Chronic lymphocytic leukemia: an enigma for both the clinician and the immunologist

The most recent years have witnessed a great progress in understanding the biology of chronic lymphocytic leukemia (CLL). This has allowed a parallel improvement in the definition of several biological parameters that have been validated as strong and independent prognostic markers now widely used in the setting of clinical trials. Among others, the study of the antigen receptors has been the most proficient, helping to better understand the cellular origin of CLL and especially to indicate the existence of a specific antigenic stimulation in the natural history of the disease. The presence or the absence of somatic mutations in the immunoglobulin heavy chain variable region (IGHV) gene sequence are considered the most reliable among the prognostic markers now used. Nevertheless, all this body of knowledge has not resulted in a parallel improvement in the management and treatment of CLL, which remains up to now an incurable disease. Somatic mutations though potent in predicting prognosis at cohort level, correlate with the clinical outcome and other biological prognostic markers in no more than 80% of the affected individuals, thereby hampering a real patient-tailored therapeutic approach. All these reasons make mandatory to further study the biology of the disease and especially the IG receptor that appears to be pivotal in the onset and progression of the disease. This will be instrumental for the identification of the patient who needs a different treatment in terms of strategy and timing, for the design of biology based therapies and for patient-tailored therapeutic approaches.