Shadman Mazyar, Munir Talha, Ma Shuo, Lasica Masa, Tani Monica, Robak Tadeusz, Flinn Ian W, Brown Jennifer R, Ghia Paolo, Ferrant Emmanuelle, Tam Constantine S, Janowski Wojciech, Jurczak Wojciech, Xu Linlin, Tian Tian, Lefebure Marcus, Agresti Stephanie, Hirata Jamie, Tedeschi Alessandra
Fred Hutchinson Cancer Center, Seattle, WA.
University of Washington, Seattle, WA.
J Clin Oncol. 2025 Jul 20;43(21):2409-2417. doi: 10.1200/JCO-25-00758. Epub 2025 May 31.
Several chronic lymphocytic leukemia (CLL) studies have demonstrated promising efficacy with the combination of BCL2 and Bruton tyrosine kinase inhibitors; however, patients with CLL with del(17p) and/or mutation (mut) comprised a small percentage of study populations or were excluded entirely. The purpose of the SEQUOIA Arm D cohort was to evaluate the combination of zanubrutinib + venetoclax in treatment-naïve (TN) patients with CLL/small lymphocytic lymphoma (SLL), in a large population of patients with -aberrant disease.
Arm D is a nonrandomized cohort of patients aged 65 years and older (or 18-64 years with comorbidities). Patients received zanubrutinib from cycle 1 and venetoclax from cycle 4 (ramp-up) to cycle 28, followed by continuous zanubrutinib monotherapy until progressive disease (PD), unacceptable toxicity, or meeting undetectable minimal residual disease (uMRD)-guided stopping criteria.
Between November 2019 and July 2022, 114 patients were enrolled: 66 (58%) with -aberrant disease, 47 (41%) without -aberrant disease, and 1 with missing results. At a median follow-up of 31.2 months, 85 patients (75%) remained on zanubrutinib monotherapy; 29 patients (25%) discontinued zanubrutinib because of adverse event, uMRD-guided stopping criteria, PD, or other. In the intention-to-treat population, 59% of patients achieved peripheral blood uMRD. The 24-month progression-free survival estimate was 92% (95% CI, 85% to 96%). The most common any-grade treatment-emergent AEs (TEAEs) were COVID-19 (54%), diarrhea (41%), contusion (32%), and nausea (30%). The most common grade ≥3 TEAEs were neutropenia (17%), hypertension (10%), diarrhea (6%), and decreased neutrophil count (6%).
Zanubrutinib + venetoclax demonstrated impressive efficacy and a favorable safety profile in patients with TN CLL/SLL, regardless of the presence of -aberrant disease.
多项慢性淋巴细胞白血病（CLL）研究表明，BCL2抑制剂与布鲁顿酪氨酸激酶抑制剂联合使用具有良好疗效；然而，伴有17p缺失和/或TP53突变（mut）的CLL患者在研究人群中所占比例较小或被完全排除。SEQUOIA研究D组的目的是在大量伴有异常疾病的患者中，评估泽布替尼+维奈克拉联合方案用于初治（TN）慢性淋巴细胞白血病/小淋巴细胞淋巴瘤（SLL）患者的疗效。
D组为非随机队列，纳入年龄≥65岁（或18 - 64岁且伴有合并症）的患者。患者从第1周期开始接受泽布替尼治疗，从第4周期（逐步递增）开始接受维奈克拉治疗直至第28周期，之后继续接受泽布替尼单药治疗，直至疾病进展（PD）、出现不可接受的毒性或达到不可检测的微小残留病（uMRD）指导的停药标准。
2019年11月至2022年7月期间，共入组114例患者：66例（58%）伴有异常疾病，47例（41%）不伴有异常疾病，1例结果缺失。中位随访31.2个月时，85例患者（75%）仍在接受泽布替尼单药治疗；29例患者（25%）因不良事件、uMRD指导的停药标准、疾病进展或其他原因停用泽布替尼。在意向性治疗人群中，59%的患者外周血达到uMRD。24个月无进展生存率估计为92%（95%CI，85%至96%）。最常见的任何级别治疗中出现的不良事件（TEAE）为COVID-19（54%）、腹泻（41%）、挫伤（32%）和恶心（30%）。最常见的≥3级TEAE为中性粒细胞减少（17%）、高血压（10%）、腹泻（6%）和中性粒细胞计数降低（6%）。
无论是否伴有异常疾病，泽布替尼+维奈克拉在TN CLL/SLL患者中均显示出令人印象深刻的疗效和良好的安全性。
