Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab | Demyelinating Disorders | JAMA Neurology | JAMA Network
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1.
Coles  AJ, Compston  DA, Selmaj  KW,  et al; CAMMS223 Trial Investigators.  Alemtuzumab vs interferon beta-1a in early multiple sclerosis.  N Engl J Med. 2008;359(17):1786-1801.PubMedGoogle ScholarCrossref
2.
Cohen  JA, Coles  AJ, Arnold  DL,  et al; CARE-MS I investigators.  Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.  Lancet. 2012;380(9856):1819-1828.PubMedGoogle ScholarCrossref
3.
Coles  AJ, Twyman  CL, Arnold  DL,  et al; CARE-MS II investigators.  Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial.  Lancet. 2012;380(9856):1829-1839.PubMedGoogle ScholarCrossref
4.
Tuohy  O, Costelloe  L, Hill-Cawthorne  G,  et al.  Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy.  J Neurol Neurosurg Psychiatry. 2015;86(2):208-215.PubMedGoogle ScholarCrossref
5.
Haghikia  A, Dendrou  CA, Schneider  R,  et al.  Severe B-cell–mediated CNS disease secondary to alemtuzumab therapy.  Lancet Neurol. 2017;16(2):104-106.PubMedGoogle ScholarCrossref
6.
Senior  P, Arnold  D, Cohen  J,  et al Incidence and timing of thyroid adverse events in patients with RRMS treated with alemtuzumab through 5 years of the CARE-MS studies. Neurology. 2016;86(16):suppl P2.086.
7.
Cossburn  MD, Harding  K, Ingram  G,  et al.  Clinical relevance of differential lymphocyte recovery after alemtuzumab therapy for multiple sclerosis.  Neurology. 2013;80(1):55-61.PubMedGoogle ScholarCrossref
8.
Kousin-Ezewu  O, Azzopardi  L, Parker  RA,  et al.  Accelerated lymphocyte recovery after alemtuzumab does not predict multiple sclerosis activity.  Neurology. 2014;82(24):2158-2164.PubMedGoogle ScholarCrossref
9.
Havari  E, Turner  MJ, Campos-Rivera  J,  et al.  Impact of alemtuzumab treatment on the survival and function of human regulatory T cells in vitro.  Immunology. 2014;141(1):123-131.PubMedGoogle ScholarCrossref
10.
Zhang  X, Tao  Y, Chopra  M,  et al.  Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with relapsing-remitting multiple sclerosis.  J Immunol. 2013;191(12):5867-5874.PubMedGoogle ScholarCrossref
11.
Jones  JL, Thompson  SA, Loh  P,  et al.  Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation.  Proc Natl Acad Sci U S A. 2013;110(50):20200-20205.PubMedGoogle ScholarCrossref
12.
van Oosten  BW, Lai  M, Hodgkinson  S,  et al.  Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial.  Neurology. 1997;49(2):351-357.PubMedGoogle ScholarCrossref
13.
Llewellyn-Smith  N, Lai  M, Miller  DH, Rudge  P, Thompson  AJ, Cuzner  ML.  Effects of anti-CD4 antibody treatment on lymphocyte subsets and stimulated tumor necrosis factor alpha production: a study of 29 multiple sclerosis patients entered into a clinical trial of cM-T412.  Neurology. 1997;48(4):810-816.PubMedGoogle ScholarCrossref
14.
Cox  AL, Thompson  SA, Jones  JL,  et al.  Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis.  Eur J Immunol. 2005;35(11):3332-3342.PubMedGoogle ScholarCrossref
15.
Thompson  SA, Jones  JL, Cox  AL, Compston  DA, Coles  AJ.  B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis.  J Clin Immunol. 2010;30(1):99-105.PubMedGoogle ScholarCrossref
16.
Hartung  HP, Arnold  DL, Cohen  J,  et al.  Lymphocyte subset dynamics following alemtuzumab treatment in the CARE-MS I study.  Mult Scler J. 2012;18(S4):427-428.Google Scholar
17.
