ORIGINAL (On)
`Reduction of Disease Activity and
`Disability With High-Dose
`Cyclophosphamidein Patients
`With Aggressive Multiple Sclerosis
`
`= —
`ARCHIVES EXPRESS
`= =
`
`Chitra Krishnan, MHS; AdamI. Kaplin, MD, PhD; Robert A. Brodsky, MD; Daniel B. Drachman. MD;
`RichardJ. Jones,MD; Dzung L. Pham, PhD; NancyD. Richert, MD, PhD; Carlos A. Pardo, MD;
`David M. Yousem, MD, MBA; Edward Hammond, MD, MPH; Megan Quigg, BA; Carrilin Trecker, BA;
`Justin C. McArthur, MBBS, MPH; Avindra Nath, MD; Benjamin M. Greenberg, MD, MHS;
`Peter A. Calabresi, MD; Douglas A. Kerr, MD, PhD
`
`Objective: To explore the salety and effectiveness of
`high-dose cyclophosphamide (HiCy) without bone mar-
`rowtransplantationin patients with aggressive multiple
`sclerosis (MS).
`
`Design: A 2-year open-label trial of patients with ag-
`gressive relapsing-remilting multiple sclerosis (RRMS)
`given an immunoablative regimen of HiCy (50 mg/ke/d
`for + consecutive days) with ne subsequent immuno-
`modulatorytherapy unless disease activity reappeared that
`required rescue therapy.
`
`Setting: The Johns Hopkins University Multiple Scle-
`tosis Center, Baltimore, Maryland.
`
`Patients: A total of 21 patients with RRMS were screened
`for eligibility and 9 patients were enrolled in thetrial.
`Patients were required to have 2 or more gadolinium-
`enhancing lesions on each of 2 pretreatment magnetic
`resonance imagingscans, at least ] clinical exacerbation
`in the 12 months prior to HiCy treatment, or a sus-
`tained increase of 1.0 point or higher on the Expanded
`Disability Status Scale (EDSS) in the preceding year.
`
`Intervention: Patients received 50 mg/kg/d of cyclo-
`phosphamideintravenously for 4 consecutive days, fol-
`lowed by5 jtg/kg/d of granulocyte colony-stimulating
`factor 6 days after completion of HiCy treatment, until
`the absolute neutrophil count exceeded 1.0 X 10° cells/L
`for 2 consecutive days.
`
`
`
`tients with RRMS. Secondary outcome measures in-
`cluded a change in gadolinium-enhancinglesions on mag-
`netic resonance images and a changein disability measures
`(EDSS and Multiple Sclerosis Functional Composite).
`
`Results: Ninc patients were treated and followed up for
`a meanperiod of 23 months. Eight patients had failed con-
`ventional therapy and 1 was treatment naive. The median
`age at time of entry was 29 years (range. 20-47 years). All
`patients developed transienttotal or near-total pancytope-
`nia as expected, followed by hematopoietic recoveryin 10
`to 17 days, stimulated by granulocyte colony—stimulating
`factor. There were no deaths or unexpected serious ad-
`verse events. There was a statistically significant reduc-
`tion in disability (EDSS) at follow-up (mean |SD] de-
`crease, 2.11] 1.97], 39.4%; P=.02). The mean(SD) number
`of gadolinium-enhancing lesions on the 2 pretreatment
`scans were 6.5(2.1) and 1.2 (2.3) at follow-up (81.4% re-
`duction; P=.01). Two patients required rescue treatment
`with other immunomodulatorytherapies during the study
`owing to MS exacerbations.
`
`Conelusion: Treatment with HiCywas safe and welltol-
`erated in our patients with MS. Patients experienced a
`pronounced reduction in disease activity and disability
`after HiCy treatment. This immunoablative regimen of
`cyclophosphamidefor patients with aggressive MS is wor-
`thy of further study and maybe analternative to bone
`marrowtransplantation.
`
`Main Outcome Measures: [he primary outcome of
`Arch Neurol. 2008:65(8): 1044-1051
`the study was the safety and tolerability of HiCyin pa-
`
`
`sons in the United States.'* Four pathologic
`subtypes of MS have beenidentified, each
`of which represents a distinct autoimmune
`process.*
`
`ULTIPLE SCLEROSIS
`
`(MS) is an inflamma-
`tory demyelinating
`disease of the central
`nervous system olpre-
`sumed autoimmuneetiology. It is the most
`common nontraumatic cause of neuro-
`logic disability in young adults and af-
`fects between 250000 and 400000 per-
`
`Author Affiliations are listed at
`the end of this article.
