Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab | Demyelinating Disorders | JAMA Neurology | JAMA Network
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Original Investigation
August 2017

Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab

Author Affiliations
  • 1Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, England
  • 2Emergency Care and Acute Medicine, Clinical Academic Group Neuroscience, Barts Health NHS (National Health Service) Trust, The Royal London Hospital, London, England
JAMA Neurol. 2017;74(8):961-969. doi:10.1001/jamaneurol.2017.0676
Key Points

Question  Are lymphocyte subset reconstitution kinetics associated with efficacy and adverse effects of alemtuzumab administration in multiple sclerosis?

Findings  Analysis of previously unpublished data from pivotal phase 3 trials in the regulatory submissions of alemtuzumab indicated that efficacy was associated with long-term depletion of memory T and B cells, whereas rapid hyperrepopulation of immature B cells in the relative absence of regulatory CD4 and CD8 T cells create the environment for the generation of secondary B-cell autoimmunity, including anti–drug antibodies.

Meaning  Controlling this B-cell hyperrepopulation after alemtuzumab administration may limit the risk for secondary autoimmunity if administration can be performed safely.


Importance  Alemtuzumab, a CD52-depleting monoclonal antibody, effectively inhibits relapsing multiple sclerosis (MS) but is associated with a high incidence of secondary B-cell autoimmunities that limit use. These effects may be avoided through control of B-cell hyperproliferation.

Objective  To investigate whether the data describing the effect of alemtuzumab on lymphocyte subsets collected during the phase 3 trial program reveal mechanisms explaining efficacy and the risk for secondary autoimmunity with treatment of MS.

Design, Setting, and Participants  Lymphocyte reconstitution data from regulatory submissions of the pivotal Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I and II (CARE-MS I and II) trials were obtained from the European Medicines Agency via Freedom of Information requests. Data used in this study were reported from June 22 to October 12, 2016.

Main Outcomes and Measures  Tabulated data from T- and B-lymphocyte subset analysis and antidrug antibody responses were extracted from the supplied documents.

Results  Alemtuzumab depleted CD4+ T cells by more than 95%, including regulatory cells (−80%) and CD8+ T cells (>80% depletion), which remained well below reference levels throughout the trials. However, although CD19+ B cells were initially also depleted (>85%), marked (180% increase) hyperrepopulation of immature B cells occurred with conversion to mature B cells over time. These lymphocyte kinetics were associated with rapid development of alemtuzumab-binding and -neutralizing antibodies and subsequent occurrence of secondary B-cell autoimmunity. Hyperrepopulation of B cells masked a marked, long-term depletion of CD19+ memory B cells that may underpin efficacy in MS.

Conclusions and Relevance  Although blockade of memory T and B cells may limit MS, rapid CD19+ B-cell subset repopulation in the absence of effective T-cell regulation has implications for the safety and efficacy of alemtuzumab. Controlling B-cell proliferation until T-cell regulation recovers may limit secondary autoimmunity, which does not occur with other B-cell–depleting agents.