Alemtuzumab in the treatment of multiple sclerosis: patient selection and special considerations.Dörr J, Baum K.
Multiple sclerosis (MS) is among the most common chronic inflammatory diseases of the central nervous system. Although not curable, the constantly increasing armamentarium of disease-modifying drugs now allows control of disease activity in many patients. The humanized monoclonal antibody alemtuzumab is a powerful drug licensed for the treatment of MS. Upon binding to the CD52 surface protein on CD4+ and CD8+ T cells, B cells, and monocytes, circulating CD52+ cells are eliminated via antibody- and complement-mediated lysis, and a less autoreactive adaptive immune system is reconstituted. The efficacy of alemtuzumab in terms of both clinical and magnetic resonance imaging outcomes has been demonstrated in several phase II/III trials including long-term extensions and follow-up studies. Treatment response to alemtuzumab is strongest as long as active inflammation is the predominant pathophysiological feature, and it is becoming less efficacious in neurodegeneration-dominated later stages of the disease. Thus, the optimal placement of alemtuzumab within treatment algorithms of MS is crucial. The impressive efficacy of alemtuzumab is counteracted by a less favorable safety profile. Besides usually manageable infusion-associated side effects, development of secondary autoimmunity in almost half of treated patients is the most disconcerting risk of alemtuzumab. The high frequency, the delayed occurrence, and the potentially severe course of secondary autoimmune diseases require awareness and a close long-term monitoring of patients treated with alemtuzumab. Biomarkers that would allow prediction of treatment response to alemtuzumab on the one hand and identification of patients at risk for the development of secondary autoimmune diseases on the other are not yet available. Thus, the overall success of alemtuzumab treatment critically depends on the patient selection. The aim of this article is therefore, to characterize the significance of alemtuzumab in the treatment of MS with a focus on the selection of the optimal patient.
Alemtuzumab binds to CD52 on the surface of T cells, B cells and monocytes. This then effectively removes these cells form circulation, but the popular belief is that the cells in the lymphoid organs (e.g. lymph nodes) are spared. Subsequently, their is reconstitution of the immune population from the cells that have escaped eradication. The dynamics of the re-population differs from cell to cell, with B cells and monocytes reappearing well before the T cells, which may take on average 5 years to return to pre-treatment levels. The latter may explain the durability of treatment effect, with low sustained relapse rates and stability in MS over this period.
The Achilles heel of Alemtuzumab is the predilection for autoimmunity. It was originally published that baseline IL-21 (a cytokine) may predict the development of autoimmune disorders following Alemtuzumab treatment, however this has not panned out on repeat testing. There are therefore ongoing studies to look for changes in the immune system profile after Alemtuzumab to see if certain changes are predictive of the development of autoimmunity (e.g. NCT02419378).
Markers of treatment response beyond the standard clinical scores and MRI markers are also scarce. Importantly, biomarkers that can predict those most likely to benefit from the treatment are also scarce. Again there are ongoing clinical studies in this area: 1) Diffusion and myelin fraction water changes on MRI and changes in normal appearing white matter (studying disease activity and repair) NCT01395316, and 2) Motor evoked potentials to determine who will require a third cycle of Alemtuzumab.
In all, as we understand more about how these treatments work at a biological level, the more likely we would be able to select the most appropriate treatments and of course monitor them!