Are we finally getting personal? Moving towards a personalized approach in chronic lymphocytic leukemia

With its heterogeneous biological features and clinical course, chronic lymphocytic leukemia (CLL), the most frequent adult leukemia in the Western world, is a paradigmatic condition requiring a tailored approach and a precise knowledge of the biology behind each individual patient. This personalized management is becoming even more crucial, since, after decades of preclinical work unravelling the key role of the B-cell receptor (BcR) signalling pathways and the anti-apoptotic mechanisms in CLL cell survival and proliferation, we have now BcR and BCL2 inhibitors available in clinical practice. Thanks to this, we are now able to exploit specific biomarkers to tailor our treatment strategies and improve long-term disease control, patient outcome and quality of life. That notwithstanding, as the disease itself remains incurable, novel challenges and unmet clinical needs have risen from the introduction of novel targeted agents, including mechanisms of resistance at both genetic and epigenetic levels. In this review, we summarize the currently established predictive biomarkers (i.e. IGHV mutation status and TP53 gene disruption) that should be applied in clinical practice to inform treatment decision in 2021 but also discuss the most promising prognostic biomarkers (B-cell receptor stereotypy, complex karyotype, somatic gene mutations, measurable residual disease - MRD) that might become key to define the management of our patients in a near future.