Optimizing frontline therapy of CLL based on clinical and biological factors

The heterogeneity of the clinical course of chronic lymphocytic leukemia (CLL) ranges from an indolent course, where patients do not require therapy for many years, to a very aggressive disease, where treatment is required soon after diagnosis and relapses may occur early. The improved tools for prognostication allow predicting the outcome of patients with increasing reliability. Some markers also allow selecting more specific therapies with improved activity in the presence of certain genetic or clinical features of CLL. Of these markers, TP53 dysfunction, age, the presence of comorbidities and the immunoglobulin heavy-chain variable region gene mutational status, or serum markers such as β₂-microglobulin have shown independent prognostic value in multiple prospective trials. During the last 10 years, multiple novel agents have become available. The advent of oral kinase inhibitors or Bcl-2 antagonists has provided highly effective options with acceptable toxicity. This manuscript summarizes the current evidence of the available treatment options and proposes an integrated algorithm for the frontline therapy of CLL.