Using the biology of chronic lymphocytic leukemia to choose treatment.

In recent years, our understanding of the pathophysiology of chronic lymphocytic leukemia (CLL) has advanced significantly. It is now clear that CLL is a relatively proliferative disorder that requires the help of its microenvironment to be maintained and to progress. The stimulation of the CLL cell occurs in most, if not all, patients through antigen stimulation via the BCR. In addition, there is now a clearer appreciation of the role of the p53 pathway leading to chemoresistance. These insights are allowing a more targeted approach with the use of p53-independent drugs such as mAbs and high-dose steroids to overcome genetically poor-risk CLL. The elucidation of the molecular and intracellular signaling mechanisms of disease is just beginning to facilitate the development of several targeted small molecules that promise to revolutionize the treatment of CLL. The measurement of the level of minimal residual disease (MRD) in CLL is becoming more available, facilitating approaches in which the aim of therapy is the eradication of detectable MRD. This also promises to improve personalization of therapy to the individual. Recently, the addition of rituximab to fludarabine plus cyclophosphamide (FCR) has improved overall survival in CLL for the first time, and it appears that this will only be the first small step on the path to much more effective therapies and, hopefully, less toxic targeted therapies.