ELSEVIER
`
`Clinical Neurology and Neurosurgery I 06 (2004) 270--274
`
`Clinical Neurology
`and Neurosurgery
`
`www.elsevier.com/locate/clineuro
`
`Campath-lH treatment of multiple sclerosis: lessons
`from the bedside for the bench
`
`Alasdair Coles*, Jackie Deans, Alastair Compston
`
`Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 2QQ, UK
`
`Keywords: Campath-lH; Humanised monoclonal antibody; Multiple sclerosis
`
`1. Introduction
`
`Most therapies in modem medicine have been discovered
`by serendipity. But there is a growing strand of medicines
`that have emerged from basic science into the clinic through
`rational design. One such is Campath-lH. The technology to
`produce industrial quantities of monoclonal antibodies was
`developed in the early 1970s by Kohler and Milstein in Cam(cid:173)
`bridge [1]. One ofMilstein's students, Herman Waldmann,
`set about finding a rat monoclonal antibody that would lyse
`human lymphocytes and so treat lymphocytic malignancies.
`He developed the Campath-1 (from "Cambridge Pathology"
`department) series of antibodies. These were amongst the
`first monoclonal antibodies to be "humanised" by Greg Win(cid:173)
`ter, another Cambridge academician, this process reduces
`the chances that patients mount an immune response against
`the therapeutic antibody [2] . So Campath-l"H" was born.
`It targets the CD52 antigen present on all lymphocytes and
`monocytes and causes sustained depletion of T-cells. It has
`recently been licensed by the FDA and EMEA as a treatment
`for fludarabine-resistant CLL. But over the last 15 years or
`so, it has been trialled in transplantation and autoimmune
`conditions [3-11].
`In 1991, we started to treat multiple sclerosis (MS) using
`Campath-1 H. Our hope was that the T-cell repertoire regen(cid:173)
`erated after lymphocyte depletion by Campath-lH would
`exclude the aberrant autoimmune responses underlying MS.
`We proceeded with caution, treating one patient in 1991, six
`more during 1993 [12] and a total of36 up to 1999 [13], all
`had SPMSs with Kurtzke scores of 6.0 or less at the time of
`
`• Corresponding author. Present address: Department of Neurology,
`Addenbrooke's Hospital, Box 165, Cambridge CB2 2QQ, UK.
`Tel. : +44-1223-216571 ; fax: +44-1223-336941.
`E-mail address: ajc1020@medschl.cam.ac.uk (A. Coles).
`
`0303-8467/$ - see front matter© 2004 Published by Elsevier B.V.
`doi: 10.1016/j .clineuro.2004.02.013
`
`entry into an MRI screening programme during which one
`gadolinium-enhancing lesion had to be present in the three
`months before patients were treated electively. The lessons
`learned from that cohort led to a change in strategy and we
`have since treated 22 patients earlier in the disease with ac(cid:173)
`tivity confined to RRMS and before onset of the secondary
`progressive phase. Here we show how understanding the ef(cid:173)
`fects of this prototypical "bench to bedside" therapy have
`revealed aspects of the pathogenesis of MS sending us back
`to the bench.
`
`2. Methods
`
`We treated two cohorts of patients with MS, a "progressive"
`and a "relapsing" group. The progressive cohort consisted
`of 36 patients (22 women) with SPMS defined as a period
`of sustained increase in disability unaccompanied by iden(cid:173)
`tifiable relapses but following an earlier period of episodes
`with full or partial recovery. At the time of treatment, dis(cid:173)
`ease duration was 11.2 years (S.D. ±6.1 years) of which 3.6
`years (±2.6 years) had been in the progressive phase, and
`mean EDSS was 5.8 (±0.8, range 3.5-7.0). One selection
`criterion for treatment was an increase in disability in the
`year before treatment of at least one EDSS point, during
`which annual relapse rate was shown to be 0.7 patient per
`year. Seven patients in this cohort received a second dose
`of Campath-lH, 2-4 years after the first treatment. The
`relapsing group consisted of 22 patients (17 women) with
`active RRMS. They received Campath-lH, either following
`the failure of licensed treatments to control their disease or
`because a high relapse rate early in the disease raised the
`prospect of a poor prognosis. Disease duration ranged from
`9 months to 12 years (mean 2.7 ± 2.9 years) before elective
`treatment with Campath-lH, at which time mean EDSS was
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`271
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`4.8 (±2.0, range 1.0-7.5). As a group, they had experienced
`a total of 13 3 relapses over 60 patient-years of combined
`disease history before treatment, giving an annual relapse
`rate of 2.2 per patient, this rose to 2.94 per patient in the
