Real‑life diagnostic and therapeutic approach to CLL/SLL in tuscany: the 2025 consensus

Management of chronic lymphocytic leukemia/ small lymphocytic lymphoma. (CLL/SLL) has undergone a significant paradigm shift, with chemo immunotherapy being virtually abandoned in favor of targeted agents. A panel of CLL/SLL experts from Tuscany proposes an updated real-life diagnostic and therapeutic approach that integrates genomic and somatic prognostic factors into routine risk stratification and treatment decisions. While the safety and efficacy of new agents are well-established in both clinical trials and real-world series, the rapid introduction of second-generation BTK inhibitors and BCL-2 antagonists necessitates a uniform and shared approach for daily clinical practice. This updated consensus reinforces the essential role of FISH for 17p deletion and TP53 mutational status before every treatment line, while IGHV mutation status should be performed for initial risk assessment. Reflecting current evidence, the proposal emphasizes a comprehensive pretreatment workup, with a particular focus on cardio-oncological screening and monitoring according to recent ESC guidelines to mitigate risks associated with BTKIs. The consensus reaffirms abdominal and superficial lymph node ultrasound as the gold standard radiological investigation for both diagnosis and response evaluation in CLL, offering a practical and radiation-free tool for longitudinal monitoring. Treatment selection is tailored based on age, genetic risk, and comorbidities, prioritizing zanubrutinib, acalabrutinib, and venetoclax-based regimens to prevent unnecessary toxicities. Furthermore, the consensus addresses the management of high-risk scenarios, including Richter transformation and the emerging role of pirtobrutinib and BTK degraders. By combining the latest clinical evidence with extensive daily experience, this updated Tuscany consensus provides a practical framework for optimized, personalized management of CLL/SLL patients in the modern therapeutic era.