Multiple Sclerosis and Related Disorders (2013) 2, 92–95

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COMMENTARY

Lessons from clinical trials of alemtuzumabin multiple sclerosis

Abhijit Chaudhuria,n, Peter O. Behanb

aEssex Centre for Neurological Sciences, Consultant Neurologist, Queen’s Hospital, Rom Valley Way, Romford,Essex, RM7 0AG, United KingdombDivision of Clinical Neurosciences, University of Glasgow, United Kingdom

Received in revised form 21 August 2012

Alemtuzumab is a humanised monoclonal antibody thatselectively targets CD52 leucocytes. Originally developed inthe Cambridge Pathology laboratory (hence its earlier nameCampath 1-H), subcutaneous injection of alemtuzumab iscurrently licensed as a second or third line therapy of chroniclymphocytic leukaemia, and has also been used as aninduction agent in renal transplantation costing an averageof US $2000 per treatment course. Alemtuzumab causesprofound and long term depletion of lymphocytes and aftera single subcutaneous dose, CD4+and CD8+T-cells, CD3-/CD56+NK cells, CD3+/CD56+T-cells and CD19+/CD5- B-cellswere all decreased to o25% of baseline at 9 months (Lundinet al., 2004). B-cell suppression generally recovers earlierthan T-cells, usually within 3–4 months; and patients withrheumatoid arthritis remained lymphopenic 12 years after asingle dose of alemtuzumab, indicating that its lympho-cytotoxic effect results in permanent alteration in T-andB-lymphocyte subsets (Anderson et al., 2012).

Alemtuzumab was first introduced to the therapeutics ofmultiple sclerosis (MS) by the Cambridge neurologists in the1990s. After intravenous alemtuzumab, the disease activitywas found to persist for several weeks before stabilisationof clinical symptoms in a small group of 27 MS patients(Coles et al., 1999). Infusion-associated reactions afteralemtuzuab were caused by cytokine release syndrome,and necessitated use of high dose corticosteroids, anti-

ont matter & 2012 Elsevier B.V. All rights reserved.0.1016/j.msard.2012.08.005

thor.

haudhuria@gmail.com (A. Chaudhuri).

histamine and analgesics as pre-medications. Patientsexperienced transient exacerbation of disease symptomsafter alemtuzumab and in about half all cases, disability andbrain atrophy continued to progress regardless of treat-ment, that was presumptively attributed to pre-existingdisease burden. This initial unblinded study was followed bya phase II single (rater)- blinded randomised clinical trial oftreatment-naı̈ve relapsing remitting MS patients with lowdisability (EDSS score r3.0) and early symptomatic disease(duration r3 years). In this trial (CAMMS 223), frequentadministration of alemtuzumab (up to 3 annual intravenouspulses of 3–5 day cycles) was more effective than thriceweekly subcutaneous injection of high dose (44 mg) inter-feron b-1a in reducing annualised relapse rates (CAMMS223,2008). There was no difference in clinical outcome betweenthe two dosages of alemtuzumab (12 mg and 24 mg/day) in thisclinical trial to confirm the hypothesis that dose-dependentsuppression of inflammatory activity early in the course ofrelapsing-remitting MS is alters the natural history of thedisease. There is no published dose-response study of alemtu-zumab in relapsing-remitting MS to suggest that doses lowerthan 12 mg/day would not be effective or safer.

The phase II clinical trial (CAMS 223) however exposedsome unusual side effects of alemtuzumab. Its use in theclinical trial was briefly suspended after immune thrombo-cytopenic purpura (ITP) developed in three study patientsresulting in one fatality. In the same year when the Phase IIstudy was published, the first report of two patients (oneof them had MS) developing anti-glomerular basement

93Lessons from clinical trials of alemtuzumab in multiple sclerosis

membrane (GBM)-antibody mediated renal disease (Good-pasture’s syndrome) after alemtuzumab therapy was pre-sented from Cambridge (Clatworthy et al., 2008). From asafety point of view, there was also a concern about thecumulative risk of autoimmune disease on alemtuzumab, andthe obvious paradox that a treatment targeting presumedautoimmune disease mechanisms in MS increased the risk ofother organ-specific and systemic autoimmune diseases.

