Real-World Determinants of Treatment Selection in Frontline Chronic Lymphocytic Leukemia: The FIRST-CLL Study

Multiple targeted agents are available for first-line treatment of chronic lymphocytic leukemia (CLL), yet the absence of mature head-to-head comparisons makes treatment selection challenging. The prospective, multicenter FIRST-CLL study evaluated real-world treatment allocation, and the contribution of biological, clinical, logistical and patient-related factors to first-line regimen choice in Italy. 285 consecutive patients with CLL/small lymphocytic lymphoma initiating first-line therapy across 13 Centers were included. Treating physicians rated predefined variables guiding treatment selection using the 5-point relevance score. Overall, 116 patients (41%) received continuous Bruton tyrosine kinase inhibitors (BTKi), 114 (40%) ibrutinib plus venetoclax (IV), and 55 (19%) venetoclax plus obinutuzumab (VO). Continuous BTKi were more frequently prescribed in older and comorbid patients, whereas IV was preferentially used in younger individuals. TP53 disruption was associated with BTKi use, while mutated immunoglobulin heavy chain status was common in patients receiving VO. According to relevance scores, age, treatment duration and administration route, and patient preference were the most influential determinants of treatment selection. Comorbidity burden additionally guided BTKi prescription, whereas molecular features were more relevant in the selection of fixed-duration regimens. This study offers a real-world quantitative assessment of treatment decision drivers in frontline CLL, offering a data-driven framework to interpret clinical decision-making.