`immediate year before Campath-lH. This cohort included
`17 drug-nai:ve patients in whom disease duration ranged
`from 9 to 41 months (mean 1.7 ± 0.9 years). During that
`time, the annualised relapse rate of this group was 2.8 per
`year, rising to 3.4 in the year before treatment, during which
`disability had increased by 0-7.5 (mean 2.1 ± 2.0) EDSS
`points. None of these patients had received concomitant
`therapy with any licensed or putative disease-modifying
`treatment for MS. Five additional patients had failed treat(cid:173)
`ment with IFN-13. Their disease duration was necessarily
`longer ranging from 17 months to 12 years (mean 6.3 ± 4.9
`years). Their increase in EDSS ranged from Oto 5.5 (mean
`2.4 ± 2.3) EDSS points in the previous year during which
`the relapse rate was 2.0 per patient. Patients were assessed
`every 3-6 months for the first 3 years after Campath-1 H
`treatment and then annually, but with additional visits trig(cid:173)
`gered by clinical events. A sustained increase in disability
`was defined as an increase in the EDSS of at least 1.0 point
`on consecutive examinations over 6 months, if the baseline
`EDSS was less than 6.0, or an increase of 0.5 point on con(cid:173)
`secutive examinations over 6 months, if the baseline was 6.0
`or greater. The use of Campath-1 H in this off-license study
`was approved by a local Ethics Committee (Cambridge
`LREC 02/315) and the United Kingdom Medicines Control
`Agency. Our early experience was with Campath-lH made
`by the Therapeutic Antibody Centre, Oxford.
`We administered 100mg of Campath-lH as five daily
`doses of 20 mg given intravenously over 4 h. Most patients
`were pre-medicated with TV methylprednisolone, 1 g over
`1 h preceding the Campath-lH doses on days 1-3. Seven of
`36 patients in the progressive cohort were re-treated with
`Campath-lH in order to maintain or increase perceived im(cid:173)
`provements. Subsequently, we offered elective re-treatment
`after 12-18 months giving a fixed total dose of60mg over
`three consecutive days (20 mg per day), again pre-medicated
`with corticosteroids, 9/22 of the acute relapsing group have
`now received a second course of Campath-lH. Patients in
`the progressive cohort were scanned intensively for the first
`18 months after treatment, as previously described [14].
`
`3. Results
`
`The 5 8 patients treated to date have received a total of 7 4
`courses of Campath-lH and have been followed prospec(cid:173)
`tively for 280 patients-years. CD4 cells were depleted for a
`median of 61 months and CD8 cells for 30 months (19-46).
`B-cell numbers rose to 124% (S.D. ±74%) of pre-treatment
`levels at 27 (±15) months after treatment. In 13 patients,
`B-cell numbers had returned to baseline when last measured,
`at a mean of 62 (±17) months after treatment. However,
`in 18 patients, the most recent B-cell count, at 63 (±20)
`
`months, was still +66 (±48%) above baseline. These el(cid:173)
`evations in B-cell count rarely rose above the upper limit
`of the normal range. Those treated with Campath-1 H alone
`experienced an acute cytokine response that we have de(cid:173)
`scribed elsewhere [15], which is very significantly reduced
`by pre-treatment with corticosteroids. Seven infections that
`might represent adverse effects of Campath-lH have oc(cid:173)
`curred, all were mild and none required hospitalisation: they
`included spirochaetal gingivitis (at 10 days), measles (at 11
`days), herpes zoster (two instances, at 6 and 9 months, re(cid:173)
`spectively), varicella zoster (at 2 years), recurrent aphthous
`mouth ulcers ( from 6 to 9 months) and pyogenic granuloma
`(at 22 months). The principal adverse effect ofCampath-lH
`therapy in patients with MS is Graves' disease [16]. One pa(cid:173)
`tient had experienced Graves' disease prior to Campath-1 H
`treatment but to date, we have observed 15 new cases in
`the remaining 57 patients (27%), with one additional case
`of autoimmune hypothyroidism. Graves' disease developed
`within 5-21 months of the first treatment ( 14 patients) and
`2 years after the second treatment ( one patient). Ten of
`15 cases were detected pre-symptomatically by screening
`for TSH. Three patients developed Graves' ophthalmopathy.
`This was transient in two cases. However, one of the 15/57
`patients with Graves' disease has a permanent and cosmeti(cid:173)
`cally unpleasant ophthalmopathy, which has not threatened
`vision. All patients were initially managed using standard
`therapy for Graves' disease (carbimazole in the UK, the
`pro-drug of methimazole) for 6 months. Nine patients re(cid:173)
`lapsed after treatment and received radioactive thyroid ab(cid:173)
`lation.
