While the standard of care for chronic lymphocytic leukaemia (CLL) leads to high overall response rates and a long progression-free survival, it can be highly toxic for many patients, particularly in the elderly who often present concurrent diseases with associated morbidities. Treatment-related immune system burden and complications are challenging as most CLL patients already show immunodeficiency and are at high risk of infection. The latter are the main cause for increased morbidity and mortality and are correlated with disease severity and type of therapy. In the last few years, many new approaches and innovative agents such as second-generation anti-CD20 monoclonal antibodies, lenalidomide, B cell receptor signalling inhibitors, and novel cellular therapies have advanced the outlook for CLL management. Indeed, novel therapies could soon be addressing the need to promote immune reactivation and re-sensitise the immune system. By doing so, they could reach two main objectives, namely lowering the high proportion of patients at risk of infection, and acting as effective tools for the immune system to overcome its defects and fight malignant cells.
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