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

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.

Acquired haemophilia A complicating alemtuzumab therapy for multiple sclerosis

“…However, its use is complicated by secondary B cell-mediated autoimmunity that typically peaks 2–3 years post-treatment initiation 4. Following each course of treatment, T cell repopulation is driven by early homeostatic proliferation of predominately CD8+ memory T lymphocytes1 followed by slower reconstitution of CD4+ cells with median recovery time to baseline of 61 months following a single infusion 11. Conversely, early B cell hyperpopulation is seen at 3 to 6 months post-treatment, driven by an arrested cell phenotype 12.…”

“…Conversely, early B cell hyperpopulation is seen at 3 to 6 months post-treatment, driven by an arrested cell phenotype 12. Despite a rise in the proportion of T-regulatory lymphocytes (T-regs) following alemtuzumab therapy,13 absolute counts of T-regs remain below baseline during the period of B cell reconstitution 1. Thus, it is proposed that hyperpopulation of naïve B cells regenerating in the absence of T-regs may allow the development of autoreactive populations 1 12.…”

“…Alemtuzumab is administered as an initial course of five daily infusions of 12 mg which is followed by a second course of three daily doses of 12 mg 12 months later. As CD52 is highly expressed on the surface of T and B lymphocytes treatment results in profound lymphopenia 1. Alemtuzumab use in patients with multiple sclerosis (MS) is associated with improvement in disability, and a sustained reduction in both relapse rate and MRI disease activity for up to 5 years in 70% of patients 2 3.…”

Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis

“…The reduction in the level of circulating B and T cells by alemtuzumab and subsequent repopulation may reduce the potential for relapse, which ultimately delays disease progression. Several lines of clinical evidence indicate that alemtuzumab alters the number, proportions and properties of some lymphocyte subsets after repopulation [23,[26][27][28][29][30].…”

Thymosins in multiple sclerosis and its experimental models: moving from basic to clinical application

“…The profound and rapid depletion of B cells that arises after treatment with these mAbs is then followed by repletion of lymphocytes with a more regulatory phenotype. However, in some cases (as for example following CD52 depletion) there is a hyperpopulation of immature B cells that may be responsible for secondary autoimmunity, a major drawback of alemtuzumab therapy (Baker et al, 2017). As in the combination regimens of chemotherapeutics plus Tα1 adopted for treatment of many cancer types (Garaci et al, 2015), in MS a combination of disease modifying therapies with synthetic Tα1 may help in addressing and correctly modulating the repopulation of B cell compartment towards a more regulatory and anti-inflammatory phenotype.…”