Landscape of BCL2 Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax.

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 mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common mutations G101V and D103Y, sensitive (10) screening for the most common 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, 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 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 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 uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for resistance mutations in R/R CLL.