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The oral, highly selective Bcl2 inhibitor venetoclax has substantially improved the therapeutic landscape of chronic lymphocytic leukemia (CLL). Despite the remarkable response rates in patients with relapsed/refractory (R/R) disease, acquired resistance is the leading cause of treatment failure, with somatic <i>BCL2</i> mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common <i>BCL2</i> mutations G101V and D103Y, sensitive (10⁻⁴) screening for the most common <i>BCL2</i> mutations G101V and D103Y was performed in 67 R/R CLL patients during venetoclax single-agent or venetoclax–rituximab combination therapy. With a median follow-up time of 23 months, <i>BCL2</i> G101V and D103Y were detected in 10.4% (7/67) and 11.9% (8/67) of the cases, respectively, with four patients harboring both resistance mutations. Ten out of eleven patients carrying <i>BCL2</i> G101V and/or D103Y experienced relapse during the follow-up period, representing 43.5% of the cases (10/23) showing clinical signs of disease progression. All <i>BCL2</i> G101V or D103Y variants were detected in patients receiving venetoclax as a continuous single-agent treatment while these mutations were not observed during or after fixed-duration venetoclax therapy. Targeted ultra-deep sequencing of <i>BCL2</i> uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of <i>BCL2</i> mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which <i>BCL2</i> resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for <i>BCL2</i> resistance mutations in R/R CLL.