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Meta-Analysis
. 2016 Apr 15;4(4):CD011203.
doi: 10.1002/14651858.CD011203.pub2.

Alemtuzumab for multiple sclerosis

Rachel Riera  1 , Gustavo J M Porfírio, Maria R Torloni
Affiliations
Meta-Analysis

Alemtuzumab for multiple sclerosis

Rachel Riera et al. Cochrane Database Syst Rev. .

Update in

  • Alemtuzumab for multiple sclerosis.
    Riera R, Torloni MR, Martimbianco ALC, Pacheco RL. Riera R, et al. Cochrane Database Syst Rev. 2023 Jun 5;6(6):CD011203. doi: 10.1002/14651858.CD011203.pub3. Cochrane Database Syst Rev. 2023. PMID: 37272540 Free PMC article. Review.

Abstract

Background: Multiple sclerosis (MS) is an autoimmune, T-cell-dependent, inflammatory, demyelinating disease of the central nervous system, with an unpredictable course. Current MS therapies focus on treating exacerbations, preventing new exacerbations and avoiding the progression of disability. However, at present there is no effective treatment that is capable of safely and effectively reaching these objectives. This has led to the development and investigation of new drugs. Recent clinical trials suggest that alemtuzumab, a humanised monoclonal antibody against cell surface CD52, could be a promising option for MS.

Objectives: To assess the safety and effectiveness of alemtuzumab used alone or associated with other treatments to decrease disease activity in patients with any form of MS.

Search methods: We searched the Trials Register of the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group (30 April 2015), which contains trials from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, LILACS and the trial registry databases ClinicalTrials.gov and WHO International Clinical Trials Registry Platform. There was no restriction on the source, publication date or language.

Selection criteria: All randomised clinical trials (RCTs) involving adults diagnosed with any form of MS according to the McDonald criteria, comparing alemtuzumab alone or associated with other medications, at any dose and for any duration, versus placebo or any other active drug therapy or alemtuzumab in other dose, regimen or duration. The co-primary outcomes were relapse-free survival, sustained disease progression and number of participants with at least one of any adverse events, including serious adverse events.

Data collection and analysis: Two independent review authors performed study selection, data extraction and 'Risk of bias' assessment. A third review author checked the process for accuracy. We used the Cochrane 'Risk of bias' tool to assess the risk of bias of the studies included in the review. We used the GRADE system to assess the quality of the body of evidence. To measure the treatment effect on dichotomous outcomes we used the risk ratio (RR); for the treatment effect on continuous outcomes, we used the mean difference (MD) and for time-to-event outcomes we used hazard ratio (HR). We calculated 95% confidence intervals (CI) for these measures. When there was no heterogeneity, we used a fixed-effect model to pool data.

Main results: Three RCTs (1713 participants) fulfilled the selection criteria and we included them in the review. All three trials compared alemtuzumab versus subcutaneous interferon beta-1a for patients with relapsing-remitting MS. Patients were treatment-naive in the CARE-MS and CAMMS223 studies. The CARE-MS II study included patients with at least one relapse while being treated with interferon beta or glatiramer acetate. Alemtuzumab was given for 12 or 24 months; for some outcomes, the follow-up period reached 36 months. The regimens were (a) 12 mg or 24 mg per day administered intravenously, once a day for five consecutive days at month 0 and 12 or (b) 24 mg per day, intravenously, once a day for three consecutive days at month 12 and 24. The patients in the other arm of the trials received interferon beta-1a 44 μg subcutaneously three times weekly after dose titration.At 24 months, alemtuzumab 12 mg was associated with: (a) higher relapse-free survival (hazard ratio (HR) 0.50, 95% CI 0.41 to 0.60; 1248 participants, two studies, moderate quality evidence); (b) higher sustained disease progression-free survival (HR 0.62, 95% CI 0.44 to 0.87; 1191 participants; two studies; moderate quality evidence); (c) a slightly higher number of participants with at least one adverse event (RR 1.04, 95% CI 1.01 to 1.06; 1248 participants; two studies; moderate quality evidence); (d) a lower number of participants with new or enlarging T2-hyperintense lesions on magnetic resonance imaging (MRI) (RR 0.74, 95% CI 0.59 to 0.91; 1238 participants; two studies; I(2) = 80%); and (e) a lower number of dropouts (RR 0.31, 95% CI 0.23 to 0.41; 1248 participants; two studies, I(2) = 29%; low quality evidence).At 36 months, alemtuzumab 24 mg was associated with: (a) higher relapse-free survival (45 versus 17; HR 0.21, 95% CI 0.11 to 0.40; one study; 221 participants); (b) a higher sustained disease progression-free survival (HR 0.33, 95% CI 0.16 to 0.69; one study; 221 participants); and (c) no statistical difference in the rate of participants with at least one adverse event. We did not find any study that reported any of the following outcomes: rate of participants free of clinical disease activity, quality of life, fatigue or change in the numbers of MRI T2- and T1-weighted lesions after treatment. It was not possible to perform subgroup analyses according to disease type and disability at baseline due to lack of data.

