Cardiac-Related Infusion-Associated Reactions in Relapsing-Remitting Multiple Sclerosis Patients Treated with Alemtuzumab

Background: Alemtuzumab, approved in the European Union, Australia, and Canada for relapsing-remitting multiple sclerosis (RRMS), demonstrated superior efficacy vs subcutaneous IFNB-1a in RRMS patients with well-characterized safety and tolerability profile. The most common adverse events (AEs) were infusion-associated reactions (IARs; class effect of monoclonal antibody therapies), usually mild-to-moderate severity (91.6%); IAR serious AEs (SAEs) were infrequent (2.5%).

Objectives: To summarize cardiac-related alemtuzumab IARs in RRMS patients in core and extension studies of phase 2 and 3 clinical program.

Methods: In 36-month, phase 2 CAMMS223 (NCT00050778) and 24-month, phase 3 CARE-MS I (NCT00530348) and CARE-MS II (NCT00548405) core studies, RRMS patients received alemtuzumab intravenously 12 or 24 mg/day (only 12 mg/day in CARE-MS I) on 5 consecutive days at baseline and 3 consecutive days 12 months (24 months in CAMMS223) later. All studies included an extension (NCT00930553) with as-needed alemtuzumab re-treatment. For IAR mitigation during and after infusions, methylprednisolone premedication (and optional treatment with antipyretics, antihistamines, and anti-emetics) and infusion management strategies were implemented. IARs were defined as AEs beginning during or within 24 h after any alemtuzumab infusion. Serious IARs identified by standard ICH criteria. All IAR SAEs in cardiac disorders System Organ Class and other relevant events are reported.

Results: Incidence of any IAR cardiac event was 12.5% among alemtuzumab-treated patients (n=1485), most frequently tachycardia (6.7%), bradycardia (2.8%), and palpitations (2.6%). Serious cardiac-related IARs occurred in 0.5% (n=8): bradycardia (2), sinus bradycardia (1), atrial fibrillation (3), and sinus tachycardia (2). Other serious IARs included hypotension (3) and hypertension (2), and 1 anaphylaxis event (investigator later characterized as nonanaphylactoid hypotension). Risk of event was not increased with course number/re-treatment. Events were most frequent on Day 1. All events resolved with treatment. All patients continued on study; however, 2 (0.1%) discontinued alemtuzumab treatment.

Conclusions: Cardiac symptoms, most commonly tachycardia, can occur with alemtuzumab infusions. In studies, symptoms resolved and did not preclude further alemtuzumab treatment. SAEs were uncommon. Given potential for these symptoms, it is important to be aware of patients’ cardiac history prior to first infusion.

Study supported by: Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals