Department of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Niguarda Cancer Center, Milan, Italy.
Department of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Niguarda Cancer Center, Milan, Italy.
Lancet Oncol. 2024 Oct;25(10):1298-1309. doi: 10.1016/S1470-2045(24)00396-6. Epub 2024 Sep 10.
The diffuse large B-cell lymphoma (DLBCL) variant of Richter transformation (DLBCL-RT) is typically chemoresistant with poor prognosis. Aiming to explore a chemotherapy-free treatment combination that triggers anti-tumour immune responses, we conducted a phase 2 study of atezolizumab (a PD-L1 inhibitor) in combination with venetoclax and obinutuzumab in patients with DLBCL-RT.
This was a prospective, open-label, multicentre, single-arm, investigator-initiated, phase 2 study in 15 hospitals in Italy and Switzerland. Eligible patients had a confirmed diagnosis of chronic lymphocytic leukaemia or small lymphocytic lymphoma as per the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria with biopsy-proven transformation to DLBCL; had not previously received treatment for DLBCL-RT, although they could have received chronic lymphocytic leukaemia therapies; were aged 18 years or older; and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. No previous treatment with any of the drugs in the triplet combination was allowed. Patients received 35 cycles of 21 days of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, 1000 mg on day 8 and day 15 of cycle 1; 1000 mg on day 1 of cycles 2-8) and intravenous atezolizumab (1200 mg on day 2 of cycle 1 and 1200 mg on day 1 of cycles 2-18), and continuous oral venetoclax (ramp-up from 20 mg/day on day 15 of cycle 1 according to chronic lymphocytic leukaemia schedule, then 400 mg/day from day 1 of cycle 3 to day 21 of cycle 35). The primary endpoint was overall response rate at day 21 of cycle 6 in the intention-to-treat population. We considered an overall response rate of 67% or more to be clinically active, rejecting the null hypothesis of a response of 40% or less. The study is registered with ClinicalTrials.gov, NCT04082897, and has been completed.
Between Oct 9, 2019, and Oct 19, 2022, 28 patients were enrolled (12 [43%] male patients and 16 [57%] female patients). Median follow-up was 16·8 months (IQR 7·8-32·0). At cycle 6, 19 of 28 patients showed a response, yielding an overall response rate of 67·9% (95% CI 47·6-84·1). Treatment-emergent adverse events that were grade 3 or worse were reported in 17 (61%; 95% CI 40·6-78·5) of 28 patients, with neutropenia being the most frequent (11 [39%; 21·5-59·4] of 28 patients). Serious treatment-emergent adverse events were reported in eight (29%; 14·2-48·7) patients, which were most commonly infections (five [18%; 6·1-36·9] of 28 patients). There were two (7%) deaths attributable to adverse events during the study: one from sepsis and one from fungal pneumonia, which were not considered as directly treatment-related by the investigators. Six (21·4%) patients had immune-related adverse events, none of which led to discontinuation. No tumour lysis syndrome was observed.
The atezolizumab, venetoclax, and obinutuzumab triplet combination was shown to be active and safe, suggesting that this chemotherapy-free regimen could become a new first-line treatment approach in patients with DLBCL-RT.
Roche.
弥漫性大 B 细胞淋巴瘤（DLBCL）的里希特转化（DLBCL-RT）变体通常对化疗具有耐药性，预后较差。为了探索一种无需化疗的治疗组合，以触发抗肿瘤免疫反应，我们在意大利和瑞士的 15 家医院进行了一项 II 期研究，评估 atezolizumab（一种 PD-L1 抑制剂）联合 venetoclax 和 obinutuzumab 治疗 DLBCL-RT 患者的疗效。
这是一项前瞻性、开放标签、多中心、单臂、研究者发起的 II 期研究，纳入了 15 家意大利和瑞士医院的患者。符合条件的患者具有慢性淋巴细胞白血病（CLL）或小淋巴细胞淋巴瘤的确诊病例，根据国际慢性淋巴细胞白血病研讨会（IWCLL）2008 标准经活检证实转化为 DLBCL；之前未接受过 DLBCL-RT 的治疗，尽管他们可能接受过 CLL 的治疗；年龄在 18 岁及以上；东部肿瘤协作组（ECOG）体能状态为 0-2 分。不允许患者之前接受过三联药物治疗。患者接受 35 个周期的 21 天静脉注射 obinutuzumab（第 1 天 100mg，第 2 天 900mg，第 1 周期第 8 天和第 15 天 1000mg；第 1 周期第 2 天和第 18 天 1000mg）和静脉注射 atezolizumab（第 1 周期第 2 天 1200mg，第 1 周期第 2 天和第 18 天 1200mg），以及持续口服 venetoclax（根据 CLL 方案，第 1 周期第 15 天开始从 20mg/天逐渐增加，第 3 周期第 1 天开始每天 400mg，持续到第 35 天）。主要终点是意向治疗人群在第 6 周期第 21 天的总体缓解率。我们认为总体缓解率为 67%或更高为临床有效，拒绝 40%或更低的反应率为无效假设。该研究在 ClinicalTrials.gov 注册，编号为 NCT04082897，现已完成。
2019 年 10 月 9 日至 2022 年 10 月 19 日期间，共纳入 28 例患者（12 例男性，43%；16 例女性，57%）。中位随访时间为 16.8 个月（IQR 7.8-32.0）。在第 6 周期，28 例患者中有 19 例出现缓解，总体缓解率为 67.9%（95%CI 47.6-84.1）。28 例患者中有 17 例（61%；95%CI 40.6-78.5）发生了 3 级或更高级别的治疗相关不良事件，中性粒细胞减少最常见（28 例患者中 11 例[39%；21.5-59.4]）。8 例（29%；95%CI 48.7-78.5）患者发生严重治疗相关不良事件，最常见的是感染（28 例患者中 5 例[18%；6.1-36.9]）。在研究期间有 2 例（7%）患者因不良事件死亡：1 例为败血症，1 例为真菌性肺炎，研究者认为与治疗无直接关系。6 例（21.4%）患者发生免疫相关不良事件，均未导致停药。未观察到肿瘤溶解综合征。
atezolizumab、venetoclax 和 obinutuzumab 三联药物治疗在 DLBCL-RT 患者中表现出了活性和安全性，提示这种无需化疗的治疗方案可能成为 DLBCL-RT 患者的一种新的一线治疗方法。
罗氏公司。
