Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab.
JAMA Neurol
; 74(8): 961-969, 2017 08 01.
Article
em En
| MEDLINE
| ID: mdl-28604916
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, andParticipants:
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 andMeasures:
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Linfócitos B
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Linfócitos
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Anticorpos Monoclonais Humanizados
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Linfopenia
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Esclerose Múltipla
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Antineoplásicos
Tipo de estudo:
Clinical_trials
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Female
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Humans
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Male
Idioma:
En
Revista:
JAMA Neurol
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Reino Unido