Venetoclax and ibrutinib: Two partners for the front-line treatment of chronic lymphocytic leukemia

: The combination of ibrutinib and venetoclax (I+V), has shown benefit in treating chronic lymphocytic leukemia (CLL) due to their complementary mechanisms of action and synergistic effects. The fixed duration of the I+V regimen results in high response rates, including undetectable measurable residual disease (MRD), in treatment-naïve patients with CLL, even among those with high-risk abnormalities. Additionally, the efficacy of the I+V combination is being currently evaluated in an MRD-guided approach, where treatment continues until a deep response with undetectable MRD (uMRD) is achieved. This review analyzes data from 7 clinical trials that investigated the efficacy and safety of the I+V regimen when administered as a first-line treatment in at least 50 patients, either in a fixed-duration schedule (CAPTIVATE and GLOW trials) or in an MRD-guided manner (MDACC, FLAIR, ERADIC, and HOVON NEXT STEP trials). Despite variations in patient characteristics, treatment protocols, follow-up durations, and treatment lengths, the I+V combination led to high response rates (% range, 81-97) and undetectable MRD (% range, 52-82) with high progression-free survival (PFS) rates. The MRD-guided treatment yields promising results, with high rates of deep responses and prolonged PFS, even in patients with unmutated immunoglobulin heavy-chain variable region (IGHV) genes (3-year PFS: 90% in the MDACC trial and 98% in the FLAIR trial) and in those with TP53 disruptions (3-year PFS: 86.1% in the MDACC trial). The I+V regimen is generally manageable and well-tolerated, with toxicities consistent with those reported for single-agent use. Nonetheless, concerns regarding cardiovascular toxicities have been raised, particularly among older patients.