`
`WWW_ARCHNEUROL COM
`Merck 2006
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`(REPRINTED) ARCH NEUROL/ VOL 65 (NO. 8), AUG 2008
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`
`CMEavailable online at
`www.jamaarchivescme.com
`and questions on page 1016
`
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`
`

`

`tures not previously studied and had a longerfollow-up
`(23 months) than previously published.** We found that
`HiCy treatment induced a significant reductionin dis-
`ease activity and disability in most patients. Some pa-
`tients experienced sustained remission ofall detectable
`disease activity despite receiving no subsequent immuno-
`modulatorytherapy.
`
`Eady
`STUDY DESIGN AND INCLUSION CRITERIA
`
`A total of 21 patients were screenedforeligibility and 9 were
`enrolled between October 2003 and July 2006. Men and women
`between the ages of 18 and 70 years whohadfailed or refused
`conventional therapyand hadactive disease were enrolled. Ac-
`tive disease was defined as 1 clinical exacerbation between 6
`and 12 months prior to HiCy treatment or a sustained in-
`crease in more than | ExpandedDisabilityStatus Scale (EDSS)
`point in the past year and 2 or more gadolinium-enhancingle-
`sions (GELs) on each of2 pretreatment MRIscans. Patients were
`excluded if they had a clinical exacerbation within 3 months
`prior to administration of HiCy, as those patients might not have
`hadstable disability. These criteria were designedto identify a
`patient population with ongoing inflammatorydisease activ-
`ity, high risk of continued progression, and loss of function.
`
`STUDY TREATMENT
`
`Becauseofthis clinical and immunopathologic hetero-
`geneity, immunomodulatorystrategies to treat MS have
`been suboptimal. Current Food and Drug Administration-
`approved immunomodulatorytherapies for MS do notabol-
`ish inflammation ordisease progression, and the vast ma-
`jority of patients continueto accrue progressive disability
`despite these therapies.
`Cyclophosphamide (Cy) andits active metabolites
`diffuse into cells and are converted into the alkylating
`compound phosphoramide mustard through simple
`intracellular decomposition.* Cyclophosphamideis a
`nonspecific immunosuppressant that affects both T-
`and B-cell function, and in MS maysuppress interleu-
`kin (IL)-12 and T-helper type 1 (Th1)-type responses
`and enhance Th2/Th3 responses.’ These changes are
`transient when Cyis given by standard pulse doses, and
`the immunesystem returns to baseline within a few
`monthsto a year after cessation.**
`Cyclophosphamidehas been used extensivelyin treat-
`ing MS, with mixed results. In several studies, pulse Cy
`alone or in combination with corticotropin (adrenocor-
`ticotropic hormone)orinterferon resulted in stabiliza-
`tion or improvement in manypatients, thoughtoxicity
`was a major limitation of these regimens.”!* In oth-
`ers,'*!* standard induction regimensof Cywith or with-
`out pulse boosters did not halt disease progression in pa-
`tients with progressive MS.
`Recently, several groups have treated patients with MS
`with more aggressive immune system ablation, requir-
`Approval from theJohns Hopkins institutional review board was
`ing autologous hematopoietic progenitor rescue.'*'* In
`obtained. Patients gave consent twice, al screening and prior to
`enrollmentinto the studyif they metall inclusioncriteria. All pa-
`the majority of these studies, there was an apparent im-
`tient case summaries were presentedto a Steering committee to
`provementorstabilization of the clinical course. Addi-
`ensure by unanimous approval that they metall inclusion crite-
`tionally, standard magnetic resonance imaging (MRI) mea-
`ria and noexclusioncriteria. Pretreatment studies included elec-
`sures of disease activity have shown dramatic, if not
`trocardiogram, echocardiogram or multiple gated acquisition scan,
`complete, stabilization with such regimens.'*”° In sev-
`sinus computed tomography, and extensive blood work.
`eral patients, long-term remission of both inflammation
`Patients received 50 mg/kg/dof Cyintravenouslyfor 4 con-
`and progression was achieved. However, some patients
`secutive days. The dose of Cywas calculated according to ideal
`developed accelerated brain atrophyasaresult of the con-
`bodyweight. Prophylaxis against Cy-induced hemorrhagic cys-
`ditioning regimen and transplant-related mortalityin such
`titis (generally Mesna [Uromitexan; Baxter, Deerfield, Illi-
`nois}) was directed according to establishedclinical practice
`patients was between 5% and 15%.'°)7'"?!
