The times they are a-changin': Prognostic markers in the new era of BCR-targeting therapies for CLL

Given the highly variable clinical presentation and prognosis in patients with chronic lymphocytic leukemia (CLL), prognostic markers have typically been used for estimating the risk of disease progression and prognosis in individual patients. The traditional clinical staging systems continue to be used for treatment decisions, but they do not allow for predictions in early-stage patients. Molecular and cytogenetic risk factors allow us to predict the risk for disease progression response to 'standard' therapy and prognosis. Increasing evidence indicates robust connections of several CLL risk factor markers to B-cell receptor (BCR) function and signaling. Areas covered: Several CLL risk factors (immunoglobulin heavy chain variable region mutational status, CD38 and ZAP-70 expression, CCL3 plasma levels) are related to the function of the BCR, a key factor in CLL pathogenesis. Their implications in the context of novel BCR-targeted therapies will be discussed. Expert opinion: With the emergence of inhibitors of BCR-associated kinases (Btk-, Syk- and PI3 kinase inhibitors) in CLL and other B cell malignancies, BCR-related risk factors may help with identification of patients who are likely to respond and/or for response assessment (i.e., CCL3 plasma levels). The negative prognostic impact of BCR-related risk factors may improve with the use of these new, targeted agents.