The 5-year extension of this phase II trial suggests a prolonged benefit of alemtuzumab for up to 3 years after the last treatment.
Alemtuzumab is an investigational humanized monoclonal antibody that selectively targets CD52, leading to long-term depletion of T-lymphocytes and B-lymphocytes. A phase II study involving 334 patients with relapsing-remitting multiple sclerosis (RRMS) demonstrated superior clinical efficacy of alemtuzumab over interferon Î²-1a given three times weekly (N Engl J Med 2008; 359:1786). Now, researchers have conducted a manufacturer-supported extension study to assess longer-term treatment effect and safety.
The original trial lasted 36 months, with 334 patients with RRMS enrolled from 2002 through 2004. However, one patient died of immune thrombocytopenia (ITP), resulting in an alemtuzumab dosing suspension between 2005 and 2008. Therefore, fewer patients received second or third courses of alemtuzumab than received a single course (see Figure 1 top). For this current extension trial, 198 of the original 334 patients were enrolled, of whom 183 provided data at 60 months (see Figure 1 bottom).
During the full 5 years, disability progression remained significantly lower in the alemtuzumab group than in the interferon group (a 72% difference). Other significant differences were the change over 5 years in mean Expanded Disability Status Scale score (0.30-point improvement with alemtuzumab, 0.46-point worsening with interferon) and annualized relapse rate over 5 years (0.11 with alemtuzumab, 0.35 with interferon). Annualized relapse rate between years 3 and 5 was 0.14 with alemtuzumab and 0.28 with interferon (P=0.072).
Deaths included three from the original alemtuzumab trial: one each from ITP, non-EBV-associated Burkitt lymphoma, and cardiovascular disease. One interferon recipient died of an accident. ITP was identified in 2.8% of alemtuzumab recipients; no new cases occurred in the extension phase. The incidence of thyroid-associated events increased in the final 2 years: 30% with alemtuzumab during the 5-year period (23% after 3 years) and 4% with interferon (3% after 3 years). One case of anti glomerular basement membrane (GBM) disease occurred 39 months after a second alemtuzumab course. Six malignancies were identified in the alemtuzumab group overall: lymphoma, breast, and cervical cancer in situ during the initial 3 years; papillary thyroid carcinoma and two cases of basal cell carcinoma in the extension study.
Comment: This phase II extension demonstrates a long-term effect of alemtuzumab, which can last years after the final dose, in patients with active, early MS. Even after just two or three treatments, patients have maintained low relapse rates and disability progression. The efficacy of this medication is impressive, but the long-term safety data need to be carefully considered. For example, one case of anti-GBM disease occurred 3 years after the last infusion. Thus, this medication is a long-term commitment between doctor and patient, and potentially has a role in treatment of aggressive, early MS or treatment-refractory MS.
Robert T. Naismith, MD
Dr. Naismith is a consultant for Bayer Corporation, a co-supporter of the current study. He was not involved in this phase II study, but he served on an independent and blinded adjudication panel to confirm relapses for the two phase III studies.
Published in Journal Watch Neurology April 10, 2012