`guidelines. On day 6 (6 days after completion of HiCytreat-
`Despite its immunoablative properties, high doses
`ment) all patients received 5 pg/kg/d of the myeloid growthfac-
`(120-200 mg/kg) of Cy (HiCy) used as conditioningfor
`torfilgrastim (granulocyte colony-stimulating factor) until the
`transplantis well tolerated and spares hematopoietic stem
`absolute neutrophil count exceeded 1.0 X 10° cells/L for 2 con-
`cells, as demonstrated by rapid hematopoietic recovery
`secutive days. Patients also routinely received prophylactic an-
`and immunereconstitution following this treatment in
`tibiotics (norfloxacin, fluconazole, and valacyclovir) while
`patients with severe autoimmunediseases.” The ma-
`granulocytopenic.
`jor mechanism of Cydetoxification is inactivationofal-
`dophosphamide by cellular aldehyde dehydrogenase to
`form the inert compound carboxyphosphamide.* Alde-
`hyde dehydrogenase is highly expressed in hematopoi-
`etic stem cells, whereas all mature or maturingcells, in-
`cluding lymphocytes, express relatively low levels of
`aldehyde dehydrogenase and are thereforerapidlyelimi-
`nated by HiCy.* Recently, 13 patients with severe refrac-
`tory MS (7 with secondary progressive MS and 6 with
`relapsing-remitting MS) were studied following treat-
`ment with HiCy, and many were found to havestabili-
`zation or improvementofdisability. All reported an im-
`provementin quality-of-life measures.”°
`In our study, HiCytreatment without hematopoietic
`stem cell transplantation was studiedin patients with se-
`vere MS. This study examinedradiologic andclinical fea-
`
`OUTCOME MEASURES
`
`Patients were evaluated at the Johns Hopkins GeneralClinical
`Research Center every 3 months. Evaluations included stan-
`dard bloodprofile, urinalysis, electrocardiogram, echocardio-
`gram, neurologic examination, and MRI evaluations. Disabil-
`ity was measured using the EDSS and Multiple Sclerosis
`Functional Composite (MSFC).”’
`Magnetic resonance imaging scans were performedat 1.5 T
`(General Electric, Milwaukee, Wisconsin) with an echo speed
`or twin speed gradients, using the Excite platform (General
`Electric Healthcare, Chalfont St Giles, United Kingdom).
`Magnetic resonance imaging pulse sequences included axial
`proton density T2-weighted combined pulse sequence, fluid-
`attenuated inversion recovery sequences, and axial pregado-
`linium and postgadolinium T1-weighted scans (0.2 mmol/kg
`
`(REPRINTED) ARCH NEUROL/ VOL 65 (NO, 8), AUG 2008
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`
`

`

`EDSS Score of Enhancing Lesions
`
`Past Treatments
`
`Steroids, Avonex,? Rebif,° IVIG, pulse
`cyclophosphamide
`Steroids, Avonex
`Rebif, Avonex, steroids
`Avonex, steroids, glatiramer acetate
`Steroids, Betaseron,° Rebif, glatiramer acetate
`Rebif, glatiramer acetate
`Avonex,steroids, Celicept®
`No past treatment
`Steroids, Avonex
`
`7.0
`
`(2 Pretreatment Scans)
`45
`
`5.5
`8
`10
`
`96
`
`5
`
`763
`
`.5
`
`Table 1. Demographic Characteristics and Disease History
`
`a P
`
`rior to HiCy Treatment
`
`Pretreatment=Baseline Average No.
`Baseline
`Patient No./Sex/Age,y,
`Disease
`Annualized
`at Entry Into Study
`Duration, y
`Relapse Rate
`/M/47
`15
`1.5
`
`1.17
`1.67
`
`21
`
`31
`
`.5
`15
`1.8
`
`,33
`
`92
`
`15
`15
`
`341
`
`4
`
`5
`
`Abbreviations: EDSS, Expanded Disability Status Scale; IVIG, intravenous immunoglobulin; HiCy, high-dose cyclophosphamide
`*Biogen Idec, Cambridge. Massachusetts.
`bEMD Serono, Rockland, Massachusetts.
`© Bayer Healthcare Pharmaceuticals, Wayne, New Jersey.
`*Roche Pharmaceuticals, Nutley, New Jersey.
