Optimizing Frontline Targeted Therapies in Chronic Lymphocytic Leukemia: An Italian Inter‐Regional Delphi Consensus on Patient Risk Stratification, Cardiovascular Safety, and Endpoint Interpretation

Background While landmark trial data have established targeted agents as the frontline standard of care in chronic lymphocytic leukemia (CLL), real‐world clinical gaps remain regarding high‐risk disease biology, patient frailty, cardiovascular comorbidities, healthcare accessibility, and the clinical interpretation of surrogate endpoints. Methods A modified two‐round Delphi process engaged an expert panel of 19 Italian hematology specialists and a multidisciplinary scientific board to evaluate 16 evidence‐based statements across four key clinical domains. Statements were formulated based on literature evidence‐informed from a systematic review of the literature. When high‐tier evidence was lacking, statements used lower‐level data and expert consensus to address clinical gaps. Consensus was pre‐defined as an aggregate agreement of 70% using a forced‐choice 4‐point Likert scale. Results Continuous monotherapy with second‐generation covalent BTK inhibitors (cBTKis) was preferred over time‐limited regimens for patients with TP53‐disrupted disease (94.6%), individuals aged > 80 years or meeting frailty criteria (100%), and those with socio‐logistic or caregiver constraints (95.0%). Conversely, time‐limited regimens were universally favored for fit patients aged < 70 years without TP53 aberrations (100%), while remaining a viable option in young, fit patients with TP53 disruptions (78.9%). Baseline cardiovascular risk stratification using population‐validated tools (SCORE2, SCORE2‐OP, SCORE2‐Diabetes) reached 85.0% agreement. Second‐generation cBTKis were preferred over ibrutinib in patients with elevated cardiovascular risk (95.0%). Panelists agreed that undetectable measurable residual disease (uMRD) is not a universal surrogate for progression‐free survival (70.0%). Time to next treatment (TTNT) was unanimously endorsed as an efficacy indicator for time‐limited therapy (100%), but viewed primarily as a safety surrogate during continuous cBTKi therapy (79.0%). Upon relapse after time‐limited cBTKi–venetoclax therapy, re‐challenge with a covalent BTKi was established as the preferred option (89.5%). Conclusion This consensus bridges clinical guidelines and real‐world practice, providing a structured framework that incorporates molecular risk, functional frailty, cardiovascular scoring, and healthcare accessibility to guide frontline CLL management.