast the intrapatient variability appeared to besmaller implying a relative predictability of B cell re-population in individuals which will help monitoringWe noted that the shortest time to repopulationoccurred with the lowest rituximab doses and the lon-gest with the highest doses as previously observed29

although other variables likely play a role in B cellrepopulation We also observed that younger patientsrepopulated faster than older patients

In our study we observed that genuine treatmentfailure with rituximab occurred in only 1 patientwhereas relapses were otherwise attributable to thechallenges associated with monitoring and redosingWe confirm that rituximab efficacy is associated withCD19 depletion and our data suggest that the detec-tion of repopulation over 10 3 106 cellsL shouldalert the clinician to the likely possibility of furtherB cell rise and relapse risk Considering the significantvariability observed in the time to B cell repopulationfurther efforts should be made to optimize rituximabmonitoring A possible individualized strategyto minimize relapses involves rigorous CD19 moni-toring (ie monthly especially after the thirdmonth) particularly during first courses and rapidredosing on repopulation detection Given thelatency of B cell depletion after rituximab infusionthere is a risk of relapse during this repopulatedperiod especially when there is delay in redosingIn view of this an alternative strategy involvesplanned rituximab redosing at regular intervalsbefore B cell repopulation occurs as previouslydescribed91020 and shown in figure 3B which mayreduce the relapse risk but will result in increasedtherapy cost As shown in figure 2B there is signifi-cant variability in B cell repopulation between pa-tients including early repopulation (3ndash6 months)even for higher dose regimens (375 mgm2 3 4 and1000 mgm2 3 2) Therefore planned redosingwould need to be at short intervals (3ndash4 months)to minimize the chance of B cell repopulation

The retrospective design the lack of standardiza-tion and the relatively small number of patients arethe main limitations of our study However we haveconfirmed rituximab efficacy demonstrated chal-lenges in monitoring and provided data on B cell re-population This will improve redosing of rituximabin children with NMO and other serious autoim-mune disorders of the CNS

AUTHOR CONTRIBUTIONSDr Margherita Nosadini data analysis and first draft critical revision of

the manuscript for important intellectual content editing and approval of

final draft Dr Gulay Alper acquisition of data critical revision of the

manuscript for important intellectual content editing and approval of

final draft Dr Catherine J Riney acquisition of data critical revision

of the manuscript for important intellectual content editing and approval

of final draft Dr Leslie A Benson acquisition of data critical revision of


final draft Dr Shekeeb S Mohammad acquisition of data critical revi-

sion of the manuscript for important intellectual content editing and

approval of final draft Dr Sudarshini Ramanathan acquisition of data

critical revision of the manuscript for important intellectual content ed-

iting and approval of final draft Dr Melinda Nolan acquisition of data


iting and approval of final draft Dr Richard Appleton acquisition of

data critical revision of the manuscript for important intellectual content

editing and approval of final draft Dr Richard J Leventer acquisition of


editing and approval of final draft Dr Kumaran Deiva acquisition of


editing and approval of final draft Dr Fabienne Brilot acquisition of


editing and approval of final draft Dr Mark P Gorman acquisition of


editing and approval of final draft Dr Amy T Waldman acquisition of


editing and approval of final draft Dr Brenda Banwell acquisition of


editing and approval of final draft Dr Russell C Dale project concep-

tion design and modification data analysis and first draft critical

revision of the manuscript for important intellectual content study

supervision

ACKNOWLEDGMENTThe authors thank the patients and their families M Nosadini has appre-

ciated funding from Petre Foundation (Australia) and the University of Pa-

dua (Italy)

