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Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab.
JAMA Neurol. 2017 08 01; 74(8):961-969.JN

Abstract

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.

Authors+Show Affiliations

Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, England.Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, England.Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, England.Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, England. Emergency Care and Acute Medicine, Clinical Academic Group Neuroscience, Barts Health NHS (National Health Service) Trust, The Royal London Hospital, London, England.Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, England. Emergency Care and Acute Medicine, Clinical Academic Group Neuroscience, Barts Health NHS (National Health Service) Trust, The Royal London Hospital, London, England.

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Multicenter Study

Language

eng

PubMed ID

28604916

Citation

Baker, David, et al. "Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab." JAMA Neurology, vol. 74, no. 8, 2017, pp. 961-969.
Baker D, Herrod SS, Alvarez-Gonzalez C, et al. Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. JAMA Neurol. 2017;74(8):961-969.
Baker, D., Herrod, S. S., Alvarez-Gonzalez, C., Giovannoni, G., & Schmierer, K. (2017). Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. JAMA Neurology, 74(8), 961-969. https://doi.org/10.1001/jamaneurol.2017.0676
Baker D, et al. Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. JAMA Neurol. 2017 08 1;74(8):961-969. PubMed PMID: 28604916.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. AU - Baker,David, AU - Herrod,Samuel S, AU - Alvarez-Gonzalez,Cesar, AU - Giovannoni,Gavin, AU - Schmierer,Klaus, PY - 2017/6/13/pubmed PY - 2017/8/23/medline PY - 2017/6/13/entrez SP - 961 EP - 969 JF - JAMA neurology JO - JAMA Neurol VL - 74 IS - 8 N2 - 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. SN - 2168-6157 UR - https://www.unboundmedicine.com/medline/citation/28604916/Interpreting_Lymphocyte_Reconstitution_Data_From_the_Pivotal_Phase_3_Trials_of_Alemtuzumab_ L2 - https://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/jamaneurol.2017.0676 DB - PRIME DP - Unbound Medicine ER -