`ln the SPMS cohort, Campath-lH reduced radiological
`evidence of disease activity, new lesions continued to fonn
`over 4 weeks but, thereafter, radiological markers of cere(cid:173)
`bral inflammation were suppressed maximally by >90% for
`at least 18 months and no new clinical relapses occurred.
`However, even during the first 18 months after treatment,
`dissociation emerged between the suppression of inflamma(cid:173)
`tion and disease progression [13] which has become even
`more apparent after longer follow-up. This cohort has now
`been observed for a total of 243 patient-years, giving an
`overall mean follow-up of 6. 7 (S.D. ±2.1) years from treat(cid:173)
`ment. Two patients have been lost to follow-up and three
`others have died (one suicide, one possible suicide and one
`death through sepsis in a severely disabled patient 7 years
`after Campath-1 H). The remaining patients have been sys(cid:173)
`tematically followed by the same investigator for a mean
`of 7.6 years (±1.4 years, range 6.4-11.9 years). One year
`after Campath-lH, 33/36 patients in our progressive cohort
`had maintained their pre-treatment EDSS. With time, this
`proportion decreased, at last follow-up, only 4/36 had no
`sustained worsening of disability from their pre-treatment
`EDSS 7.5 years (±0.5) after treatment (7/36 if the more lax
`criterion for disability progression of just one EDSS point
`confirmed at 6 months throughout the EDSS is used). As a
`group, the mean rate of increase in disability after treatment
`was + 0.2 EDSS points per patient per year, with a statis-
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`tically significant reduced rate of progression compared to
`the year before treatment ( P < 0.001 ), and a tendency for
`systematic reduction in the rate of disability acquisition.
`There was no difference in the rate at which disability
`accumulated between patients with early progression af(cid:173)
`ter treatment and those who were initially stable. Relapse
`rate, expected to decline as part of the natural history of
`MS in the secondary progressive phase, changed from 0.7
`patient per year before treatment to an annualised rate of
`0.02 patient per year, over the entire follow-up period of
`243 patients per year, this group of 36 patients has expe(cid:173)
`rienced just six episodes, of which three occurred in the
`first 2 months after Campath-lH treatment, none have been
`associated with a persistent increase in disability.
`Patients who had already progressed from baseline at the
`first follow-up interval (18 months) showed reduced brain
`volume at the time of initial treatment with Campath-lH by
`comparison with patients showing initial stability of clinical
`progression [13]. When 13 patients from this original cohort
`were re-examined 6 years after their last scan (which was
`itself I 8 months after Campath-1 H), there was no evidence
`for an increase in proton density or Tl lesion volume in the
`intervening period. However, 11/13 patients had evidence of
`further cerebral atrophy. The two with stable brain volumes
`were both amongst the group without atrophy in the first
`18 months, however, one had shown significant progression
`of disability. The mean absolute change in cerebral volume
`was -1.37 (±l.28)ml per year (P = 0.002). Five patients
`had new T2 lesions at follow-up and eight patients did not.
`The RRMS cohort consisted of 17 drug-nai:ve patients and
`five who had failed licensed therapy, observed now for a
`mean of 19 months ( range 6- 7 4 months) after treatment, rep(cid:173)
`resenting 32 patient-years of follow-up. Before treatment,
`their relapse rate was 2.2lper patient per year (2.94 per pa(cid:173)
`tient in the immediate year preceding treatment). After treat(cid:173)
`ment this cohort has had five confirmed episodes, giving a
`relapse rate of 0.14 and representing a 94% reduction in re(cid:173)
`lapse rate. The extent of relapse rate reduction is the same if
`patients previously treated with IFN-B are excluded, falling
`from 2.74 in the 28.5 patient-years before treatment (3.24
`per patient in the immediate year before treatment) to 0.19
`over the 26.3 patient-years of observation after treatment
`(93% reduction). Comparing, the accumulation of disability
`in the RR- and SPMS-groups in the year before treatment,
`the former showed a mean annual increase of +2.2 EDSS
`points. Mean annualised changes over the periods 0--6, 6--12
`and 12- 24 months were - 2.4, - 0.6 and - 0.4 and + 0.2,
`+0.1 and +0.3 for the RR- and SPMS-groups, respectively.
`
`4. Discussion
`
`This is the record of our total experience of the use of
`a humanised monoclonal antibody, Campath-1 H, used to
`treat 58 patients since 1991. At first, we used this drug in
`patients with relatively advanced SPMS. Inflammation was
`
`suppressed but disease progression continued, suggesting the
`need for exposure to anti-inflammatory therapy earlier in the
`disease course. Despite adverse effects, we considered that
`safety data accumulated from this cohort were sufficiently
`encouraging to justify treating a group of patients with early
`clinically active MS.
