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Clinical Trial
. 2017 Aug 1;74(8):961-969.
doi: 10.1001/jamaneurol.2017.0676.

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

David Baker  1 , Samuel S Herrod  1 , Cesar Alvarez-Gonzalez  1 , Gavin Giovannoni  1   2 , Klaus Schmierer  1   2
Affiliations
Clinical Trial

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

David Baker et al. JAMA Neurol. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Baker reports being a founder and consultant to Canbex Therapeutics and receiving research funds from Canbex Therapeutics, Sanofi-Genzyme, and Takeda in the past 3 years. Dr Giovannoni reports receiving fees for participation in the advisory board for AbbVie Biotherapeutics, Biogen, Canbex, Ironwood, Novartis, Merck, Inc, Merck Serono, Roche, Sanofi Genzyme, Synthon, Teva, and Vertex; speaker fees from AbbVie, Biogen, Bayer HealthCare, Genzyme, Merck Serono, Sanofi-Aventis, and Teva; and research support from Biogen, Genzyme, Ironwood, Merck, Inc, Merck Serono, and Novartis. Dr Schmierer reports being a principal investigator of trials sponsored by Novartis, Roche, Teva, and Medday; involved in trials sponsored by Biogen, Sanofi-Genzyme, BIAL, Cytokinetics, and Canbex; and receiving speaking honoraria for lecturing and advisory activity and/or meeting support from Biogen, Merck, Inc, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Kinetic Analysis of T-Cell Subsets After Alemtuzumab Infusion in the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I Trial
Data are represented as the approximate change in the number of T cells at different points after administration of 12 mg of alemtuzumab (blue dotted lines). A, Mean (SD) baseline level of CD4 T cells was 970/μL (380/μL) (includes 376 people with multiple sclerosis, ranging from 361 to 374 per time point). B, Mean (SD) baseline level of CD8 T cells was 500/μL (220/μL) (includes 376 people with multiple sclerosis, ranging from 361 to 374 per time point). C, Mean (SD) baseline level of naive CD4 (CD45RA+) T cells was 380/μL (200/μL) (includes 98 people with multiple sclerosis, ranging from 53 to 94 per time point). D, Mean (SD) baseline level of memory CD4 (CD45RO+) T cells was 650/μL (60/μL) (includes 98 people with multiple sclerosis, ranging from 43 to 94 per time point). E and F, Mean (SD) baseline levels of CD4 and CD8 (CD25intermediate/bright and CD127-/low) T regulatory cells were 650/μL (60/μL) (includes 98 people with multiple sclerosis, ranging from 43 to 94 per time point). To convert lymphocyte counts to ×109 per liter, multiply by 0.001.
Figure 2.
Figure 2.. Kinetic Analysis of B-Cell Subsets After Alemtuzumab Administration in the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I Trial
Data are represented as the approximate change in the number of B cells at different points after administration of 12 mg of alemtuzumab (blue dotted lines). A, Mean (SD) baseline level of CD19 B cells was 270/μL (130/μL) (includes 376 people with multiple sclerosis, ranging from 361 to 374 per time point). B, Mean (SD) baseline level of immature B cells (CD19+, CD27−, IgD+, CD38+, and CD10+) was 10/μL (10/μL) (includes 98 people with multiple sclerosis, ranging from 41 to 94 per time point). C, Mean (SD) baseline level of mature/naive B cells (CD19+, CD27−, IgD+, CD38+, and CD10−) was 180/μL (160/μL) (includes 98 people with multiple sclerosis, ranging from 41 to 94 per time point). D, Mean (SD) baseline level of memory B cells (CD19+ and CD27+) was 270/μL (130/μL) (includes 98 people with multiple sclerosis, ranging from 42 to 94 per time point). To convert lymphocyte counts to ×109 per liter, multiply by 0.001.
Figure 3.
Figure 3.. Summary of Lymphocyte Subset Repopulation Kinetics After Alemtuzumab Treatment
Lymphocyte reconstitution after alemtuzumab administration leads to control of multiple sclerosis and secondary B-cell autoimmunity.
See this image and copyright information in PMC

Comment in

References

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