Shadman Mazyar, Burke John M, Cultrera Jennifer, Yimer Habte A, Zafar Syed F, Misleh Jamal, Rao Subramanya S, Farber Charles M, Cohen Aileen, Yao Hui, Idoine Adam, An Qi, Flinn Ian W, Sharman Jeff P
Division of Medical Oncology, Fred Hutchinson Cancer Center, University of Washington, Seattle, WA.
Rocky Mountain Cancer Centers, US Oncology Research, Aurora, CO.
Blood Adv. 2025 Aug 26;9(16):4100-4110. doi: 10.1182/bloodadvances.2024015493.
Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib (ibr) revolutionized chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treatment, although treatment-related toxicities limit the use of some BTK inhibitors. Zanubrutinib, a potent next-generation BTK inhibitor, has higher selectivity than ibrutinib or acalabrutinib. The ongoing phase 2, single-arm BGB-3111-215 study investigates the safety and efficacy of zanubrutinib in patients with B-cell malignancies who are intolerant of ibrutinib and/or acalabrutinib. Here, results in patients with CLL/SLL are presented. Patients received zanubrutinib 160 mg twice daily or 320 mg once a day. With a 34.5-month median follow-up, 71 patients (ibrutinib intolerant only, n = 44; acalabrutinib intolerant only, n = 17; ibrutinib and acalabrutinib intolerant, n = 10) received ≥1 zanubrutinib dose. On zanubrutinib, 54% (28/52) of ibrutinib-intolerant patients and 70% (19/27) of acalabrutinib-intolerant patients experienced no recurrence of intolerance adverse events (AEs); 60% and 72% of intolerance AEs did not recur, respectively. Of recurrent ibrutinib-intolerance AEs, 64% were lower grade; 44% of acalabrutinib-intolerance AEs were lower grade. No intolerance AEs recurred at a higher grade with zanubrutinib. The most common recurrent ibrutinib-intolerance and acalabrutinib-intolerance AEs were fatigue and diarrhea, respectively. The most common treatment-emergent AEs (TEAEs) with zanubrutinib were fatigue (32%) and COVID-19 (28%). Grade ≥3 TEAEs occurred in 61%, serious TEAEs in 32%, and TEAEs leading to discontinuation in 11%. Of 67 efficacy-evaluable patients, 94% experienced disease control: 30% had a best response of stable disease and 64% had a partial or complete response. These data demonstrate that patients intolerant of ibrutinib/acalabrutinib may benefit from switching to zanubrutinib therapy. This trial was registered at www.ClinicalTrials.gov as #NCT04116437.
布鲁顿酪氨酸激酶（BTK）抑制剂，如伊布替尼（ibr），彻底改变了慢性淋巴细胞白血病/小淋巴细胞淋巴瘤（CLL/SLL）的治疗方式，尽管治疗相关毒性限制了某些BTK抑制剂的使用。泽布替尼是一种强效的新一代BTK抑制剂，其选择性高于伊布替尼或阿卡拉布替尼。正在进行的2期单臂BGB-3111-215研究调查了泽布替尼在对伊布替尼和/或阿卡拉布替尼不耐受的B细胞恶性肿瘤患者中的安全性和疗效。在此，报告了CLL/SLL患者的结果。患者接受每日两次160mg或每日一次320mg的泽布替尼治疗。中位随访34.5个月，71例患者（仅对伊布替尼不耐受，n = 44；仅对阿卡拉布替尼不耐受，n = 17；对伊布替尼和阿卡拉布替尼均不耐受，n = 10）接受了≥1剂泽布替尼治疗。使用泽布替尼后，54%（28/52）的伊布替尼不耐受患者和70%（19/27）的阿卡拉布替尼不耐受患者未出现不耐受不良事件（AE）复发；不耐受AE分别有60%和72%未复发。在复发性伊布替尼不耐受AE中，64%为较低级别；44%的阿卡拉布替尼不耐受AE为较低级别。使用泽布替尼后，没有不耐受AE以更高级别复发。最常见的复发性伊布替尼不耐受和阿卡拉布替尼不耐受AE分别是疲劳和腹泻。使用泽布替尼最常见的治疗中出现的不良事件（TEAE）是疲劳（32%）和COVID-19（28%）。≥3级TEAE发生率为61%，严重TEAE发生率为32%，导致停药的TEAE发生率为11%。在67例可评估疗效的患者中，94%实现了疾病控制：30%的最佳反应为病情稳定，64%有部分或完全缓解。这些数据表明，对伊布替尼/阿卡拉布替尼不耐受的患者可能从改用泽布替尼治疗中获益。该试验在www.ClinicalTrials.gov上注册，编号为#NCT04116437。