STUDY FUNDINGNo targeted funding reported

DISCLOSUREM Nosadini and G Alper report no disclosures CJ Riney received

speaker honoraria andor travel funding from Biogen Idec and UCB Aus-

tralia Pty Ltd and received research support from Novartis and UCB

LA Benson received research support from Boston Childrenrsquos Hospital

SS Mohammad received travel funding from the Movement Disorders

Society and received research support from NHMRC S Ramanathan

received research support from NHMRC M Nolan reports no disclo-

sures R Appleton served on the scientific advisory board for SHIRE

received speaker honoraria from EISAI and received publishing royalties

from Oxford University Press and Cambridge University Press RJ Lev-

enter received travel funding and speaker honoraria from Asia Oceania

Congress of Child Neurology received research support from NHMRC

and Campbell Edwards Trust Research K Deiva received travel funding

from Biogen Idec Merck Serono and Genzyme F Brilot is an associate

editor for Journal of Visualized Experiments and received research support

from NHMRC The Star Scientific Foundation Australia The Trish

Multiple Sclerosis Foundation Australia Multiple Sclerosis Research Aus-

tralia Multiple Sclerosis Angels Melbourne Australia and Petre Founda-

tion Australia MP Gorman received research support from NIH

United States Department of Defense and Multiple Sclerosis Society

AT Waldman is on the scientific advisory board for Johns Hopkins

University and Childrenrsquos Hospital of Philadelphia received travel fund-

ing from Novartis received publishing royalties from UpToDate has

consulted for OptumInsight Life Sciences Inc participated in NIH Loan

Repayment Program received research support from Biogen Idec NIH

NINDS and Childrenrsquos Hospital of Philadelphia and holds stock or

stock options in Pfizer and Spark Therapeutics B Banwell served on

the scientific advisory board for Biogen Idec Sanofi Eli Lilly and No-

vartis received travel funding andor speaker honoraria from Biogen Idec

Merck Serono Teva Neuroscience and Bayer is on the editorial board



for Neurology and Multiple Sclerosis and Related Disorders has consulted

for Biogen Idec Eli Lilly and Sanofi has spoken at an event supported

by the Consortium of MS Centers received research support from Cana-

dian Institute of Health Research Multiple Sclerosis Society of Canada

Multiple Sclerosis Scientific Research Foundation and National Multiple

Sclerosis Society RC Dale served on the scientific advisory board for

Queensland Childrenrsquos Medical Institute received speaker honoraria

from Biogen Idec and Bristol-Myers-Squibb is an editorial advisory

board member for Multiple Sclerosis and Related Disorders and an editorial

board member for Neurology Neuroimmunology amp Neuroinflammation

and European Journal of Paediatric Neurology received publishing royalties

from Biogen and Bristol-Myers-Squibb and received research support

from NHMRC and Multiple Sclerosis Research Australia Go to

Neurologyorgnn for full disclosure forms

Received April 24 2015 Accepted in final form September 29 2015

REFERENCES1 Wingerchuk DM Weinshenker BG Neuromyelitis optica

(Devicrsquos syndrome) Handb Clin Neurol 2014122581ndash

599

2 Lennon VA Wingerchuk DM Kryzer TJ et al A serum

autoantibody marker of neuromyelitis optica distinction

from multiple sclerosis Lancet 20043642106ndash2112

3 Wegner C Recent insights into the pathology of multiple

sclerosis and neuromyelitis optica Clin Neurol Neurosurg

2013115S38ndashS41

4 Kim SH Kim W Li XF Jung IJ Kim HJ Does inter-

feron beta treatment exacerbate neuromyelitis optica spec-

trum disorder Mult Scler 2012181480

5 Kleiter I Hellwig K Berthele A et al Failure of natalizu-

mab to prevent relapses in neuromyelitis optica Arch

Neurol 201269239ndash245

6 Min JH Kim BJ Lee KH Development of extensive

brain lesions following fingolimod (FTY720) treatment

in a patient with neuromyelitis optica spectrum disorder

Mult Scler 201218113ndash115

7 Trebst C Jarius S Berthele A et al Update on the diag-

nosis and treatment of neuromyelitis optica recommenda-

tions of the Neuromyelitis Optica Study Group

(NEMOS) J Neurol 20142611ndash16

