Background Alemtuzumab is a lymphocyte depleting monoclonal antibody that has demonstrated superior efficacy over interferon β-1a for relapsing–remitting multiple sclerosis (MS), and is currently under investigation in phase 3 trials. One unresolved issue is the duration and significance of the lymphopenia induced. The long term effects on lymphocyte reconstitution of a single course, and the consequences that this has on disability, morbidity, mortality and autoimmunity, were examined.
Methods The lymphocyte reconstitution (n=36; 384 person years) and crude safety data (n=37; 447 person years) are reported for the first patients with progressive MS to receive alemtuzumab (1991–1997). Reconstitution time was expressed as a geometric mean or, when a non-negligible number of individuals failed to recover, as a median using survival analysis.
Results Geometric mean recovery time (GMRT) of total lymphocyte counts to the lower limit of the normal range (LLN; ≥1.0×109 cells/l) was 12.7 months (95% CI 8.8 to 18.2 months). For B cells, GMRT to LLN (≥0.1×109/l) was 7.1 months (95% CI 5.3 to 9.5); median recovery times for CD8 (LLN ≥0.2×109 cells/l) and CD4 lymphocytes (LLN ≥0.4×109 cells/l) were 20 months and 35 months, respectively. However, CD8 and CD4 counts recovered to baseline levels in only 30% and 21% of patients, respectively. No infective safety concerns arose during 447 person years of follow-up.
Conclusions Lymphocyte counts recovered to LLN after a single course of alemtuzumab in approximately 8 months (B cells) and 3 years (T cell subsets), but usually did not recover to baseline values. However, this long lasting lymphopenia in patients with a previously normal immune system was not associated with an increased risk of serious opportunistic infection.
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Funding During the course of this work, AJC was supported by an MRC Clinical Training Fellowship, Wellcome Intermediate Fellowship and now by the Biomedical Research Centre, Cambridge, NIHR. JLJ is also supported by the Biomedical Research Centre, Cambridge, NIHR. The original studies were supported by a grant from MuSTER.
Competing interests AJC, DASC and JLJ have received personal travel costs, occasional honoraria and departmental support from Genzyme Corporation. GG has received honoraria and consulting fees from Genzyme Corporation and Sanofi-Aventis.
Ethics approval Ethics approval was provided by the local research ethics committees.
Provenance and peer review Not commissioned; externally peer reviewed.