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      No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine

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      , BA, , MD, DPhil, , BA, DPhil, PGCE, MSc, FHEA, , BSc, PhD, , MD, FRCP, , MD, PhD, , MD, , PhD, , MA, PhD, FRCP, , PhD, FRCP
      Neurology® Neuroimmunology & Neuroinflammation
      Lippincott Williams & Wilkins

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          Abstract

          Objective:

          To compare the cancer risk of cladribine and other disease-modifying drugs (DMDs) in trials of people with relapsing multiple sclerosis (pwRMS).

          Methods:

          Meta-analysis of phase III trials of licensed DMDs for pwRMS and a phase III trial of cladribine (CLARITY). Cancer rates were compared using Fisher exact test.

          Results:

          Eleven trials were included. Investigated treatments included cladribine, dimethyl fumarate, fingolimod, teriflunomide, natalizumab, alemtuzumab, and glatiramer acetate. The cancer rate in the CLARITY treatment group (0.34%) was not increased compared to all other treatment groups, whether including placebo-controlled trials only (0.6%, p = 0.4631) or all trials, i.e., including those with an active comparator arm (0.67%, p = 0.3669). No cancer was reported in the CLARITY placebo group, whereas the combined cancer rate of all other placebo groups was 1.19% ( p = 0.0159). The cancer rate of zero in the CLARITY placebo group was also lower than that in the phase III trial of cladribine in people with clinically isolated syndrome (ORACLE MS, 2.91%, p = 0.0012). In fact, no difference was detected between cancer rates in the treatment groups of CLARITY (0.34%) and ORACLE MS (0.49%) ( p = 0.6546).

          Conclusions:

          Our study does not support an increased cancer risk from cladribine in the doses used in CLARITY and ORACLE MS, which previously contributed to refusal of market authorization of cladribine in Europe. Longer-term follow-up is required to assess the safety profile of cladribine, as well as currently licensed DMDs, to definitively assess cancer risk.

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          Most cited references26

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          THE USE OF CONFIDENCE OR FIDUCIAL LIMITS ILLUSTRATED IN THE CASE OF THE BINOMIAL

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            Multiple sclerosis

            The Lancet, 372(9648), 1502-1517
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              Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.

              The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial. In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00530348. 187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32-0·63]; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40-1·23]; p=0·22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the alemtuzumab group developed thyroid papillary carcinoma. Alemtuzumab's consistent safety profile and benefit in terms of reductions of relapse support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here. Genzyme (Sanofi) and Bayer Schering Pharma. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Neurol Neuroimmunol Neuroinflamm
                Neurol Neuroimmunol Neuroinflamm
                nnn
                NEURIMMINFL
                Neurology® Neuroimmunology & Neuroinflammation
                Lippincott Williams & Wilkins (Hagerstown, MD )
                2332-7812
                01 October 2015
                December 2015
                01 October 2015
                : 2
                : 6
                : e158
                Affiliations
                From Blizard Institute (Neuroscience) (J.P., G.D., M.M., D.B., K.S.), Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK; Oxford University Medical School (J.P.), John Radcliffe Hospital, Oxford, UK; London School of Hygiene and Tropical Medicine (D.R.A.), London, UK; Centre for Health Services Research (S.P.), Leeds Institute of Health Sciences, University of Leeds, Leeds, UK; Barts Health NHS Trust (B.P.T., M.M., K.S.), The Royal London Hospital, London, UK; Stem Cell Centre (G.J.), Lund University, Lund, Sweden; and Queen Square Multiple Sclerosis Centre (J.C.), Department of Neuroinflammation, UCL Institute of Neurology, University College London and National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London UK.
                Author notes
                Correspondence to Dr. Schmierer: k.schmierer@ 123456qmul.ac.uk

                Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was paid by Barts Charity, London, UK.

                Article
                NEURIMMINFL2015005454
                10.1212/NXI.0000000000000158
                4592538
                26468472
                00022866-676c-48b2-9264-29c459166a46
                © 2015 American Academy of Neurology

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (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.

                History
                : 12 June 2015
                : 05 August 2015
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