`
`years) are described in Table 1. There were 3 African
`American patients (patients 5, 7, and 9). The mean dis-
`ease duration was 7.6 years (median,4 years; range, 1.5-15
`years). This cohort had a baseline annualized relapse rate
`of 1.7 episodesperyear (historical data),a mean EDSSscore
`of 5.0, and a mean (SD) of 6.5(2.1) GELs using double-
`dose gadolinium (Table 1). Eight patients had failed con-
`ventional immunomodulatorytherapyand 1 patient was
`treatmentnaiveat entry. The meantimeto follow-up after
`HiCytreatment in this cohort was 23 months.
`
`HEMATOLOGIC RECOVERY
`
`Thetotal white bloodcell countfell to fewer than 80 cells/
`mm?’ in all patients, with recovery measuring more than
`3500cells/mm? ata median of 15 (range, 13-30) days af-
`ter the last dose of Cy (Figure 1). The median number
`of red blood cell transfusions was2 (range, 0-4), and the
`median numberofplatelet transfusions was 1 (range, 0-3).
`
`SAFETY
`
`using Omniscan |General Electric Healthcare}; this is double
`the dose compared with conventional scanning protocols).
`
`STATISTICAL ANALYSIS
`
`Statistical tests were performed using SPSS 15.0 (SPSS, Chicago,
`Ilinois). Although 2 patients received other immunomodula-
`tory treatments during follow-up,all patients were followed up
`for safety and included in the effectiveness analysis (intention-
`to-treat analysis). Means, medians, and standarddeviations were
`calculated. Nonparametric tests (Wilcoxon rank sum test) were
`used to evaluate the change at follow-up compared with base-
`line. The MSFC z scores werecalculated using a standardized rel-
`erence population from the National Multiple Sclerosis Society
`Task Force data set.”’** Baseline EDSS and MSFCscores were used
`to calculate the percentage of changein disability scores at follow-
`up. The screening data were used for patient 5, as the baseline
`MSFCvisit was missing.
`
`MRI ANALYSIS
`
`Brain parenchymalfraction (BPF) was computedas theratio ofbrain
`volumetointracranial volume,as previouslydescribed.” The T2
`plaque volumes were semiautomaticallyobtained using a fuzzyseg-
`mentation procedure”applied to the brain-extracted fluid-
`attenuatedinversion recoveryimages by modeling plaque inten-
`sities as outliers, similar to the approach described by Van Leem-
`putetal,*’ The resulting segmentationwasinclusiveof the plaques
`but included false-positives that were manually removed bya trained
`operator using information from both the fluid-attenuated inver-
`sion recovery and T2-weighted scans. Changesin lesion volume
`were measured on T2-weighted imagesfrom baseline to the most
`recent follow-upvisit, and annualized changes in BPF were cal-
`culated using the Wilcoxonsigned ranktest.
`
`High-dose cyclophosphamide waswell tolerated, with no
`serious or unexpected adverse events. Twopatients devel-
`oped febrile neutropenia, and 3 had self-limited docu-
`mented infections. There was | episode of confusion (pa-
`tient 3) at 15 monthsthat was probably unrelated to the
`HiCytreatment. The patient was also taking lithium and
`amitriptyline and had not decreased his dose as suggested
`by his physician. There were 4 hospital or emergencyde-
`partment admissions during the studyfollow-up. Patient
`1 was admitted to the hospital on 2 occasions owing to sus-
`pected MS exacerbation that was not confirmed by MRI.
`——ki—
`The patient was treated with rituximab 10 months after
`HiCytreatment and pulse cyclophosphamide at month 12.
`The patient's EDSS score was 7.0 at 9 months and 8.0 at
`the 12-month follow-up visit. The EDSS score had de-
`creased to 7.5 at 15 months. Although there was no clear
`changein the patient's disability immediatelyafter either
`
`DEMOGRAPHICS
`
`The baseline demographic characteristics of this study popu-
`lation (6 men, 3 women; mean [SD] age at entry, 35 [3.5]
`
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`

`
`Patients
` 24000
`
`
`@: V4 @7
`
`
`E
`2 M5
`>8
`22000
`on
`73 O6 ag
`
`
`
`20000
`
`
`
` 18000
`
` 16000
`
`14000
`
`12000
`
`8000
`
`
`
`
`
`10000
`
`WBCCount,Cells/mm?
