Safety of alemtuzumab in relapsing-remitting multiple sclerosis patients who relapsed on prior therapy (CARE-MS II)

OBJECTIVE: Describe the safety profile of alemtuzumab in the CARE-MS II study of patients with relapsing-remitting multiple sclerosis (RRMS) who relapsed on prior therapy. BACKGROUND: Alemtuzumab met both co-primary endpoints in CARE-MS II, reducing relapse rate by 49% (p<0.0001) and 6-month sustained accumulation of disability by 42% (p=0.0084) over 2 years compared with SC IFNB-1a. METHODS: RRMS patients who relapsed on prior therapy were randomized to alemtuzumab 12 mg/day IV on 5 days initially and 3 days 1 year later or SC IFNB-1a 44μg 3 x weekly (in an exploratory arm, patients received alemtuzumab 24 mg/day; results not reported here). Safety measures included patient and investigator education, monthly patient questionnaires, and laboratory monitoring (complete blood counts with platelets, serum creatinine and urinalysis with microscopy). RESULTS: 637 patients received treatment. Nearly all patients reported ≥1 adverse event (AE) (alemtuzumab, 98.4%; SC IFNB-1a, 94.6%), most of which were mild to moderate in severity. Two non–treatment-related deaths occurred with alemtuzumab. The most common alemtuzumab-associated AEs were infusion associated reactions (IARs), with symptoms including headache, rash, nausea, pyrexia, urticaria, and pruritus. IARs were reduced with pre-medication. Infections were common in both groups but more frequent with alemtuzumab (76.8% vs 66.3% for SC IFNB-1a); 94.5% were mild or moderate, with no treatment-related life-threatening infections. Incidence of serious infections was 3.7% vs 1.5%, alemtuzumab vs SC IFNB-1a. The most common infections with alemtuzumab included upper respiratory and urinary tract infections, sinusitis and herpes simplex. Thyroid disorders were more common with alemtuzumab (15.9% vs 5.0% for SC IFNB-1a). 94.5% were mild or moderate, and most were managed conventionally, although 1 patient required thyroidectomy. Immune thrombocytopenia (ITP) occurred in 4 (0.9%) alemtuzumab and no SC IFNB-1a patients. One patient with ITP had previously developed non-serious autoimmune hemolytic anemia that resolved spontaneously. ITP was detected through clinical and laboratory monitoring with prompt treatment responses. No anti-glomerular basement membrane disease was seen. Two malignancies occurred in each treatment group. CONCLUSIONS: Alemtuzumab’s safety profile in CARE-MS II was consistent with previous use in MS. CARE-MS II demonstrated a favorable benefit/risk balance for alemtuzumab in patients who relapsed on prior therapy.