8 Dale RC Brilot F Duffy LV et al Utility and safety of

rituximab in pediatric autoimmune and inflammatory

CNS disease Neurology 201483142ndash150

9 Jacob A Weinshenker BG Violich I et al Treatment of

neuromyelitis optica with rituximab retrospective analysis

of 25 patients Arch Neurol 2008651443ndash1448

10 Bedi GS Brown AD Delgado SR Usmani N Lam BL

Sheremata WA Impact of rituximab on relapse rate and

disability in neuromyelitis optica Mult Scler 201117

1225ndash1230

11 Kim SH Huh SY Lee SJ Joung A Kim HJ A 5-year

follow-up of rituximab treatment in patients with neuro-

myelitis optica spectrum disorder JAMA Neurol 201370

1110ndash1117

12 Mealy MA Wingerchuk DM Palace J Greenberg BM

Levy M Comparison of relapse and treatment failure rates

among patients with neuromyelitis optica multicenter study

of treatment efficacy JAMA Neurol 201471324ndash330

13 Lotze TE Northrop JL Hutton GJ Ross B Schiffman JS

Hunter JV Spectrum of pediatric neuromyelitis optica

Pediatrics 2008122e1039ndashe1047

14 McKeon A Lennon VA Lotze T et al CNS aquaporin-4

autoimmunity in children Neurology 20087193ndash100

15 Beres SJ Graves J Waubant E Rituximab use in pediatric

central demyelinating disease Pediatr Neurol 201451

114ndash118

16 Longoni G Banwell B Filippi M Yeh EA Rituximab as a

first-line preventive treatment in pediatric NMOSDs pre-

liminary results in 5 children Neurol Neuroimmunol

Neuroinflamm 20141e46 doi 101212NXI

0000000000000046

17 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF

Weinshenker BG Revised diagnostic criteria for neuromy-

elitis optica Neurology 2006661485ndash1489

18 Wingerchuk DM Lennon VA Lucchinetti CF

Pittock SJ Weinshenker BG The spectrum of neuromy-

elitis optica Lancet Neurol 20076805ndash815

19 Dale RC Tantsis EM Merheb V et al Antibodies to MOG

have a demyelination phenotype and affect oligodendrocyte

cytoskeleton Neurol Neuroimmunol Neuroinflamm 2014

1e12 doi 101212NXI0000000000000012

20 Pellkofer HL Krumbholz M Berthele A et al Long-term

follow-up of patients with neuromyelitis optica after

repeated therapy with rituximab Neurology 201176

1310ndash1315

21 Kosmidis ML Dalakas MC Practical considerations on

the use of rituximab in autoimmune neurological disor-

ders Ther Adv Neurol Disord 2010393ndash105

22 Kitley J Woodhall M Waters P et al Myelin-oligoden-

drocyte glycoprotein antibodies in adults with a neuromy-

elitis optica phenotype Neurology 2012791273ndash1277

23 Kim SM Park J Kim SH et al Factors associated with

the time to next attack in neuromyelitis optica accelerated

failure time models with random effects PLoS One 2013

8e82325

24 Wang H Wang K Zhong X et al Cerebrospinal fluid

BAFF and APRIL levels in neuromyelitis optica and mul-

tiple sclerosis patients during relapse J Clin Immunol

2012321007ndash1011

25 Nakashima I Takahashi T Cree BA et al Transient increases

in anti-aquaporin-4 antibody titers following rituximab treat-

ment in neuromyelitis optica in association with elevated

serum BAFF levels J Clin Neurosci 201118997ndash998

26 Gredler V Mader S Schanda K et al Clinical and immu-

nological follow-up of B-cell depleting therapy in CNS

demyelinating diseases J Neurol Sci 201332877ndash82

27 Jarius S Aboul-Enein F Waters P et al Antibody to

aquaporin-4 in the long-term course of neuromyelitis op-

tica Brain 20081313072ndash3080

28 He D Yu Y Yan W Dai Q Xu Z Chu L Individualized

rituximab treatment for relapsing neuromyelitis optica a

pediatric case report Pediatr Neurol 201451255ndash258

29 Greenberg BM Graves D Remington G et al Rituximab

dosing and monitoring strategies in neuromyelitis optica

patients creating strategies for therapeutic success Mult

Scler 2012181022ndash1026



DOI 101212NXI000000000000018820163 Neurol Neuroimmunol Neuroinflamm

Margherita Nosadini Gulay Alper Catherine J Riney et al disorder

Rituximab monitoring and redosing in pediatric neuromyelitis optica spectrum

This information is current as of January 21 2016

2016 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy

is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm

ServicesUpdated Information amp

httpnnneurologyorgcontent31e188fullhtmlincluding high resolution figures can be found at