The investigators of the CAMMS 223 trial have recentlypublished their 5-year follow up results (Coles et al., 2012).Of the 334 patients recruited in the original study, data wereavailable in about 60% (183) patients at the end of 5 years(month 60) and 12% (40 patients) at 6 years (month 72); nearlyhalf of interferon b-1a (20 out of 42) arm and three quarters(107 out of 141) of patients assigned to two treatment dosesof alemtuzumab were not on any disease-specific treatmentby the end of fifth year. The authors observed a statisticallysignificant difference in the 5-year change of disability,measured as changes in EDSS scores, between treatmentgroups (0.30 point improvement with alemtuzumab,0.46 pointworsening with interferon) and annualised relapse rates(0.11 with alemtuzumab, 0.35 with interferon). There werethree deaths in alemtuzumab arm (ITP, non-EBV associatedBurkitt’s lymphoma and cardiovascular disease); there weresix malignancies (lymphoma, breast, cervical cancer, papillarycarcinoma of thyroid and basal cell carcinoma). The onlydeath in the interferon arm was because of an accident. Therewas 30% incidence of thyroid-associated autoimmunity inalemtuzumab arm with a progressive increase in incidencein later years; one patient developed anti-GBM antibodydisease. Serious infections were seen in over twice as manypatients on alemtuzumab (7% vs. 3% in interferon b-1a arm).

In an open label study of 39 patients selected across threecentres with aggressive relapsing MS and a mean follow upperiod just short of 2 years, alemtuzumab was considered tobe effective, although transient worsening neurologicalsymptoms was observed in three patients and nearly a thirddeveloped autoimmune thyroid or skin disease (Hirst et al.,2008). The mean improvement in EDSS score was less thanthe average change at or after the first year of treatment.There is no information from clinical trials yet that thepotential benefits of alemtuzumab outweigh the safety risksin highly aggressive or actively relapsing remitting MS, andhence the possible use of alemtuzumab as a second or thirdline rescue treatment option remains unsubstantiated atpresent.

The superiority of alemtuzumab over high dose highfrequency interferon b-1a in reducing disability progressionin relapsing-remitting MS was not entirely reproduced in oneof the phase III trials (CARE-MS 1) the interim results ofwhich were presented at the ECTRIMS congress in October2011. Like CAMMS 223, CARE-MS 1 was similar in design toCAMMS 223 trial, a rater-blinded active comparator studyagainst thrice weekly high dose interferon b-1a, but thisphase III study only evaluated a single 12 mg/day dose ofalemtuzumab (given in 2 short annual cycles of 5 day and3 day); however the recruitment phase was extended tofirst 5 years of disease onset. There was no statisticallysignificant difference in disability progression between thetwo treatment arms, but the relative reduction of annual-ised relapse rate on alemtuzumab (55%) was broadly similarto the rate observed in the extended follow up period of the

phase-II study (69%). There were three cases of ITP, twocases of thyroid cancer and twice as many cases of seriousinfection in patients receiving alemtuzumab. Patients withonset of disease symptoms within 10 years and on anexisting first-line treatment (beta-interferon or glatiramerfor six months or longer) were enroled in a second Phase IIItrial (CARE MS 2); results presented at the AmericanAcademy of Neurology meeting in April 2012 showed that47% patients on high dose, thrice weekly interferon b-1a and65% of patients on the annual cycle of 12 mg/day alemtu-zumab were relapse-free after 2 years; the EDSS scorechange at the end of two years was 0.41 in favour ofalemtuzumab (mean change of -0.17 on alemtuzumab and0.24 on interferon b-1a from baseline scores). There was ahigher incidence of infections in the alemtuzumab group;the most common infections included upper respiratory andurinary tract infections, cutaneous fungal infections andoral herpes. Serious infections occurred in 3.7 percent ofthe alemtuzumab group as compared to 1.5 percent of theinterferon b-1a group. Within the two year period, one ofevery six alemtuzumab-treated patients developed autoim-mune thyroid disorder compared to one of twenty patientson interferon b-1a; 0.9% of alemtuzumab-treated patientsdeveloped ITP. Based on these results, Genzyme (manufac-turer of alemtuzumab) submitted licensing applications toFDA and EMA in June 2012. If approved as a treatment forrelapsing-remitting MS, the cost of intravenous alemtuzu-mab is anticipated to be around US$60,000 per patientper year.