`6000
`
`
`
`Figure 1. White blood cell (WBC) responseto high-dose cyclophosphamide (HiCy). Patients were assessed for peripheral WBC counts, with administration of
`HiCy beginning on day -4. On day 6 (6 days after completion of HiCy treatment) all patients received the myeloid growth factor,filgrastim (granulocyte
`colony-stimulating factor [G-CSF]).
`
`board. Atthe last evaluation, the mean (SD) EDSSscore
`of these treatments, he did have an improvement; his symp-
`for all patients in the study was 3.06(2.36) (range, 0-7;
`toms were back to baseline by the completion ofthe study.
`P=.02). This represents an aggregate 39.4% reduction in
`Patient 5 had a clinical exacerbation 4 days prior to
`disability in an average follow-up of 23 months. Indi-
`her scheduled 18-month visit and wastreated with ste-
`vidual EDSSscores at baseline and follow-up are shown
`roids. Her baseline EDSS score was 6.5 and she had an
`in Table 2. Fourof the patients had no changeorless than
`average of 9 GELs prior to HiCytreatment. At 18 months,
`a 1-point change on the EDSSatthelast follow-up from
`her EDSSscore was 3.5. She developed mild truncal ataxia
`baseline, while 5 had a sustained decreaseof greater than
`and recurrenceoffatigue that had been debilitating prior
`1 point on the EDSSthatpersisted through thelast exami-
`to HiCytreatment. Her MRIrevealed 3 possible lesions
`nation. In the subgroupof patients who improved by more
`with weak gadolinium enhancement, and shestarted an
`than 1 EDSS point at the last follow-up, there was a 65%
`intravenoussteroid regimen, resulting in some improve-
`reduction in EDSSscores.
`ment,followed by ongoing monthly daclizumabtherapy.
`Patients were administered the MSFC, a multidimen-
`At her 24-month follow-up, she had an EDSS score of
`sionalclinical outcome measure that measures upperex-
`3.5 and 1 GEL on her MRI.
`tremity, lower extremity, and cognitive function at screen-
`Patient 9 was admitted to the emergencydepartmentat
`ing, baseline, and at each study visit at 3-monthintervals
`12 months,following a motorvehicle crash. She developed
`understandardized conditions. The baseline scores were
`aurinarytract infection,resulting in an increase in her EDSS
`usedto calculate the MSFC z scores, to accountfor prac-
`score at 12 months. Patient 7 had a hospital admission at
`
`19 months owing to confusion and cognitive changes and tice effects. The cohort hadastatisticallysignificant im-
`was diagnosed withbipolaraffective disorder.
`provement in MSFCzscores (average improvement, 87%;
`P=.03). The improvementwasnotedin all 3 of the MSFC
`subscores, although a change in the 9-Hole Peg Test score
`did notreachstatistical significance (Table 3). At base-
`line, patient 9 was unable to complete the Timed 25-
`Foot Walk within 3 minutes. By the 3-month follow-up,
`the time to complete the Timed 25-Foot Walk was 6.5
`seconds, and at 12 monthsit was 4.9 seconds.
`
`The mean (SD) baseline EDSSscore of the cohort was 5.17
`(1.84) (range, 1.5-7.0). Patients 1 and 2 worsened by0.5
`point on the EDSS betweenscreeningandbaseline; this pro-
`tocol deviation was reported to the institutional review
`
`DISABILITY (EDSS AND MSFC SCORES)
`
`
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`

`

`Table 2. Change in Disability (EDSS Score) at 12-Month Follow-up and Last Follow-up
`
`12-Month
`Follow-up
`
`Last
`
`Abbreviation: EDSS, Expanded Disability Status Scale.
`@Patient 9 has completed 15-monthfollow-up
`5 P= 02 (Wilcoxon rank sum test)
`
`Table 3. Change in Each Component of MSFC (z Score) From Baseline
`
`Follow-up®
`oonowns.wn—
`-6.25 to 0.71
`
`T25FW
`Mean (SD)
`Range
`SHPT
`Mean (SD)
`Range
`PASAT3
`Mean (SD)
`Range
`MSFC
`Mean (SD)
`Range
`
`Baseline
`(n=9)
`
`-4.91 (6.77)
`-13.7 to 0.45
`
`1.82 (1.86)
`~4,22 to 0.71
`
`~1.38 (1.43)
`-3.73 to 0.33
`
`2.70 (2.86)
`-7.22 to 0.16
`
`Last Follow-up
`(n=9)
`
`-2.75 (6.21)
`-13,7 to 0.51
`
`-0.97(1.84)
`-3.91 to 1.05
`
`-0.40 (1.28)
`-2.49 to 1.24
`
`~1,38 (2.76)
`
`Abbreviations: 9HPT, 9-Hole Peg Test; MSFC, Multiple Sclerosis Functional Composite; PASAT3, Paced Auditory Serial Addition Test with 3-second interstimulus
`interval; T25FW, Timed 25-Foot Walk.