Supplementary Material httpnnneurologyorgcontentsuppl2016012131e188DC1

Supplementary material can be found at

References httpnnneurologyorgcontent31e188fullhtmlref-list-1

This article cites 29 articles 1 of which you can access for free at

Citations httpnnneurologyorgcontent31e188fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome

httpnnneurologyorgcgicollectionclass_ivClass IV

httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseases

httpnnneurologyorgcgicollectionall_pediatricAll Pediatricfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

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The course of NMO is characterized by ahigh relapse rate with accumulation ofneurologic disability potentially causingpermanent blindness and paralysis There-fore relapse prevention is crucial Differenti-ation from MS is important because someMS therapies fail to control or may aggravateNMO4ndash6 Even though the optimal thera-peutic regimen has not been establishedacute NMO attacks are mainly treatedwith corticosteroids plasma exchange andIV immunoglobulin (IVIg) azathioprinemethotrexate mycophenolate mofetil ritux-imab mitoxantrone cyclophosphamide andtocilizumab have been used to preventrelapses7

Rituximab is an anti-CD20 chimericmonoclonal antibody that depletes B cellsthat is used in severe autoimmune andinflammatory CNS disorders despite the riskof infections as recently demonstrated in alarge pediatric study8 One prospective and3 retrospective adult NMO studies demon-strated reduced annualized relapse rate(ARR) and significantly improved ExpandedDisability Status Scale (EDSS) score with rit-uximab9ndash12 Pediatric data are more limitedand retrospective13ndash16 No study specificallyaddresses optimal rituximab monitoring andredosing to prevent relapses and reduce dis-ability To clarify these aspects we retrospec-tively studied 16 children with NMO whoreceived $2 rituximab courses in order toestablish rituximab efficacy the time fromrituximab to B cell repopulation and therelationship between B cell repopulationand relapses

METHODS Patients We identified 16 patients with NMO

who received $2 rituximab courses (18 years at first dose)

from 9 international pediatric neuroimmunology centers

NMO was defined according to the revised Wingerchuk cri-

teria for NMO17 and NMO spectrum disorders (NMOSD)18

In 13 of 16 patients diagnosis of definite NMO was met based

on the presence of both optic neuritis (ON) and transverse

myelitis (TM)19 The remaining 3 children had NMOSD (1

had a single attack of isolated TM 1 had an attack of TM and

brainstem manifestations and 1 had recurrent ON) and these

patients were all NMO-IgG positive Regarding serologic

status 15 of 16 patients were positive for NMO-IgG or

AQP4 antibodies 12 were tested and positive for NMO-

IgG using immunofluorescence and 3 were tested and

positive for both NMO-IgG (using immunofluorescence)

and anti-AQP4 antibodies (using cell-based assay) One

patient was negative for NMO-IgG but positive for antindash

myelin oligodendrocyte glycoprotein (MOG) antibodies

using cell-based assay (not tested for anti-AQP4 antibodies)

(patient 7)

Data collection Data were retrospectively collected by the

main investigator (RCD) through telephone interviews to

the physicians using a structured questionnaire created for this

study Information recorded included demographics clinical

characteristics of disease immune therapies received besides

rituximab rituximab regimen CD19 count measurements

and outcome Data collection focused on the relationship

between rituximab administration (timing dose number of

courses adverse reactions) CD19 counts and relapses

First-line immune therapy was defined as corticosteroids

IVIg and plasma exchange whereas second-line immune

therapy included rituximab cyclophosphamide azathioprine

and mycophenolate mofetil Disease duration pre-rituximab

was defined as the time between onset (first event) and

initiation of rituximab treatment Rituximab treatment

duration was defined as the time between rituximab

initiation and last follow-up (for patients with ongoing

rituximab) or the date of final CD19 repopulation (for

patients who stopped rituximab)

