Two Is Not Enough: Efficacy of Alemtuzumab in Subsequent Cycles

Alemtuzumab in the Treatment of MS

Alemtuzumab is a humanized monoclonal antibody selectively targeting the CD52 cell surface antigen. It induces depletion of B and T cells, followed by a unique type of repopulation associated with a shift towards a less inflammatory cytokine profile. The resulting re-established balance of the immune system is a key component of the mechanism of action, leading to disease activity suppression. However, the entire mechanism of action is not yet fully understood.

Alemtuzumab is typically administered in 2 cycles (12 mg/day for 5 days at the beginning and for 3 days 12 months after the first dose). Patients with persistent disease activity can receive additional 3-day cycles as needed. In Europe, two additional cycles may be administered based on clinical or imaging-defined disease activity, with a minimum interval of 1 year.

Evaluated Population and Analyzed Data

Post hoc subgroup analyses defined by the total number of alemtuzumab cycles administered (2, 3, 4, and > 4) were conducted on patients treated with alemtuzumab in the CARE-MS I and II studies who were subsequently included in extension studies.

The analysis included data from 655 patients who were monitored for at least 12 months after the last alemtuzumab cycle and did not receive any other disease-modifying therapy (DMD) during the 8-year period. Of these individuals, 607 were included in the efficacy subgroup analyses: 362 (60%) received exactly 2 cycles, 144 (24%) received exactly 3 cycles, 62 (10%) received exactly 4 cycles, and 39 (6%) received ≥ 5 cycles. Of these, 74%, 83%, 81%, and 87%, respectively, remained in the study for the full 8 years. Baseline characteristics were comparable across all groups, except patients in the ≥ 4 cycles group had a higher number of baseline gadolinium-enhancing lesions in the core studies.

Key Findings

In the groups receiving additional cycles, the 3rd and 4th cycles reduced the annualized relapse rate (ARR; 12 months pre-cycle: 0.73 and 0.74; 12 months post-cycle: 0.07 and 0.08). For 36 months post 3rd and 4th cycles, 89% and 92% of patients, respectively, did not experience a 6-month confirmed disability worsening, and 20% and 26% of patients, respectively, achieved a 6-month confirmed improvement (assessed using the EDSS – Expanded Disability Status Scale). Absence of disease activity on MRI increased after the 3rd and 4th cycles (12 months pre-cycle: 43% and 53%; 12 months post-cycle: 73% and 74%).

Treatment safety was similar across all groups. The rate of serious adverse events was comparable regardless of the number of cycles. Over the 8-year period, the incidence of infections (84.3% vs. 89.1%), thyroid adverse events (48.6% vs. 45.4%), idiopathic thrombocytopenic purpura (1.9% vs. 1.0%), and nephropathy (0.3% vs. 0.3%) were similar between the 2-cycle group and the additional cycles group.

Conclusion

Approximately 60% of the study participants did not receive more than 2 cycles of alemtuzumab over the 8-year period. An important finding is that these patients, who had active disease at the start, maintained low annual relapse rates and low MRI activity over the 8 years, despite receiving no further therapy.

Additional cycles of alemtuzumab in patients with relapsing-remitting multiple sclerosis from the CARE-MS studies, who exhibited persistent disease activity after the 2nd cycle, significantly improved key outcomes (clinical and MRI disease activity) without compromising treatment safety.

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Source: Comi G., Alroughani R., Boster A. L. et al. Efficacy of alemtuzumab in relapsing-remitting MS patients who received additional courses after the initial two courses: pooled analysis of the CARE-MS, extension, and TOPAZ studies. Mult Scler 2019 Nov 25: 1352458519888610, doi: 10.1177/1352458519888610.