Alemtuzumab—A New Efficacy Benchmark in Relapsing–Remitting Multiple Sclerosis?
Notable AEs occurring in both the alemtuzumab (pooled analysis) and IFNβ-1a groups were: autoimmune thyroid disorders (23 and 3%), idiopathic thrombocytopenic purpura (ITP) (3 and 1%), and infections (66 and 47%).62
Figure 4: Study Design of CARE-MS I and CARE-MS II Phase III Clinical Trials
Among the other events, the most frequent were influenza-like illness (4 versus 27%; p<0.001), fatigue (31 versus 30%), headache (31 versus 28%), pyrexia (11 versus 10%), and rash (26 versus 14%). Apart from influenza-like symptoms, the differences in incidence in these events between alemtuzumab- and IFNβ-1a-treated groups were not significant.62
The first case of ITP went unrecognized and following several weeks of typical symptoms, presented with a fatal cerebral hemorrhage. However, the other ITP cases were self-limiting or responsive to treatment, all patients achieved durable remission and no ITP was reported >16 months after treatment.65
It was previously hypothesized
that patients who had autoimmune AEs following alemtuzumab had a fundamentally different immune reconstitution and may be less likely to respond to treatment compared with patients without such events. The study data show that this is not the case; patients with autoimmune events through 36 months showed a 66% reduction in the risk of SAD (p=0.03) and a 78% reduction in risk of relapse (p<0.0001) compared with patients receiving IFNβ-1a.66
Therefore, patients who experienced
autoimmunity were equally likely to benefit from alemtuzumab efficacy as those without such events.
In the CAMMS223 trial, one patient developed antiglomerular basement membrane (anti-GBM, Goodpastures syndrome). The patient developed hypothyroidism at month 24 (day 733) and at month 51 (39th month after the second alemtuzumab cycle), showed increased serum creatinine (1.9mg/dl at diagnosis and peaking at 2.8mg/dl) with hematuria. A renal biopsy showed anti-GBM. The patient also had an upper respiratory infection and rash, which are typical of anti-GBM, just prior to the onset of hematuria. The patient was treated with a course of plasmapheresis, cyclophosphamide, and steroids. Seventeen months after diagnosis, the patient remains in remission with elevated but stable serum creatinine and is MS relapse-free. In CAMMS223 to date, only one patient has developed anti-GBM disease (frequency 0.5%, event rate one per 981 patient-years).63,67
However, the immunosuppressive effects of alemtuzumab may be selective with relative sparing of the lymphoid organs including the spleen, thymus, and lymph nodes. These observations demonstrate a favorable safety profile but larger phase III trial safety data are awaited.
In MS patient populations treated with alemtuzumab to date, the incidence of any serious opportunistic infections has been low and the infections that have occurred were mostly of mild to moderate severity.62,65
Hypotheses Concerning Delayed or Secondary Autoimmunity
The mechanism of action of alemtuzumab and the process by which it might induce secondary autoimmunity in a subset of MS patients have received attention in several studies. Recent clinical data on a subset of 94 of the 232 patients in the CAMMS223 trial who had RRMS and received alemtuzumab has shown that those who develop lymphopenia-associated autoimmunity (mainly to the thyroid gland) have greater levels of T-cell apoptosis and T-cell cycling driven by substantially
US NEUROLOGY
Alemtuzumab 24mg IV*
Study design of (A) Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I study (CARE-MS I) and (B) Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis II study (CARE-MS II).
*Exploratory 24mg intravenous (IV) group with limited recruitment. IFNβ= interferon beta; SC = subcutaneous.
higher baseline levels (two-fold) of interleukin 21 (IL-21) than patients who do not develop autoimmunity.68
The study also showed that IL-21
expression is genetically pre-determined. It was proposed that following lymphocyte depletion by alemtuzumab, overproduction of IL-21 in some individuals results in excess T-cell cycling and apoptosis and thereby increases the stochastic opportunities for T-cells to encounter self antigen and break tolerance and for autoimmunity to develop. Increased IL-21 levels may also act to promote B-cell differentiation and antibody production.56
A Study duration (months) 012
Alemtuzumab 12mg IV
Randomization 2:1
High-dose IFNβ-1a 44µg SC 3 times weekly B Study duration (months) 012
Alemtuzumab 12mg IV
Randomization 2:1
High-dose IFNβ-1a 44µg SC 3 times weekly
Daily x5
Daily x3
24 Extension study
Daily x5
Daily x3
24 Extension study
Therefore, IL-21 levels could be used as a biomarker prior to alemtuzumab treatment, to indicate which patients may be at increased risk of developing secondary autoimmunity.
Other immunological studies have shown that although lymphocytes are repeatedly depleted during cycles of alemtuzumab treatment, the capacity of the immune system to regenerate remains unimpaired. After exposure to alemtuzumab, B-cell reconstitution is rapid, with levels returning to baseline by three months and to higher levels by 12 months.60
The most abundant B-cell subtype one month after treatment are immature transitional B cells. At the same time, there is an increase (33%) in serum levels of B-cell activating factor (BAFF) that is sustained for at least 12 months. BAFF is essential for transition of immature B cells to a mature naïve B-cell phenotype and has been associated with the development of autoimmunity by an as yet, incompletely understood mechanism.60
A potential factor contributing to
autoimmunity following alemtuzumab treatment is the delayed proliferation of T-cell populations, including T-regulatory cells, at a time of rapid proliferation of unregulated B-cells.54,60,69
87
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