`*Wilcoxon signed rank test.
`
`RADIOLOGICAL MEASURES
`
`The mean (SD) number of GELs at baseline was 6.5
`(2.1) (range, 2-11 at screening and baseline). At the last
`follow-up, there were a mean (SD) of 1.2(2.3) (range,
`0-7), representing an 81%reduction (P=.01). Figure 2
`graphically depicts each patient's treatment response
`(baseline visit prior to treatment with HiCy is time 0) as
`the change in EDSS scores and numberof GELs at each
`point assessed during the course of the study, Three pa-
`tients had a recurrenceofclinicallysilent radiological dis-
`ease activity, as defined bythe presence of new GELs al-
`ter achieving complete cessation of GELs following HiCy
`treatment that did not correlate with a clinical exacer-
`bation or worsening of disability (patients 3, 6, and 7).
`Patients 5 and 9 continued to have GELs at and beyond
`6 monthsafter HiCytherapy.
`The T2 lesion burden wasassessedat baseline and at
`—_ia7__
`the last follow-up. The change in the total volume of T2
`burden was -0.93% at an average follow-up of 22.1
`months (P>.05). Four patients had a reduction in T2
`plaque burden.
`
`High-dose cyclophosphamide treatment of patients with
`aggressive MSwassafe and well tolerated anddid not lead
`
`Brain parenchymal fraction was measured at base-
`line, 3 months, and from follow-up to 24 months in 8
`patients (Table 4). We first measured changes in the
`BPF between baseline and the 3 monthsafter the HiCy
`MRIto determine whether HiCytreatment induced any
`accelerated atrophy(Table 4). There was a -2.4% change
`(annualized change, -9.4%) in BPF between baseline
`(prior to acute therapy) and 3 monthsafter treatment with
`HiCy(median BPFat baseline, 0.807; range, 0.75-0.87
`vs median BPF at 3 months, 0.797; range, 0.70-0,86;
`P=.01). There wasnostatistically significant difference
`at follow-up (mean, 23 months) in the annualized change
`in BPF (-0.23%; P>.05) when compared with the MRI
`3 months after HiCytreatment. This suggests thatthe re-
`duction in BPF associated with HiCytreatment mayre-
`flect the resolution of inflammation (pseudoatrophy).
`
`
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`

`

`Ny
`
`=]
`g
`a
`a
`&
`
`Ss
`zs
`2
`&
`a
`2
`.
`8
`
`
`
`—42-36-30-24-18-12 -6 0
`Time. mo
`
`6
`
`12 18 24 30
`
`-42-36-30-24-18-12 -6 0
`Time. mo
`
`G6
`
`12 18 24 30
`
`
` Patient 3
` Patient 1
`
`Pulse Cy
`
`Rituximab4
`
`
` EDSSScore
`
`
`
`
`EDSSScore
`S739JO‘ON
`
`EDSSScore
`5799$0ON
`5739j0ON
`
`
`
`
`
`
`
`
`
`
`®EDSS score
`
`2 No. of GELs i
`
`~42-36-30-24-18-12-6 0
`6
`12
`18 24 30
`—42-36-30-24-18-12 -6 0
`6
`12 18 24 30
`-42~-36-30-24-18-12-6 0
`6
`12
`18 24 30
`
`
`
`
`
`Time, mo
`Time, mo
`Time, mo
`
`
`10
`Patient 4
`12
`10
`Patient 5
`12
`10
`Patient 6
`10
`8
`8
`
`
`
`
`=
`=
`2
`z
`©
`
`S
`S
`2
`Ss
`S
`S
`2
`&
`e
`@&
`e
`&
`Qa
`wn
`aq
`o
`wo
`&
`a
`2
`F
`3
`i
`w
`un
`w
`w
`uw
`
`18 24 30
`~42-36-30-24-18-12 -6 0
`-42-36-30-24-18-12 -6 0
`—42-36-30-24-18-12 -6 0
`
`Time, mo
`Time, mo
`Time, mo
`
`
`
`
`Figure 2. Clinical and radiologic response to high-dose cyclophosphamide (HiCy). Data prior to entry into study were obtained by historical assessment.
