First-line treatment for CLL in the era of targeted therapy

In the decade since FDA approval of the first-generation Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, the treatment landscape for chronic lymphocytic leukemia (CLL) has transformed. Targeted agents, as monotherapy or in combination regimens, have decisively replaced chemoimmunotherapy as the standard of care. In national CLL guidelines updated from 2023 through 2025 - including those from France, Germany, and the US - chemoimmunotherapy is considered a treatment option in only exceptional cases, reflecting broad consensus among experts that targeted therapies should be used universally in the management of previously untreated CLL. The primary first-line treatment options for CLL comprise continuous therapies based on the BTK inhibitors ibrutinib, zanubrutinib, or acalabrutinib, or fixed-duration regimens combining the BCL2 inhibitor venetoclax with obinutuzumab or the BTK inhibitors ibrutinib or acalabrutinib (with or without obinutuzumab). Selecting the appropriate targeted therapy requires careful evaluation of a multitude of factors, including molecular disease features (especially del[17p]/TP53 and IGHV mutational status), comorbidities, comedications, and the patient's preferences. Focusing on primary treatment options, we review data from the key controlled trials that support the first-line use of targeted therapies for patients with CLL, consider ongoing trials that may support clinical decision-making in the future, and assess the potential to personalize treatment regimens in CLL based on minimal residual disease status.