Biomarker-informed decision nodes in the management of newly presented CLL. At the time of treatment requirement, the presence of TP53 mutation/deletion represents an indication for treatment with kinase inhibitors, for example, ibrutinib or, alternatively, idelalisib. Patients who require first-line treatment and carry a wild-type TP53 gene may be candidate to chemoimmunotherapy with one of the available combinations, especially in the presence of mutated IGHV genes. In patients with wild-type, a TP53 gene, and unmutated IGHV genes, the role of chemoimmunotherapy is under debate, and kinase inhibitors may represent a valuable option. CIRS, Cumulative Illness Rating Scale.