How persuasive are the efficacy and safety data to justifyalemtuzumab as a treatment in relapsing-remitting MS?Available evidence from the published phase II trial suggestsa benefit of alemtuzumab in reducing relapse frequency, butonly in early disease (o3 years) and in treatment-naı̈vepatients with low baseline levels of disability (EDSSr3.0).From the presented but unpublished phase III trials, alem-tuzumab is seen as superior to interferon b-1a as a treat-ment option for relapsing-remitting MS, but given theprojected cost of therapy (US $60,000 per annum), whetherthis fact alone can meet the QALY target of healtheconomics in MS patients with relatively early disease andmild to moderate disability is difficult to predict. In ouropinion, the projected benefit of alemtuzumab in preven-tion of disability progression is rather modest in terms ofclinical outcome. Assuming that a patient started a first linetreatment on an EDSS score of 3.0, based on the long termdata of CAMMS 223 trial, an average alemtuzumab-treatedpatient would be better off to a score of 2.7 (clinical EDSS3.0) compared to a patient on interferon b-1a who would beworse off to a score of 3.4 (clinical EDSS 3.5) after 5 years oftreatment. The clinical benefit after 2 years based on meanEDSS score change in phase III trial also seems to bemarginal (2.8 and 3.2 for alemtuzumab and interferonb-1a respectively, both approximate to a clinical score of 3.0).

The key issue, clearly, is the long term safety ofalemtuzumab and associated risks of local and systemicinfections, organ-specific autoimmune disease and malig-nancy (thyroid papillary carcinoma and lymphoma), in atarget population of predominantly young and womenpatients. Depletion of CD4+-T cells after alemtuzumabmay last for many years (Anderson et al., 2012) creating astate of chronic immune deficiency in patients on regular

A. Chaudhuri, P.O. Behan94

treatment. This is evident from longer experience ofalemtuzumab use in haematological disorders that suggeststhat the risks of serious viral, bacterial and fungal infectionsare real, may be life threatening and long-term antiviraland antibiotic prophylaxis are necessary (Thursky et al.,2005) similar to the current practice in immunosuppressedHIV patients. In organ transplant recipients, alemtuzumabuse for the treatment of allograft rejection was associatedwith higher risk of opportunistic infections leading torecommendation for routine antimicrobial prophylaxis(Peleg et al., 2007). However, despite the use of herpesvirusand Pneumocystis prophylaxis, patients receiving alemtuzu-mab for lymphoproliferative disorders experienced a variedand diverse range of infections secondary to immunosup-pression (Martin et al., 2006). A related concern is thatopportunistic infections in alemtuzumab-treated patientscould be unusual and difficult to diagnose (Desoubeauxet al., 2012). While it could possibly be argued that immuneconstitution of MS patients is sufficiently different frompatients with lymphoproliferative disorders and organ-transplant recipients so that serious infectious complica-tions would not be a logical risk and antimicrobial prophy-laxis would not be required for patients receiving long-termalemtuzumab therapy, systemic infections, however, are ofcommon occurrence in MS patients even without immu-notherapy and a cohort of patients eligible for alemtuzumabare likely to have been exposed to previous immunomodu-latory treatment. Leaving aside the risks of rare andopportunistic infections, it is important to remember thatbacterial as well as viral infections are known to inducerelapses and contribute to disease progression in MS(Loebermann et al., 2012). The lessons from clinical trialsof natalizumab, the first humanised monoclonal antibodytherapy approved in MS, should not be forgotten(Chaudhuri, 2006): the first case of progressive multifocalleukoencephalopathy due to opportunistic John Cunninghamvirus infection developing as a fatal complication of nata-lizumab therapy occurred (and was initially overlooked) in aCrohn’s disease patient.

Alemtuzumab is also associated with a significant andcumulative risk of systemic autoimmune disease due toimmunosuppression. B-cell recovery after alemtuzumab ther-apy tends to precede T-cell recovery, and antibody-mediatedautoimmune diseases in alemtuzumab-treated patientsrespond to therapies achieving B-cell depletion (Clatworthyet al., 2008). There is a high incidence of autoimmune thyroiddisease in MS patients receiving alemtuzumab and thyroidautoimmunity is regarded as a non-specific marker of systemicautoimmune diseases. The cumulative risk for autoimmunedisease on alemtuzumab was recently estimated to be 22.2%over a median follow up period of 34.3 months (range 6.7–107.3 months), with the highest incidence occurring between12 and 18 months after treatment initiation (Cossburn et al.,2011). The time course of developing organ specific auto-immune disease on alemtuzumab is however unpredictableand can occur even after treatment withdrawal. One patientdeveloped Goodpasture’s syndrome 39 months after thesecond dose of alemtuzumab in the extension study (Coleset al., 2012). There is a close relationship between papillarythyroid cancer and thyroid inflammation due to autoimmunelymphocytic thyroiditis (Muzza et al., 2010) and the high riskof thyroid autoimmunity on alemtuzumab therapy is likely to