Authors' conclusions: In patients with relapsing-remitting MS, alemtuzumab 12 mg was better than subcutaneous interferon beta-1a for the following outcomes assessed at 24 months: relapse-free survival, sustained disease progression-free survival, number of participants with at least one adverse event and number of participants with new or enlarging T2-hyperintense lesions on MRI. The quality of the evidence for these results was low to moderate. Alemtuzumab 24 mg seemed to be better than subcutaneous interferon beta-1a for relapse-free survival and sustained disease progression-free survival, at 36 months.More randomised clinical trials are needed to evaluate the effects of alemtuzumab on other forms of MS and compared with other therapeutic options. These new studies should assess additional relevant outcomes such as the rate of participants free of clinical disease activity, quality of life, fatigue and adverse events (individual rates, serious adverse events and long-term adverse events). Moreover, these new studies should evaluate other doses and durations of alemtuzumab course.

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Conflict of interest statement

RR: none

GJMP: none

MRT: none

Figures

1
1
Study flow diagram.
2
2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
3
3
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Forest plot of comparison: 1 Alemtuzumab 12 mg versus interferon beta‐1a, outcome: 1.1 Relapse‐free survival.
5
5
Forest plot of comparison: 1 Alemtuzumab 12 mg versus interferon beta‐1a, outcome: 1.2 Sustained disease progression‐free survival.
6
6
Forest plot of comparison: 1 Alemtuzumab 12 mg versus interferon beta‐1a, outcome: 1.2 Rate of participants with at least one adverse event.
1.1
1.1. Analysis
Comparison 1 Alemtuzumab 12 mg versus interferon beta‐1a, Outcome 1 Relapse‐free survival.
1.2
1.2. Analysis
Comparison 1 Alemtuzumab 12 mg versus interferon beta‐1a, Outcome 2 Sustained disease progression‐free survival.
1.3
1.3. Analysis
Comparison 1 Alemtuzumab 12 mg versus interferon beta‐1a, Outcome 3 Number of participants with at least one adverse event.
1.4
1.4. Analysis
Comparison 1 Alemtuzumab 12 mg versus interferon beta‐1a, Outcome 4 Change in EDSS score.
1.5
1.5. Analysis
Comparison 1 Alemtuzumab 12 mg versus interferon beta‐1a, Outcome 5 Number of participants with new or enlarging T2‐hyperintense lesions.
1.6
1.6. Analysis
Comparison 1 Alemtuzumab 12 mg versus interferon beta‐1a, Outcome 6 Number of dropouts.
See this image and copyright information in PMC

References

References to studies included in this review

CAMMS223 {published data only}
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    1. Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, et al. Alemtuzumab versus interferon beta‐1a in early relapsing‐remitting multiple sclerosis: post‐hoc and subset analyses of clinical efficacy outcomes. Lancet Neurology 2011;10(4):338‐48. - PubMed
    1. Daniels GH, Vladic A, Brinar V, Zavalishin I, Valente W, Oyuela P, et al. Alemtuzumab‐related thyroid dysfunction in a phase 2 trial of patients with relapsing‐remitting multiple sclerosis. Journal of Clinical Endocrinology and Metabolism 2014;99(1):80‐9. - PubMed
CARE‐MS I {published data only}
    1. Arnold D, Brinar V, Cohen J, Coles A, Confavreux C, Fisher E, et al. Effect of alemtuzumab vs. RebifTM on brain MRI measurements: results of CARE‐MS I, a phase 3 study. Neurology 2012;78(1):S11.006.
    1. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, et al. Alemtuzumab versus interferon beta 1a as first‐line treatment for patients with relapsing‐remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012;380(9856):1819‐28. - PubMed
    1. Coles A, Brinar V, Arnold D, Cohen J, Confavreux C, Fox E, et al. Efficacy and safety results from comparison of alemtuzumab and RebifTM efficacy in multiple sclerosis I (CARE‐MS I): a phase 3 study in relapsing‐remitting treatment‐naive patients. Neurology 2012;78(Suppl 1):S01.006.
    1. Fox E, Arnold D, Brinar V, Cohen J, Coles A, Confavreux C, et al. Relapse outcomes with alemtuzumab vs. RebifTM in treatment‐naive relapsing‐remitting multiple sclerosis (CARE‐MS I): secondary and tertiary endpoints. Neurology 2012;78(Suppl 1):PD5.004. [DOI: 10.1212/WNL.78.1_MeetingAbstracts.PD5.004] - DOI
    1. Giovannoni G, Arnold DL, Cohen J, Coles AJ, Confavreux C, Fox HP, et al. Disease activity‐free status in comparison of alemtuzumab and RebifTM efficacy in multiple sclerosis I (CARE‐MS I) phase 3 study. Journal of Neurology 2012;259(Suppl 1):47.
CARE‐MS II {published data only}
    1. Arnold DL, Cohen J, Coles AJ, Confavreux C, Fisher E, Fox EJ, et al. Effect of alemtuzumab vs. Rebif® on brain MRI measurements. Multiple Sclerosis 2012;18(4):397.
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    1. Barkhof F, Fisher E, Palmer J, Margolin DH, Arnold DL. Alemtuzumab demonstrates improvement in MRI outcomes across baseline subgroups versus subcutaneous interferon beta‐1a in relapsing‐remitting multiple sclerosis patients who relapsed on prior therapy. European Journal of Neurology 2014;21:126‐7.
    1. Brinar V, Arnold DL, Cohen J, Coles AJ, Fox EJ, Hartung HP, et al. Alemtuzumab improves expanded disability status scale (EDSS) via effects on functional systems: CARE‐MS II. Multiple Sclerosis. Multiple Sclerosis Journal 2013;19(S1):283‐4.
    1. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease‐modifying therapy: a randomised controlled phase 3 trial. Lancet 2012;380:1829‐39. - PubMed

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Riera 2014
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