Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University Hospital Cologne, Cologne, Germany.
Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University Hospital Cologne, Cologne, Germany.
Lancet Oncol. 2018 Sep;19(9):1215-1228. doi: 10.1016/S1470-2045(18)30414-5. Epub 2018 Aug 13.
Targeted agents such as the type II anti-CD20 antibody obinutuzumab and the B-cell lymphoma-2 antagonist venetoclax have shown impressive therapeutic activity in chronic lymphocytic leukaemia. The CLL2-BAG trial was initiated to investigate the combination of these two agents in patients with chronic lymphocytic leukaemia.
In this ongoing multicentre, open-label, investigator-initiated phase 2 trial, patients (aged ≥18 years) with chronic lymphocytic leukaemia requiring treatment according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 16 sites in Germany. Patients with a relevant tumour load (absolute lymphocyte count ≥25 000 cells per μL or lymph nodes with a diameter of ≥5 cm) received sequential treatment of debulking with two cycles of bendamustine (70 mg/m intravenously on days 1 and 2 of each of the two 28-day cycles), followed by induction and maintenance with obinutuzumab (1000 mg intravenously on days 1-2, 8, and 15 of the first induction cycle, every 4 weeks in induction cycles 2-6, and every 12 weeks in the maintenance phase) and oral venetoclax (starting in induction cycle 2 with 20 mg/day, with a weekly dose escalation over 5 weeks to the target dose of 400 mg/day). The primary endpoint was the proportion of patients achieving an overall response by investigator assessment at the end of induction treatment. All patients who received at least two induction cycles were included in the efficacy analyses and all patients who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02401503.
Between May 6, 2015, and Jan 4, 2016, 66 patients were enrolled (35 treatment naive and 31 with relapsed or refractory disease), three of whom were excluded from the efficacy analysis because they received fewer than two induction cycles. Of the remaining 63 patients in the efficacy-evaluable population, 34 patients (54%) were treatment naive and 29 (46%) had relapsed or refractory disease. At data cutoff (Feb 28, 2017), all patients had completed induction treatment. At the end of the induction, 60 (95%) of 63 patients (95% CI 87-99) had responded, including all 34 patients in the treatment-naive cohort and 26 [90%] of 29 relapsed or refractory patients. The most common grade 3-4 adverse events during debulking were neutropenia and anaemia (five [11%] of 47 patients each), and thrombocytopenia and infection (three [6%] each). The most common grade 3-4 adverse events during induction were neutropenia (29 [44%] of 66 patients), infection (nine [14%]), thrombocytopenia (eight [12%]), infusion-related reactions (five [8%]), and secondary primary malignancy (four [6%]). 89 serious adverse events, including 69 related to study treatment, were reported. These serious adverse events were also mainly infections (four cases in four patients during debulking and 18 cases in 11 patients during induction) and cytopenia (four cases in four patients during debulking and ten cases in seven patients in induction). Five relapsed or refractory patients died: three cases of sepsis were deemed related to study treatment, whereas two deaths from Richter's transformation were not.
The sequential application of bendamustine and obinutuzumab combined with venetoclax caused no unexpected or cumulative toxicities. The high proportion of patients who achieved overall responses, both treatment-naive and relapsed or refractory patients irrespective of physical fitness and genetic risk factors, compare favourably to established chronic lymphocytic leukaemia therapies. Further follow-up will help to define whether the remissions with eradication of minimal residual disease achieved with this combination are durable after treatment discontinuation.
F Hoffmann-La Roche and AbbVie.
靶向药物，如 II 型抗 CD20 抗体奥滨尤妥珠单抗和 B 细胞淋巴瘤-2 拮抗剂维奈托克，在慢性淋巴细胞白血病中显示出令人印象深刻的治疗活性。CLL2-BAG 试验旨在研究这两种药物在慢性淋巴细胞白血病患者中的联合应用。
在这项正在进行的多中心、开放性、研究者发起的 2 期试验中，在德国 16 个地点招募了需要根据 2008 年国际慢性淋巴细胞白血病研讨会（IWCLL）标准和东部合作肿瘤学组体能状态 0-2 治疗的慢性淋巴细胞白血病患者（年龄≥18 岁）。具有相关肿瘤负荷（绝对淋巴细胞计数≥25000 个细胞/μL 或直径≥5 cm 的淋巴结）的患者接受两个周期的减瘤治疗，随后进行奥滨尤妥珠单抗诱导和维持治疗（第 1 天和第 2 天静脉注射 1000mg，每个 28 天周期各一次），随后进行维奈托克口服诱导和维持治疗（第 1 周期的第 1-2 天和第 8-15 天静脉注射 1000mg，随后每 4 周一次，第 2-6 个诱导周期，第 12 个周期开始维持治疗）。主要终点是研究者评估的诱导治疗结束时患者总体缓解的比例。所有接受至少两个诱导周期治疗的患者均纳入疗效分析，所有接受至少一剂研究药物的患者均纳入安全性分析。这项研究在 ClinicalTrials.gov 注册，编号为 NCT02401503。
2015 年 5 月 6 日至 2016 年 1 月 4 日期间，共纳入 66 例患者（35 例初治患者和 31 例复发或难治性疾病患者），其中 3 例因接受的诱导周期少于两个而被排除在疗效分析之外。在可评估疗效的 63 例患者中，34 例（54%）为初治患者，29 例（46%）为复发或难治性疾病患者。数据截止日期为 2017 年 2 月 28 日，所有患者均已完成诱导治疗。在诱导治疗结束时，63 例患者中有 60 例（95%CI 87-99）达到了缓解，包括初治组的 34 例患者和复发或难治性患者的 26 例[90%]。减瘤治疗中最常见的 3-4 级不良事件为中性粒细胞减少症和贫血（各 47 例中的 11 例[11%]），血小板减少症和感染（各 3 例中的 6 例[6%]）。诱导治疗中最常见的 3-4 级不良事件为中性粒细胞减少症（66 例中的 29 例[44%]）、感染（9 例[14%]）、血小板减少症（8 例[12%]）、输注相关反应（5 例[8%]）和继发性原发性恶性肿瘤（4 例[6%]）。报告了 89 例严重不良事件，包括 69 例与研究治疗相关的事件。这些严重不良事件也主要为感染（4 例患者在减瘤治疗中，11 例患者在诱导治疗中各 18 例）和细胞减少症（4 例患者在减瘤治疗中，7 例患者在诱导治疗中各 10 例）。有 5 例复发或难治性患者死亡：3 例脓毒症病例被认为与研究治疗有关，而 2 例 Richter 转化导致的死亡则与研究治疗无关。
在慢性淋巴细胞白血病中，奥滨尤妥珠单抗联合维奈托克治疗的安全性良好，无意外或累积毒性。初治和复发或难治性患者的总体缓解率都很高，无论体能状态和遗传风险因素如何，这与已有的慢性淋巴细胞白血病治疗方法相比都具有优势。进一步的随访将有助于确定在停药后，这种联合治疗能否实现持久的缓解并清除微小残留疾病。
这项研究的资金来源为 F Hoffmann-La Roche 和 AbbVie。