increase the incidence of papillary thyroid carcinoma over aperiod of time as already observed in clinical trials. Cases oflymphoma were also reported among alemtuzumab-treatedpatients in the extension phase of CAMMS 223 trial, and aswith any long-term immunosuppressive therapy, the risk ofcancer will gradually rise over the life time of a patient withlonger exposure to alemtuzumab. There has been a recentsurge of interest in B-cell mediated disease mechanisms andimmunotherapy in MS, and intuitively it begs the question ifan overactive B-cell mediated immune response developing inlater years after alemtuzumab treatment could undermine itsearly benefit in MS and increase the cumulative risks ofinfection and malignancy in patients from additional B-cellbased therapies for secondary autoimmune diseases. Statu-tory requirement of long term patient monitoring will alsosubstantially increase the indirect cost of alemtuzumab use inclinical practice.

Phase II and III clinical trials of alemtuzumab were single-(rater) blind and patient-reported outcome measures (e.g.relapse symptoms) and perceived efficacy (high expectationsof clinical benefit from alemtuzumab) could introduce apotential source of bias in trial outcome data. The clinicalimpact of efficacy data in terms of disability limitation inunpublished phase III clinical trials are timed to 6–12 months,too short a period in our opinion to judge the benefit of apotentially lifelong therapy with profound effect on immu-nity. From the analysis presented here, we feel alemtuzumabwill increase the life-time risk of infection, autoimmunediseases and possibly thyroid cancer substantially and wouldnot be safe as an unrestricted first-line long term therapy inrelapsing-remitting MS patients. A possible alternative wouldbe to limit its use to a shorter period of time, probably 12–18months, but whether treatment of relapsing-remitting MSdivided between a shorter induction phase of 12–24 monthswith a monoclonal antibody and a long term maintenanceperiod with an oral agent is practical, sufficiently cost-effective and of measurable clinical benefit needs testingin a large controlled clinical trial carried over for a period of4–5 years. It is unlikely that the pharmaceutical industry willhave the appetite to resource such a study in the currenteconomic environment.

We however do have a fundamental concern about the leapof faith that is driving the development of alemtuzumab andsimilar biological therapies in MS. The presumption of auto-immunity in MS is still an unproven hypothesis (Behan et al.,2002). Autoimmune diseases are broadly defined as conditionswhere antibodies or sensitised lymphocytes react with specifictargets in host tissue but this has never been shown to be truein MS. We consider MS to be primarily a neurodegenerativedisorder and not an autoimmune disease (Chaudhuri et al.,2004) where inflammatory changes are essentially reactive orsecondary and occur in response to tissue destruction; in thismodel primary progressive MS is the ‘‘prototype’’ neurode-generative disease and the relapsing-remitting MS representthe female predominant younger phenotype determined bythe combined metabolic influence of solar exposure in earlylife, age and gender effects. Conventional disease modifyingtherapies in MS target a secondary process, an epiphenome-non in MS pathology, without substantially influencing thenatural history of the primary neurodegenerative disease.Indeed, long term data from beta interferon therapy over pasttwo decades in multiple sclerosis (Shirani et al., 2012) attest

95Lessons from clinical trials of alemtuzumab in multiple sclerosis

to our view that reduction of relapse rates in MS does nottranslate into long term limitation of disability progression(Behan et al., 2002; Chaudhuri et al., 2004). Experience hasshown that aggressive immunosuppression with cytotoxicdrugs, total body irradiation or anti-lymphocytic globulinwas never effective in MS (Chaudhuri et al., 2004). Histori-cally, autoimmune diseases have been regarded as theproduct of a selective imbalance between immune responsepathways; a view that is supported by the high prevalence ofautoimmune diseases among patients with immune deficien-cies (Fundenberg, 1971). Therapeutic use of alemtuzumab inMS is likely to induce this imbalance of immunity in a group ofpatients who may not, after all, have an antibody or cellmediated primary autoimmune disease of their central ner-vous system.

Conflict of interest statement

We affirm that the work in original and that all authors meetthe criteria for authorship, including acceptance of respon-sibility for the scientific content of the manuscript.

We declare no potential conflicts of interest.

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