Over-expression of BCL-2 defines follicular lymphoma (FL). Venetoclax (VEN), a selective BCL-2 inhibitor, has previously been evaluated with bendamustine-based chemoimmunotherapy. VEN was given continuously, resulting in promising efficacy but unacceptable toxicity. The Phase II PrE0403 study was designed to evaluate intermittent dosing of VEN (10 days per cycle) combined with obinutuzumab and bendamustine (VEN-OB) in untreated FL subjects with high-risk features defined as a FLIPI-1 score of ≥3 and/or high tumor burden by GELF criteria. A total of 56 subjects were planned to be accrued with a goal of having 51 subjects eligible to improve the historical 50% CR rate to 65% with an 85% power and 15% type I error rate. Immunohistochemistry (IHC) expression of 3 antiapoptotic proteins (BCL-xL, MCL-1, and BCL-2) was performed and correlated with clinical outcomes. All 56 subjects were eligible and treated. CR rate was 41/56 (73.2%) and ORR was 52/56 (92.5%) meeting the primary endpoint. 2-year estimated PFS was 87.5% (90% CI: 75.3,93.9%) and 2-year estimated OS was 94.6% (90% CI: 86.7, 97.9%). However, the incidence of treatment-related adverse events ≥ grade 3 was 83.9% and serious adverse events were seen in 57.1%. After induction, atypical infections, including Grade 5 events, occurred. Anti-apoptotic protein expression by IHC was not correlated with clinical outcomes. Thus, while meeting the primary efficacy end point, VEN-OB is considered overly toxic in high-risk FL.
BCL-2过表达是滤泡性淋巴瘤（FL）的特征性表现。Venetoclax（VEN）是一种选择性BCL-2抑制剂，既往已有研究评估其联合基于苯达莫司汀的化学免疫疗法的效果。由于持续给药方案虽显示良好疗效但存在不可接受的毒性，II期PrE0403研究设计采用间歇给药方案（每周期10天）的VEN联合奥妥珠单抗与苯达莫司汀（VEN-OB），用于治疗具有高风险特征的初治FL患者（高风险定义为滤泡性淋巴瘤国际预后指数-1评分≥3和/或符合GELF标准的高肿瘤负荷）。研究计划入组56例受试者，目标为51例符合条件者，旨在将历史50%的完全缓解率提升至65%，统计把握度为85%，I类错误率设为15%。研究通过免疫组织化学检测了3种抗凋亡蛋白（BCL-xL、MCL-1和BCL-2）的表达，并分析其与临床结局的相关性。全部56例受试者均符合条件并接受治疗。完全缓解率为41/56（73.2%），总缓解率为52/56（92.5%），达到主要终点。2年预估无进展生存率为87.5%（90% CI: 75.3, 93.9%），2年预估总生存率为94.6%（90% CI: 86.7, 97.9%）。然而，≥3级治疗相关不良事件发生率为83.9%，严重不良事件发生率为57.1%。诱导治疗后出现了包括5级事件在内的非典型感染。免疫组化检测的抗凋亡蛋白表达与临床结局无相关性。因此，尽管达到了主要疗效终点，VEN-OB方案在高危FL患者中被认为存在过度毒性。
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