CD19 values and relationship to relapses The threshold forB cell repopulation was defined as CD19 count $10 3 106

cellsL as previously proposed1620 In order to study the B cell

status during relapses we used the CD19 count closest to the

clinical event (mean 46 days before or after the event median 1

range 0ndash22) We categorized a relapse as a ldquorepopulationrdquo relapse

when it was associated with B cell repopulation $10 3 106

cellsL as a ldquodepletionrdquo relapse when it occurred despite B cell

depletion 10 3 106 cellsL or as a ldquodepletion failurerdquo relapse

when it occurred following a rituximab course failing to deplete B

cells despite conventional rituximab doses and adequate CD19

monitoring In order to examine the timing of CD19 repopula-

tion we used data only from rituximab courses with evidence of

both B cell depletion and subsequent repopulation (31 courses

from 13 patients)

Therapeutic efficacy We used ARR as a clinical indicator of

therapeutic efficacy by comparing the ARR pre-rituximab and

during rituximab ARR was calculated only when a time span of

$6 months was available12 One relapse (patient 13) occurred 14

days after the first rituximab course and was considered to occur

before treatment effect because B cell depletion may take up to

1 month after rituximab administration21 Pre- and post-rituximab

ARR were compared using the Wilcoxon 2-sample test (only

patients with both pre- and post-rituximab ARR were included)

EDSS score was calculated retrospectively to assess the neurologic

outcome at the last follow-up We used Spearman correlation

coefficient (nonparametric) for correlating relapse number with

EDSS score at last follow-up

Research questions and classification of evidence Our pri-

mary research objectives were to determine the efficacy of ritux-

imab using ARR and to determine the relationship of relapses

to B cell repopulation Given the retrospective nature of our study

and lack of a control group our study represents Class IV

evidence

Standard protocol approvals registrations and patientconsents Patient data were acquired after local ethical approval

or using preexisting approved studies to collect deidentified clin-

ical data






















1 F 725 1 (5 courses) 1 2 2 2 1 2 1292


3 F 1533 1 (2 courses) 1 1 (1 cycle) 2 2 2 2 1592


5 F 808 1 (1 course) 1 2 1 (1 course) 2 2 2 817

6 F 1083 1 (8 courses) 1 2 2 2 1 1 1458

7 F 11 1 (1 course) 1 2 1 (2 courses) 2 2 2 1125

8 F 775 1 (8 courses) 1 1 (3 cycles) 2 1 1 2 1458

9 F 392 1 (6 courses) 1 2 1 (1 course) 1 1 2 1392

10 F 1242 1 (1 course) 1 2 2 2 2 2 1267


12 F 1408 1 (2 courses) 1 1 (1 cycle) 2 1 2 2 1533


14 F 567 1 (7 courses) 1 2 1 (1 course) 2 1 2 1117

15 F 1133 1 (3 courses) 1 1 (15 cycles) 2 2 2 2 1367

16 F 1125 1 (4 courses) 1 1 (3 cycles) 2 2 2 1 14















ARR duringRTX



1 675 22 5 1 089 (071) 054 1 1

2 137 23 5 5 044 (035) 261 1 0

3 4 26 2 1 mdash 046 mdash 1

4 8 173 2 2 300 (150) 139 mdash 1

5 13 275 1 2 mdash 087 mdash 0

6 45 46 9 2 240 (213) 052 3 1

7 32 31 2 1 mdash 039 mdash 1

8 823 26 10 1 146 (131) 046 3 0

9 1237 395 9 0 088 (078) 0 1 0

10 25 335 1 0 mdash 0 mdash 0

11 97 92 2 0 247 (124) 0 mdash 0

12 15 7 3 1 240 (160) 171 2 1

13 75 227 4 0 640 (480) 0 mdash 0

14 66 30 10 0 182 (164) 0 1 0

15 28 527 7 0 300 (257) 0 3 0

16 33 98 5 5 182 (145) 061 1 0



















Continued





















































supervision



dua (Italy)



















































