此项研究调查了ibrutinib与obinutuzumab联用治疗复发/难治性CLL，评估了3种顺序方案的耐受性，以及总体安全性和疗效。最初共随机分配了52名患者，比例为1：1：1，其中一组在ibrutinib治疗前1个月接受了obinutuzumab，另一组在obinutuzumab治疗前1个月接受了ibrutinib，还有一组同时接受两种药物。第一组出现了更高比例的输注反应，因此只扩大了后两组的人数。严重的4级造血毒性很少见，一般毒性包括淤血（58%）、高血压（46%）、关节痛（38%）、腹泻（37%）、转氨酶升高（35%）、房颤（21%）、严重感染（17%）。最佳总体反应率为96%（包括40%的完全缓解和56%的部分缓解）。外周血和骨髓中的最小残留病率最佳比例分别为27%和19%。随访中位数为41.5个月，四年无进展生存率和总体生存率分别为74%和93%。相关研究表明，血清CCL4和CXCL13水平与临床反应有关，BH3分析显示，在治疗中有增加的CLL细胞BCL-2和BCL-xL依赖性。总体而言，ibrutinib加obinutuzumab在复发/难治性CLL中非常有效，并且具有可控的安全性，支持进一步探索这种治疗方法的应用。 ©2023年。作者(经Springer Nature Limited独家许可)。

This study investigated ibrutinib plus obinutuzumab in relapsed/refractory CLL, evaluating tolerability of 3 sequencing regimens as well as overall safety and efficacy. Fifty-two patients were initially randomized 1:1:1 to receive either obinutuzumab 1 month before ibrutinib initiation, ibrutinib 1 month prior to obinutuzumab initiation, or to start both drugs concomitantly. Higher rates of infusion-related reactions were observed with the first sequence, and only the latter 2 cohorts were expanded. Grade 4 hematologic toxicity was uncommon, and notable all-grade non-hematologic toxicities included bruising (58%), hypertension (46%), arthralgia (38%), diarrhea (37%), transaminitis (35%), atrial fibrillation (21%), and serious infection (17%). Best overall response rate was 96% (including 40% CR and 56% PR). Best rates of undetectable minimal residual disease in peripheral blood and bone marrow were 27% and 19%, respectively. With a median follow-up of 41.5 months, four-year progression-free and overall survival rates are 74% and 93%, respectively. Correlative studies demonstrated that serum CCL4 and CXCL13 levels were associated with clinical response, and BH3 profiling revealed increased BCL-2 and BCL-xL dependence in CLL cells from patients on treatment. Overall, ibrutinib plus obinutuzumab was highly active, with a manageable safety profile, supporting further investigation of this type of approach in relapsed/refractory CLL.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.