`Clinical and radiological data from our patients with
`SPMS suggest that just one or two pulses of Campath-1 H
`significantly suppress cerebral inflammation for at least 6
`years. Our 58 patients have together experienced only 11
`episodes during 275 patient-years of follow-up during
`both the RR (32 years) and the SP (243 years) phases of
`the disease. There was no appreciable increase in the Tl
`hypointense, or proton density, lesion volume in a represen(cid:173)
`tative subgroup of patients with SP disease who agreed to
`an MRI scan some 6 years after treatment. However, there
`was evidence for progressive cerebral atrophy at a volume
`loss of + 1.37 (±1.28) ml per year. A similar dissociation
`between effective suppression of new lesions and continued
`cerebral atrophy in progressive patients has also been seen
`in a trial of the lymphocytoxic drug cladribine, a purine
`nucleoside analogue resistant to the action of adenosine
`deaminase [17,18] and ofIFN-B [19-21].
`One interpretation of these observations is that axonal
`loss and inflammation are independent pathologies-an in(cid:173)
`terpretation supported by epidemiological evidence that re(cid:173)
`lapse rate during the progressive phase of MS does not
`alter disability outcomes [22]. If so, immunotherapy may
`not influence progression of disability, however, early it is
`deployed. However, several epidemiological studies have
`confirmed that relapse rate early in the course of the dis(cid:173)
`ease is associated with time to reach fixed disability mile(cid:173)
`stones [23,24] and a relationship has also been reported
`between the load of early inflammatory lesions on MRI
`and later disability [25]. Patients in our SP cohort who
`progressed had more inflammatory load before treatment,
`confirming our belief that inflammation and axonal injury
`are intimately linked. Two processes account for axonal
`degeneration in the post-inflammatory phase: first, acutely
`transected axons undergo Wallerian degeneration over the
`subsequent 18 months [26], but this seems not to produce
`a progressive clinical deficit. Secondly, axons that escape
`injury in the acute phase may later degenerate through a
`non-inflammatory mechanism, dependent on prior inflam(cid:173)
`mation. Specifically, we favour the interpretation that axon
`degeneration results from the loss of trophic support for neu(cid:173)
`rons and axons normally provided by oligodendrocytes and
`myelin [27,28]. The influence of oligodendrocytes on ax(cid:173)
`onal calibre and function is well described; oligodendrocytes
`myelinate axons, increase axonal stability and induce local
`accumulation and phosphorylation ofneurofilaments within
`the axon [29-31]. Neuronal function is further influenced by
`oligodendrocyte-derived soluble factors that induce sodium
`channel clustering along axons, necessary for efficient salta(cid:173)
`tory conduction and maintain this clustering even in the ab(cid:173)
`sence of direct axon- glial contact [32]. We have shown that
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`273
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`soluble factors produced by cells of the oligodendrocyte lin(cid:173)
`eage support neuronal survival [33].
`The lesson is clear. Once the cascade of events leading to
`tissue injury is established, effective suppression of inflam(cid:173)
`mation does not limit brain atrophy or protect from clinical
`progression. lt follows that there may only be an opportu(cid:173)
`nity early in the disease course to suppress those compo(cid:173)
`nents of the inflammatory process that initiate the cascade
`leading to loss of tissue integrity expressed as disease pro(cid:173)
`gression. This hypothesis is being tested in CAMMS223,
`a randomised single-blind trial comparing the efficacy of
`two doses of Campath-lH and IFN-13 in the treatment of
`drug-naive patients with early, active RRMS. The hope is
`that patients receiving effective anti-inflammatory treatment
`before the cascade of events leading to uncontrolled destruc(cid:173)
`tion of the axon-glial unit is irretrievably established will
`not subsequently accumulate disability, develop cerebral at(cid:173)
`rophy or enter the secondary progressive phase of the illness.
`
`Acknowledgements
`
`We are grateful to the team at the Therapeutic Anti(cid:173)
`body Centre, Oxford, led by Professors Hale & Waldmann,
`who manufactured the CAMPATH-lH used initially in the
`treatment of our patients, to Dr. Shaun Seaman and Peter
`Holmans for statistical advice, and to Jackie Deans for in(cid:173)
`valuable assistance in patient management. MRI scans were
`performed at the Institute of Neurology. The Multiple Scle(cid:173)
`rosis Society provided the MRI scanner. AJC was previously
`supported by the Medical Research Council and is currently
`a Wellcome Advanced Clinical Fellow. Some aspects of the
`work were also supported by a grant from MuSTER.
`
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