Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia in Western countries. Historically, chemoimmunotherapy was the standard first-line approach for physically fit patients. The advent of Bruton's Tyrosine Kinase inhibitors (BTKis) ‒ ibrutinib, acalabrutinib, zanubrutinib ‒ and the BCL-2 inhibitor venetoclax has transformed this landscape. A comparative analysis with traditional regimens in fit patients is essential.

To compare efficacy and safety of targeted therapies (BTKis and venetoclax-based regimens) versus chemoimmunotherapy in first-line treatment for physically fit CLL patients, focusing on Progression-Free Survival (PFS), Overall Survival (OS), and Adverse Events (AEs).

Narrative synthesis of 50 articles, including randomized trials and network meta-analyses, emphasizing studies in physically fit cohorts or where targeted agents replaced chemoimmunotherapy.

Targeted therapies consistently outperformed chemoimmunotherapy in the frontline setting: Ibrutinib: Network meta-analyses show ∼40% reduced progression risk versus chlorambucil in fit patients. The E1912 trial confirmed superior long-term outcomes for ibrutinib-rituximab compared to FCR. Acalabrutinib: In ELEVATE-TN, acalabrutinib-obinutuzumab improved survival over chemoimmunotherapy. Fixed-duration combinations are under study. Zanubrutinib: SEQUOIA demonstrated superior PFS versus bendamustine-rituximab (BR) in treatment-naïve patients. It is emerging as a preferred option. Venetoclax combinations: GAIA/CLL13 confirmed first-line venetoclax-obinutuzumab significantly outperformed chemoimmunotherapy in fit patients, with sustained benefit at 4-years. Combined targeted approaches: Fixed-duration ibrutinib-venetoclax regimens are effective even in patients with 17p deletion. Zanubrutinib-venetoclax benefits treatment-naïve patients with del(17p)/TP53 mutation. Triple regimens (acalabrutinib, venetoclax, obinutuzumab) show promise in high-risk cases. Safety Profile: BTKis yield >85% response rates with generally tolerable safety. Second-generation BTKis offer non-inferior or superior PFS versus ibrutinib, with lower rates of atrial fibrillation and bleeding. Treatment Trends & Cost-Effectiveness: Post-2019 data reveal a shift from chlorambucil-based to BTKi-based protocols in frontline therapy. Cost-effectiveness analyses support BTKi and venetoclax combinations as viable first-line strategies.

Evidence confirms a paradigm shift from chemoimmunotherapy to targeted therapies for fit CLL patients. Superior PFS and OS, coupled with favorable safety, justify this transition. Second- generation BTKis enhance tolerability, and venetoclax-based fixed-duration regimens offer deep, durable responses. Network meta-analyses provide critical comparative data where head-to-head trials are scarce.

BTK inhibitors and venetoclax-based combinations have replaced chemoimmunotherapy as the standard first-line treatment for physically fit CLL patients. Their efficacy, manageable toxicity, and adaptability across risk groups represent a major advancement in disease management.