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Background: Small molecules targeting Bruton’s tyrosine kinase （BTK） and B-cell lymphoma-2 have become the standard of care for the treatment of chronic lymphocytic leukemia （CLL）, replacing chemoimmunotherapy （CIT） in most clinical settings. Ongoing trials explore targeted combinations and minimal residual disease-driven treatment cessation. These dramatic shifts in the current and upcoming treatment landscape of CLL raise the need to reevaluate existing prognostic markers and develop novel ones. Summary: This review examines prognostic markers in CLL patients treated with standard and investigational targeted therapies. Specifically, initial treatment of TP53 aberrant patients with a BTK inhibitor can achieve 70% progression-free survival （PFS） at 5 years, outperforming the 15% 5-year PFS with a CIT regimen containing fludarabine, cyclophosphamide, and rituximab （FCR）. The prognostic implications of the immunoglobulin heavy chain variable gene （IGHV） mutation status have also changed. Unmutated IGHV is associated with inferior PFS and overall survival after FCR and inferior PFS with fixed-duration therapy with venetoclax and anti-CD20 monoclonal antibody but not with continuous BTK inhibitor treatment. Key Messages: （1） Genetic variables （e.g., TP53 aberration, IGHV mutation, complex karyotype） have a prognostic significance in CLL patients treated with targeted therapy. （2） Understanding the prognostic and predictive values of these markers is critical for the development of a risk-adapted treatment strategy in CLL.
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