口服、高选择性Bcl2抑制剂维诺托克赛显著改善了慢性淋巴细胞白血病（CLL）的治疗方法。尽管在复发/难治（R / R）疾病患者中具有显著的反应率，但获得性耐药是治疗失败的主要原因，其中体染色体BCL2突变是支持维诺托克赛耐药性的主要遗传驱动因子。为了评估疾病进展与最常见的BCL2突变基因G101V和D103Y之间的关系，在维诺托克赛单药或维诺托克赛-利妥昔单抗联合治疗过程中，对67名R / R CLL患者进行了最常见的BCL2突变基因G101V和D103Y的敏感（10-4）筛查。随访时间中位数为23个月，在这些病例中，分别检测到10.4％（7/67）和11.9％（8/67）的BCL2 G101V和D103Y，其中四名患者携带两种耐药突变。在随访期间，携带BCL2 G101V和/或D103Y的11名患者中有10名经历了复发，代表了患病进展的23例中的43.5％（10/23）。所有BCL2 G101V或D103Y变异体均在接受维诺托克赛持续单药治疗的患者中检测到，而在固定疗程的维诺托克赛治疗期间或之后没有观察到这些突变。针对BCL2的定向超深度测序揭示了4个患者样本中的三个附加变异，这表明收敛进化并暗示BCL2突变在驱动维诺托克赛耐药性方面具有协同作用。这个队列是迄今为止最大的R/R CLL患者人群，该患者人群被调查了BCL2耐药突变。我们的研究证明了对R / R CLL进行BCL2耐药性突变的敏感筛查的可行性和临床价值。

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 BCL2 mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common BCL2 mutations G101V and D103Y, sensitive (10-4) screening for the most common BCL2 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, BCL2 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 BCL2 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 BCL2 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 BCL2 uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of BCL2 mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which BCL2 resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for BCL2 resistance mutations in R/R CLL.