据报道，接受连续单药 BTK 或 BCL2 抑制剂治疗的疾病进展 (PD) 患者中出现 BTK、PLCG2 和 BCL2 突变。在 II 期 CAPTIVATE 研究中，我们在完成固定疗程依鲁替尼加维奈托克治疗慢性淋巴细胞白血病 (CLL) 一线治疗后的 PD 患者样本中检测了这些突变。共有 191 名患者完成了固定疗程依鲁替尼加维奈托克治疗。 Venetoclax（依鲁替尼三个周期，然后依鲁替尼加 Venetoclax 12-13 个周期）。基因组风险特征 [del(11q)、del(13q)、del(17p)、12 三体、复杂核型、未突变 IGHV、TP53 突变] 以及 CLL 中反复突变的基因突变（ATM、BIRC3、BRAF、CHD2、EZH2、 FBXW7、MYD88、NOTCH1、POT1、RPS15、SF3B1、XPO1) 在数据截止时对患有和不患有 PD 的患者进行基线评估；在 PD 时评估了 BTK、PLCG2 或 BCL2 的基因变异和耐药相关突变。 在完成固定疗程依鲁替尼加维奈托克治疗的 191 名患者中，中位随访时间为 38.9 个月，其中 29 名 (15%) 发生了 PD。没有基线风险特征或基因突变与 PD 的发生显着相关。在 25 名可用样本的患者中，在 PD 时未检测到先前报道的 BTK、PLCG2 或 BCL2 耐药相关突变。在 29 名 PD 患者中，19 名需要重新治疗（单药依鲁替尼，n = 16，或依鲁替尼加维奈托克，n = 3）； 17 例达到部分缓解或更好，1 例疾病稳定，1 例正在等待疗效评估。伊布替尼加维奈托克的一线固定疗程联合治疗可能会减轻与连续单药靶向治疗相关的耐药机制的发展，从而实现有效的再治疗.©2023 作者；由美国癌症研究协会出版。

Mutations in BTK, PLCG2, and BCL2 have been reported in patients with progressive disease (PD) on continuous single-agent BTK or BCL2 inhibitor treatment. We tested for these mutations in samples from patients with PD after completion of first-line treatment with fixed-duration ibrutinib plus venetoclax for chronic lymphocytic leukemia (CLL) in the phase II CAPTIVATE study.A total of 191 patients completed fixed-duration ibrutinib plus venetoclax (three cycles of ibrutinib then 12-13 cycles of ibrutinib plus venetoclax). Genomic risk features [del(11q), del(13q), del(17p), trisomy 12, complex karyotype, unmutated IGHV, TP53 mutated] and mutations in genes recurrently mutated in CLL (ATM, BIRC3, BRAF, CHD2, EZH2, FBXW7, MYD88, NOTCH1, POT1, RPS15, SF3B1, XPO1) were assessed at baseline in patients with and without PD at data cutoff; gene variants and resistance-associated mutations in BTK, PLCG2, or BCL2 were evaluated at PD.Of 191 patients completing fixed-duration ibrutinib plus venetoclax, with median follow-up of 38.9 months, 29 (15%) developed PD. No baseline risk feature or gene mutation was significantly associated with development of PD. No previously reported resistance-associated mutations in BTK, PLCG2, or BCL2 were detected at PD in 25 patients with available samples. Of the 29 patients with PD, 19 have required retreatment (single-agent ibrutinib, n = 16, or ibrutinib plus venetoclax, n = 3); 17 achieved partial response or better, 1 achieved stable disease, and 1 is pending response assessment.First-line fixed-duration combination treatment with ibrutinib plus venetoclax may mitigate development of resistance mechanisms associated with continuous single-agent targeted therapies, allowing for effective retreatment.©2023 The Authors; Published by the American Association for Cancer Research.