Alemtuzumab treatment of MS: long-term safety and efficacy

Treatment, therapies and management:
The aim of this observational cohort study was to describe a longer-term experience of the efficacy and safety of alemtuzumab in active RRMS. The authors summarised their total experience from 1999 to 2012 of treating relapsing-remitting multiple sclerosis with alemtuzumab in two rater-blinded investigator-led open-label studies at a single site with 100% follow-up.

All (n=87) patients with relapsing-remitting multiple sclerosis were followed from two single-arm, open- label, rater-blinded, investigator-led studies, whose early results have been reported: 67 on the ‘CAMMS224’ trial (1999–2010) and 20 on the ‘SM3 trial’ (2005–2008).

Patients were seen quarterly for two years following each cycle of alemtuzumab, six-monthly over the next two years, at least annually thereafter and within a week of reporting new symptoms. Disability was assessed using the EDSS by a rater blinded to treatment and previous EDSS scores. Laboratory investigations performed at each visit included a full blood count (FBC), lymphocyte subsets, thyroid function tests, anti-nuclear antibody (ANA) and antithyroid peroxidase autoantibodies. Two cycles of alemtuzumab were administered 12 months apart; further cycles were offered if a relapse occurred.

Alemtuzumab was given by intravenous infusion on five consecutive days at baseline and on three consecutive days for subsequent cycles. Infusion-associated symptoms were reduced by corticosteroid pretreatment; most patients also required antihistamines and paracetamol. Patients in the SM3 trial also received a biologically inert variant of alemtuzumab, which prevented antialemtuzumab antibodies. Patients received no other disease-modifying therapy. Total follow-up to last-recorded EDSS was 559 patient-years, and 624 patient-years to last clinic visit.
Most patients (45; 52%) received just the two planned cycles of alemtuzumab, 12 months apart. Further cycles were offered if a relapse occurred: 31 patients (36%) received three; seven patients (8%) four; and one patient five cycles. Three patients (4%) received only one treatment cycle; one developed Goodpasture’s disease and was advised against re-treatment; and two patients declined further cycles.

Mean annualised relapse rate after alemtuzumab, recorded prospectively over all follow-up, was 0.16 (SD 0.26) compared with 1.78 (SD 0.82), assessed retrospectively, for the two pretreatment years. Clinical autoimmune disease developed in 41 patients (48%, omitting one patient with pre-existing thyroid disease); a further 12 (14%) patients developed sustained novel autoantibodies with no evidence of associated clinical disease. This occurred at a median time of 32 months after first treatment and a median 16 months since last treatment.

Thyroid autoimmunity developed in 35/86 (41%) of whom 22/35 (63%) had hyperthyroidism (Graves’ disease); one patient had transient thyroiditis, and 12 (34%) developed primary hypothyroidism with positive antithyroid peroxidase antibodies. Most patients were treated medically; three with Graves’ disease also required radio-iodine treatment. Three patients (3.5%) developed immune thrombocytopenic purpura (ITP). There were no serious infections that required hospitalisation. No malignancies were noted. Monocyte numbers recovered rapidly, whereas T cells reconstituted slowly after alemtuzumab.

Authors: Tuohy O, Costelloe L.
Source: J Neurol Neurosurg Psychiatry. 2014 May 21. pii: jnnp-2014-307721. doi: 10.1136/jnnp-2014-307721. [Epub ahead of print]
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