`Pre-HiCyclinical magnetic resonance images used single-dose gadolinium. EDSS indicates Expanded Disability Status Scale; Cy, cyclophosphamide:
`GELs. gadolinium-enhancing lesions.
`
`8 6
`§
`e
`@
`2
`2
`a
`- $*
`2
`
`6
`
`é
`2
`2
`° =
`2
`
`
`
`ria
`0
`~42-36-30-24-18-12 -6 0
`Time. mo
`
`hay
`6
`12
`18 24H
`
`0
`
`
`
`
`SleCOIMNBwnrelsZ
`
`10
`
`Patient 7
`
`0
`
`10
`
`Patient 8
`
`8
`
`10
`
`Patient 9
`
`4
`
`G&
`
`12 18 24 30
`
`6
`
`12 18 24 30
`
`6
`
`12
`
`Table 4. Change in Brain Atrophy Measures
`
`0.703
`0.827
`0.781
`0.796
`0.821
`0.798
`0.861
`0.781
`0.796 (0.046)
`
`:
`i
`e
`:
`
`.
`'
`;
`0.795 (0.040)
`
`0.849
`0.776
`0.808
`0.820
`0.784
`0.862
`0.787
`0.812 (0.033)
`
`21
`
`0.694
`0.827
`0.784
`0.809
`0.828
`0.784
`0.859
`
`0.679
`0.838
`0.789
`0.808
`0.800
`0.775
`0.863
`
`0.798 (0.053)
`
`0.793 (0.059)
`
`Mean (SD)
`
`;
`0.815 (0.039)
`
`*Changeatlast available follow-up data.
`© Data unavailable owing to motionartifact.
`;Only screening measure available for patient 2.
`P=01.
`® P=.02.
`
`to excess morbidityor accelerated brain atrophy. More-
`over, HiCy induced a functional improvement in most
`of the patients westudied. In manyof those patients, the
`
`functional improvementwas sustained through the length
`of the study (up to 24 months) despite the absence of
`any immunomodulatorytherapies beyondtheinitial HiCy
`
`
`(REPRINTED) ARCH NEUROL/ VOL65 (NO. 8), AUG 2008
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`

`treatment. Three patients had radiologic reactivation of
`disease at various intervals after treatment with HiCy, and
`1 patient had clinical and radiologic reactivation, sug-
`gesting that disease remission mayonlybe transient in
`some patients.
`The complexityof the autoimmuneresponse in MS pre-
`sents a critical strategic problem. Because individual MS
`patients mayhave distinct autoimmuneeffector mecha-
`nisms, highly specific targeted immunotherapies maybe
`effective onlyfor subsets of patients with MS. Theactiv-
`ity of HiCy does not require identifying, targeting, and
`eliminating each individual's unique aberrant immunerep-
`ertoire becauseofits activity against all arms of an immu-
`nologic response. Ideally, the goal of HiCy therapyis to
`ablate virtuallythe entire mature immunesystem, includ-
`ing the autoimmune component,allowing the individu-
`al's immunesystem to be reconstituted from the undam-
`aged stem cell population. If this is achieved, the new
`immunesystem should recognize and becometolerantof
`the antigens present, including those that previously con-
`tributed to the autoimmuneprocess. **”
`Westudied HiCytherapyin a cohortof patients with
`aggressive, inflammatory MSfor several reasons.First,
`becausethis wasa pilot study of HiCytreatment in MS,
`we wanted to explore onlythose patients who had wors-
`ening disease while receiving conventional therapies. Sec-
`ond, we reasoned that patients with active inflamma-
`tory disease would be morelikely to respond to HiCy
`therapythan those with later-stage MS and more lim-
`ited inflammation. Finally, we reasoned that such pa-
`tients might have more reversible disability than those
`with later stages ofthe disease.
`Treatmentwith HiCynot onlyhalted the accrualof dis-
`ability that occurred prior to HiCytreatment butalso sta-
`bly reduced this disability in manyof the patients. We sug-
`gest that the totaldisability in these patients is contributed
`by demyelination, axonal injury, and ongoing inflamma-
`tion. Cessation of active inflammation by HiCyablation
`mightfacilitate a permissive environment for reparative
`plasticity in the central nervous system that could ac-
`count for someofthe clinical improvement weobserved.
