Bridging Trials and Real Life in Fixed-Duration BTKi-Venetoclax for CLL: A Delphi-Enhanced Synthesis Incorporating...

Area of Science:

• Hematology
• Oncology
• Clinical Practice Guidelines

Background:

• Optimal patient selection for fixed-duration (FD) Bruton's tyrosine kinase inhibitor (BTKi)-venetoclax regimens in chronic lymphocytic leukemia (CLL) remains challenging due to trial populations differing from real-world patients.
• Existing trial data may not fully generalize to older patients or those with multiple comorbidities, necessitating pragmatic guidance.

Purpose of the Study:

• To develop harmonized, pragmatic guidance for selecting patients for FD BTKi-venetoclax therapy in CLL.
• To bridge evidence from clinical trials with routine clinical practice for physicians in a specific Italian region.

Main Methods:

• An adapted Delphi process involving nine hematologists from Campania, Italy.
• Evaluation of BTKi-venetoclax decision-making across comorbidities, genomics (TP53/del(17p), IGHV, complex karyotype), and logistics.
• A systematic literature review (2014-2025) informed 12 consensus statements.
• Artificial intelligence (AI) benchmarking using ChatGPT-4 to assess concordance with evidence.

Main Results:

• Consensus (≥75% agreement) was reached on 83.3% of statements.
• FD BTKi-venetoclax regimens were recommended for fit, younger patients with low- or intermediate-genomic risk.
• Continuous second-generation BTKi monotherapy or FD acalabrutinib-venetoclax was preferred over FD ibrutinib-venetoclax for patients with low-intermediate cardiovascular risk.
• Adverse genomic features and logistical challenges favored continuous second-generation BTKi therapy.
• AI benchmarking showed fair concordance (58.3%) with evidence briefs.

Conclusions:

• A consensus-driven framework for FD BTKi-venetoclax therapy in CLL was established, focusing on patient selection and logistical feasibility.
• The study provides a foundation for evaluating human-AI collaboration in first-line CLL therapy decisions.