599






2013115S38ndashS41
























1225ndash1230




1110ndash1117












114ndash118





0000000000000046










1e12 doi 101212NXI0000000000000012




1310ndash1315










8e82325




2012321007ndash1011









































Reprints























1 F 725 1 (5 courses) 1 2 2 2 1 2 1292


3 F 1533 1 (2 courses) 1 1 (1 cycle) 2 2 2 2 1592


5 F 808 1 (1 course) 1 2 1 (1 course) 2 2 2 817

6 F 1083 1 (8 courses) 1 2 2 2 1 1 1458

7 F 11 1 (1 course) 1 2 1 (2 courses) 2 2 2 1125

8 F 775 1 (8 courses) 1 1 (3 cycles) 2 1 1 2 1458

9 F 392 1 (6 courses) 1 2 1 (1 course) 1 1 2 1392

10 F 1242 1 (1 course) 1 2 2 2 2 2 1267


12 F 1408 1 (2 courses) 1 1 (1 cycle) 2 1 2 2 1533


14 F 567 1 (7 courses) 1 2 1 (1 course) 2 1 2 1117

15 F 1133 1 (3 courses) 1 1 (15 cycles) 2 2 2 2 1367

16 F 1125 1 (4 courses) 1 1 (3 cycles) 2 2 2 1 14















ARR duringRTX



1 675 22 5 1 089 (071) 054 1 1

2 137 23 5 5 044 (035) 261 1 0

3 4 26 2 1 mdash 046 mdash 1

4 8 173 2 2 300 (150) 139 mdash 1

5 13 275 1 2 mdash 087 mdash 0

6 45 46 9 2 240 (213) 052 3 1

7 32 31 2 1 mdash 039 mdash 1

8 823 26 10 1 146 (131) 046 3 0

9 1237 395 9 0 088 (078) 0 1 0

10 25 335 1 0 mdash 0 mdash 0

11 97 92 2 0 247 (124) 0 mdash 0

12 15 7 3 1 240 (160) 171 2 1

13 75 227 4 0 640 (480) 0 mdash 0

14 66 30 10 0 182 (164) 0 1 0

15 28 527 7 0 300 (257) 0 3 0

16 33 98 5 5 182 (145) 061 1 0



















Continued





















































supervision



dua (Italy)



















