`In this context, the 2 patients who had had a high level of
`sustained disability (patients 1 and 2; EDSS score, 7.0) did
`not experience a reductionin disability, although theydid
`experience a modest improvement in MSFC score. Per-
`hapsthis is suggestive of a limited window during which
`endogenouscentral nervous system reparationis viable.
`Therefore, it is unclearif patients with this high level of
`disability are the optimal cohort to study further because
`their response to therapy was more modest.
`
`Accepted for Publication: April 8, 2008.
`Published Online: June 9, 2008 (doi:10.1001/archneurol
`.65.8.noc80042),
`Author Affiliations: Departments of Neurology (Mss
`Krishnan and Quigg and Drs Kaplin, Drachman, Pardo,
`McArthur, Nath, Greenberg, Calabresi, and Kerr), Psy-
`chiatry and Behavioral Sciences (Drs Kaplin and
`Hammondand MsTrecker), Radiology (Drs Yousem and
`Pham), Pathology (Dr McArthur), and Epidemiology,
`Bloomberg School of Public Health (Dr McArthur), Di-
`vision of Hematology, Department of Medicine (Dr
`
`Brodsky), and Sidney Kimmel Comprehensive Cancer
`Center (Drs Brodsky and Jones), Johns Hopkins
`University, Baltimore, Maryland;and the NationalInsti-
`tute of Neurological Disorders and Stroke, National In-
`stitute of Health, Bethesda, Maryland (Dr Richert).
`Correspondence: Douglas A. Kerr, MD, PhD, Depart-
`ment of Neurology, Johns Hopkins University School of
`Medicine, 600 N Wolfe St, Path 627 C, Baltimore, MD
`21287-5371 (dkerr@jhmi.edu).
`Author Contributions: Study concept and design: Krishnan,
`Brodsky, Drachman, Jones, Richert, Pardo, Yousem,
`McArthur, Nath, Calabresi, and Kerr. Acquisition of data:
`Krishnan, Brodsky, Pardo, Yousem, Hammond,Quigg,
`Trecker, McArthur, Greenberg, and Kerr. Analysis and
`interpretation of data: Krishnan, Kaplin, Brodsky,
`Drachman, Jones, Pham, Hammond, Greenberg,
`Calabresi, and Kerr. Drafting of the manuscript: Krishnan,
`Kaplin, Richert, Hammond, McArthur, and Kerr. Criti-
`cal revision of the manuscriptfor importantintellectual con-
`tent: Kaplin, Brodsky, Drachman, Jones, Pham, Pardo,
`Yousem, Hammond, Quigg, Trecker, McArthur, Nath,
`Greenberg, Calabresi, and Kerr. Statistical analysis:
`Krishnan and Hammond. Obtained funding: McArthur,
`Calabresi, and Kerr, Administrative, technical, and mate-
`rial support: Kaplin, Brodsky, Jones, Pham, Pardo,
`Hammond, Quigg, Trecker, McArthur, Nath, and
`Greenberg. Study supervision: Kaplin, Drachman, Yousem,
`Greenberg, Calabresi, and Kerr.
`Financial Disclosure: No conflicts of interest are re-
`ported for the pilot clinical study. Ms Krishnan and Drs
`Kaplin, Hammond, and Kerr have received consulting
`honoraria from Accentia Biopharmaceuticals for design-
`ing a subsequent independentclinicaltrial involving HiCy,
`which isstill in the planning stage. Undera licensing
`agreement between Accentia Biopharmaceuticals and the
`Johns Hopkins University, Drs Brodskyand Jones are en-
`titled to a share ofroyalty received bythe university on
`sales of intellectual property (Revimmune; Accentia Bio-
`Pharmaceuticals, Tampa, Florida). The study described
`in this article could affect the value of Revimmune. The
`terms of this arrangement are being managed by Johns
`Hopkins University in accordance withits conflict of in-
`terest policies.
`Funding/Support: This study was supported by Gen-
`eral Clinical Research Centerof the Johns Hopkins School
`of Medicine (NationalInstitute of Health/National Cen-
`ter for Research Resources grant MO1-RROOO052), the
`National Multiple Sclerosis Society grant TR3760-A-3,
`the philanthropic support of Mr Alvin Myerberg, and The
`Johns Hopkins Project RESTORE.
`Additional Contributions: Wearegrateful to Donna Dorr,
`RN, MSN, AOCN, clinical nurse specialist in hematol-
`ogy, andthestaff of the Sidney Kimmel Comprehensive
`Cancer Center, whotreated thepatients.
`
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