HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary.
South-Pest Central Hospital, National Institute of Hematology and Infectology, 1097 Budapest, Hungary.
Int J Mol Sci. 2023 Mar 18;24(6):5802. doi: 10.3390/ijms24065802.
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.
口服、高度选择性 Bcl2 抑制剂 venetoclax 显著改善了慢性淋巴细胞白血病 (CLL) 的治疗前景。尽管复发/难治性 (R/R) 疾病患者的缓解率显著提高，但获得性耐药是治疗失败的主要原因，体细胞突变是 venetoclax 耐药的主要遗传驱动因素。为了评估疾病进展与最常见突变 G101V 和 D103Y 之间的相关性，在 venetoclax 单药或 venetoclax-利妥昔单抗联合治疗期间，对 67 例 R/R CLL 患者进行了最常见突变 G101V 和 D103Y 的敏感 (10) 筛选。中位随访时间为 23 个月，分别在 10.4% (7/67)和 11.9% (8/67)的病例中检测到 G101V 和 D103Y，其中 4 例患者同时携带这两种耐药突变。在随访期间，11 例携带 G101V 和/或 D103Y 的患者中有 10 例复发，占出现疾病进展临床迹象的病例的 43.5% (10/23)。所有 G101V 或 D103Y 变体均在接受 venetoclax 连续单药治疗的患者中检测到，而在 venetoclax 固定疗程治疗期间或之后未观察到这些突变。在 4 例复发患者的样本中，靶向深度测序发现了另外 3 个突变，提示存在趋同进化，并暗示突变在驱动 venetoclax 耐药方面具有协同作用。这是迄今为止报告的最大的 R/R CLL 患者人群，其中研究了耐药突变。我们的研究表明，在 R/R CLL 中进行敏感筛选检测耐药突变是可行且具有临床价值的。