Kasper  LH, Arnold  DL, Cohen  JA,  et al.  Lymphocyte subset dynamics following alemtuzumab treatment in the CARE-MS II study.  Mult Scler J. 2013;18(S1):2717-218.Google Scholar
18.
Ziemssen  T, Arnold  DL, Cohen  JA,  et al.  Immunogenicity of alemtuzumab does not impact safety and efficacy in relapsing remitting multiple sclerosis patients in the CARE-MS I study.  Mult Scler J. 2013;19(S1):212-213.Google Scholar
19.
Hu  Y, Turner  MJ, Shields  J,  et al.  Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model.  Immunology. 2009;128(2):260-270.PubMedGoogle ScholarCrossref
20.
Von Kutzleben  S, Pryce  G, Giovannoni  G, Baker  D.  Depletion of CD52 positive cells inhibits the development of CNS autoimmune disease, but deletes an immune-tolerance promoting CD8 T cell population: implications for secondary autoimmunity of alemtuzumab in multiple sclerosis.  Immunology. 2017;150(4):444-455. PubMedGoogle Scholar
21.
Hill-Cawthorne  GA, Button  T, Tuohy  O,  et al.  Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis.  J Neurol Neurosurg Psychiatry. 2012;83(3):298-304.PubMedGoogle ScholarCrossref
22.
Salou  M, Nicol  B, Garcia  A, Laplaud  DA.  Involvement of CD8+ T cells in multiple sclerosis.  Front Immunol. 2015;6:604.PubMedGoogle ScholarCrossref
23.
Mitosek-Szewczyk  K, Tabarkiewicz  J, Wilczynska  B,  et al.  Impact of cladribine therapy on changes in circulating dendritic cell subsets, T cells and B cells in patients with multiple sclerosis.  J Neurol Sci. 2013;332(1-2):35-40.PubMedGoogle ScholarCrossref
24.
Palanichamy  A, Jahn  S, Nickles  D,  et al.  Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients.  J Immunol. 2014;193(2):580-586.PubMedGoogle ScholarCrossref
25.
Giovannoni  G, Comi  G, Cook  S,  et al; CLARITY Study Group.  A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis.  N Engl J Med. 2010;362(5):416-426.PubMedGoogle ScholarCrossref
26.
Kappos  L, Li  D, Calabresi  PA,  et al.  Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial.  Lancet. 2011;378(9805):1779-1787.PubMedGoogle ScholarCrossref
27.
Burt  RK, Balabanov  R, Han  X,  et al.  Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis.  JAMA. 2015;313(3):275-284.PubMedGoogle ScholarCrossref
28.
Naismith  RT, Piccio  L, Lyons  JA,  et al.  Rituximab add-on therapy for breakthrough relapsing multiple sclerosis: a 52-week phase II trial.  Neurology. 2010;74(23):1860-1867.PubMedGoogle ScholarCrossref
29.
Song  A, Hendricks  R, Chung  S,  et al Immunogenicity with repeated dosing of ocrelizumab in patients with multiple sclerosis.  Neurology. 2016;86(16):suppl P2.086.Google Scholar
30.
Holgate  RG, Weldon  R, Jones  TD, Baker  MP.  Characterisation of a novel anti-CD52 antibody with improved efficacy and reduced immunogenicity.  PLoS One. 2015;10(9):e0138123.PubMedGoogle ScholarCrossref
31.
Somerfield  J, Hill-Cawthorne  GA, Lin  A,  et al.  A novel strategy to reduce the immunogenicity of biological therapies.  J Immunol. 2010;185(1):763-768.PubMedGoogle ScholarCrossref
32.
Coles  AJ.  Alemtuzumab therapy for multiple sclerosis.  Neurotherapeutics. 2013;10(1):29-33.PubMedGoogle ScholarCrossref
33.