599






2013115S38ndashS41
























1225ndash1230




1110ndash1117












114ndash118





0000000000000046










1e12 doi 101212NXI0000000000000012




1310ndash1315










8e82325




2012321007ndash1011









































Reprints













1 F 725 1 (5 courses) 1 2 2 2 1 2 1292


3 F 1533 1 (2 courses) 1 1 (1 cycle) 2 2 2 2 1592


5 F 808 1 (1 course) 1 2 1 (1 course) 2 2 2 817

6 F 1083 1 (8 courses) 1 2 2 2 1 1 1458

7 F 11 1 (1 course) 1 2 1 (2 courses) 2 2 2 1125

8 F 775 1 (8 courses) 1 1 (3 cycles) 2 1 1 2 1458

9 F 392 1 (6 courses) 1 2 1 (1 course) 1 1 2 1392

10 F 1242 1 (1 course) 1 2 2 2 2 2 1267


12 F 1408 1 (2 courses) 1 1 (1 cycle) 2 1 2 2 1533


14 F 567 1 (7 courses) 1 2 1 (1 course) 2 1 2 1117

15 F 1133 1 (3 courses) 1 1 (15 cycles) 2 2 2 2 1367

16 F 1125 1 (4 courses) 1 1 (3 cycles) 2 2 2 1 14















ARR duringRTX



1 675 22 5 1 089 (071) 054 1 1

2 137 23 5 5 044 (035) 261 1 0

3 4 26 2 1 mdash 046 mdash 1

4 8 173 2 2 300 (150) 139 mdash 1

5 13 275 1 2 mdash 087 mdash 0

6 45 46 9 2 240 (213) 052 3 1

7 32 31 2 1 mdash 039 mdash 1

8 823 26 10 1 146 (131) 046 3 0

9 1237 395 9 0 088 (078) 0 1 0

10 25 335 1 0 mdash 0 mdash 0

11 97 92 2 0 247 (124) 0 mdash 0

12 15 7 3 1 240 (160) 171 2 1

13 75 227 4 0 640 (480) 0 mdash 0

14 66 30 10 0 182 (164) 0 1 0

15 28 527 7 0 300 (257) 0 3 0

16 33 98 5 5 182 (145) 061 1 0



















Continued





















































supervision



dua (Italy)



















































599






2013115S38ndashS41
























1225ndash1230




1110ndash1117












114ndash118





0000000000000046










1e12 doi 101212NXI0000000000000012




1310ndash1315










8e82325




2012321007ndash1011









































Reprints















ARR duringRTX



1 675 22 5 1 089 (071) 054 1 1

2 137 23 5 5 044 (035) 261 1 0

3 4 26 2 1 mdash 046 mdash 1

4 8 173 2 2 300 (150) 139 mdash 1

5 13 275 1 2 mdash 087 mdash 0

6 45 46 9 2 240 (213) 052 3 1

7 32 31 2 1 mdash 039 mdash 1

8 823 26 10 1 146 (131) 046 3 0

9 1237 395 9 0 088 (078) 0 1 0

10 25 335 1 0 mdash 0 mdash 0

11 97 92 2 0 247 (124) 0 mdash 0

12 15 7 3 1 240 (160) 171 2 1

13 75 227 4 0 640 (480) 0 mdash 0

14 66 30 10 0 182 (164) 0 1 0

15 28 527 7 0 300 (257) 0 3 0

16 33 98 5 5 182 (145) 061 1 0



















Continued





















































supervision



dua (Italy)



















































599






2013115S38ndashS41
























1225ndash1230




1110ndash1117












114ndash118





0000000000000046










1e12 doi 101212NXI0000000000000012




1310ndash1315










8e82325




2012321007ndash1011









































Reprints
















Continued





















































supervision



dua (Italy)



















































599






2013115S38ndashS41
























1225ndash1230




1110ndash1117












114ndash118





0000000000000046










1e12 doi 101212NXI0000000000000012




1310ndash1315










8e82325




2012321007ndash1011









































Reprints






Continued





















































supervision



dua (Italy)



















































599






2013115S38ndashS41
























1225ndash1230




1110ndash1117












114ndash118





0000000000000046










1e12 doi 101212NXI0000000000000012




1310ndash1315










8e82325




2012321007ndash1011









































Reprints






















































supervision



dua (Italy)



















































599






2013115S38ndashS41
























1225ndash1230




1110ndash1117












114ndash118





0000000000000046










1e12 doi 101212NXI0000000000000012




1310ndash1315










8e82325




2012321007ndash1011









































Reprints







































supervision



dua (Italy)



















































599






2013115S38ndashS41
























1225ndash1230




1110ndash1117












114ndash118





0000000000000046










1e12 doi 101212NXI0000000000000012




1310ndash1315










8e82325




2012321007ndash1011









































Reprints





















599






2013115S38ndashS41
























1225ndash1230




1110ndash1117












114ndash118





0000000000000046










1e12 doi 101212NXI0000000000000012




1310ndash1315










8e82325




2012321007ndash1011









































Reprints

























Reprints



















Reprints




Documents

Rituximab monitoring and redosing in pediatric neuromyelitis …nn.neurology.org/content/nnn/3/1/e188.full.pdf · rituximab) or the date of final CD19 repopulation (for patients who