Willis  M, Pearson  O, Illes  Z,  et al.  An observational study of alemtuzumab following fingolimod for multiple sclerosis.  Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e320.PubMedGoogle ScholarCrossref
34.
McCarthy  CL, Tuohy  O, Compston  DA, Kumararatne  DS, Coles  AJ, Jones  JL.  Immune competence after alemtuzumab treatment of multiple sclerosis.  Neurology. 2013;81(10):872-876.PubMedGoogle ScholarCrossref
35.
Anolik  JH, Friedberg  JW, Zheng  B,  et al.  B cell reconstitution after rituximab treatment of lymphoma recapitulates B cell ontogeny.  Clin Immunol. 2007;122(2):139-145.PubMedGoogle ScholarCrossref
36.
Marrie  RA, Reider  N, Cohen  J,  et al.  A systematic review of the incidence and prevalence of autoimmune disease in multiple sclerosis.  Mult Scler. 2015;21(3):282-293.PubMedGoogle ScholarCrossref
37.
Demko  S, Summers  J, Keegan  P, Pazdur  R.  FDA drug approval summary: alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia.  Oncologist. 2008;13(2):167-174.PubMedGoogle ScholarCrossref
38.
Krupica  T  Jr, Fry  TJ, Mackall  CL.  Autoimmunity during lymphopenia: a two-hit model.  Clin Immunol. 2006;120(2):121-128.PubMedGoogle ScholarCrossref
39.
ClinicalTrials.gov. Keratinocyte Growth Factor to Prevent Autoimmunity After Alemtuzumab Treatment of Multiple Sclerosis. NCT01712945. https://clinicaltrials.gov/ct2/show/NCT01712945. Accessed February 14, 2017.
40.
Jones  JL, Phuah  CL, Cox  AL,  et al.  IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H).  J Clin Invest. 2009;119(7):2052-2061.PubMedGoogle Scholar
41.
Sakuraba  K, Oyamada  A, Fujimura  K,  et al.  Interleukin-21 signaling in B cells, but not in T cells, is indispensable for the development of collagen-induced arthritis in mice.  Arthritis Res Ther. 2016;18:188.PubMedGoogle ScholarCrossref
42.
Meffre  E, Wardemann  H.  B-cell tolerance checkpoints in health and autoimmunity.  Curr Opin Immunol. 2008;20(6):632-638.PubMedGoogle ScholarCrossref
43.
Kinnunen  T, Chamberlain  N, Morbach  H,  et al.  Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells.  Blood. 2013;121(9):1595-1603.PubMedGoogle ScholarCrossref
44.
Guiziry  DE, El  GW, Farahat  N, Hassab  H.  Phenotypic analysis of bone marrow lymphocytes from children with acute thrombocytopenic purpura.  Egypt J Immunol. 2005;12(1):9-14.PubMedGoogle Scholar
45.
Liu  B, Zhao  H, Poon  MC,  et al.  Abnormality of CD4+CD25+ regulatory T cells in idiopathic thrombocytopenic purpura.  Eur J Haematol. 2007;78(2):139-143.PubMedGoogle Scholar
46.
Brink  R.  The imperfect control of self-reactive germinal center B cells.  Curr Opin Immunol. 2014;28:97-101.PubMedGoogle ScholarCrossref
47.
Hargreaves  CE, Grasso  M, Hampe  CS,  et al.  Yersinia enterocolitica provides the link between thyroid-stimulating antibodies and their germline counterparts in Graves’ disease.  J Immunol. 2013;190(11):5373-5381.PubMedGoogle ScholarCrossref
48.
Honda  K, Littman  DR.  The microbiota in adaptive immune homeostasis and disease.  Nature. 2016;535(7610):75-84.PubMedGoogle ScholarCrossref
49.
Ascherio  A, Munger  KL.  EBV and autoimmunity.  Curr Top Microbiol Immunol. 2015;390(pt 1):365-385.PubMedGoogle Scholar
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.

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.

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