Internal Medicine III, Ulm University, Ulm, Germany.
Department of Internal Medicine, Center of Integrated Oncology KölnBonn (CIO KölnBonn), and Cluster of Excellence on Cellular Stress Responses in Aging (CECAD), University of Cologne, Cologne, Germany.
Lancet Oncol. 2016 Jun;17(6):768-778. doi: 10.1016/S1470-2045(16)30019-5. Epub 2016 May 10.
Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia.
In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4-5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment.
Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1-14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5-86·6) of 107 patients. The most common grade 3-4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7%] each), pneumonia (six [6%]), and febrile neutropenia (five [5%]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related).
Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia.
AbbVie and Genentech.
慢性淋巴细胞白血病患者染色体 17p 缺失（del[17p]）经标准化疗免疫治疗后预后极差。维奈托克是一种口服小分子 BCL2 抑制剂，可诱导慢性淋巴细胞白血病细胞凋亡。在维奈托克的首次人体研究中，77%的复发或难治性慢性淋巴细胞白血病患者获得了总体缓解。本研究旨在评估维奈托克单药治疗复发或难治性 del(17p)慢性淋巴细胞白血病患者的疗效和安全性。
在这项 2 期、单臂、多中心研究中，我们从美国、加拿大、英国、德国、波兰和澳大利亚的 31 个中心招募了年龄在 18 岁及以上的 del(17p)复发或难治性慢性淋巴细胞白血病（根据 2008 年修订的国际慢性淋巴细胞白血病工作组指南定义）患者。患者接受每周剂量爬坡方案（4-5 周内 20、50、100、200、400mg）的每日一次维奈托克单药治疗。然后，患者每天接受 400mg 连续剂量治疗，直至疾病进展或因其他原因停药。主要终点是独立评审委员会评估的患者总体缓解比例。疗效和安全性分析包括至少接受一次研究药物治疗的所有患者（按方案）。本研究在 ClinicalTrials.gov 注册，编号为 NCT01889186。随访仍在进行中，患者仍在接受治疗。
2013 年 5 月 27 日至 2014 年 6 月 27 日期间，共纳入 107 例患者。在中位随访 12.1 个月（IQR 10.1-14.2）时，独立评审评估的总体缓解率为 85（79.4%；95%CI 70.5-86.6）例患者。最常见的 3-4 级不良事件为中性粒细胞减少症（43[40%]）、感染（21[20%]）、贫血（19[18%]）和血小板减少症（16[15%]）。59（55%）例患者发生严重不良事件，无论其与治疗的关系如何，最常见的（≥5%的患者）为发热和自身免疫性溶血性贫血（各 7[7%]）、肺炎（6[6%]）和发热性中性粒细胞减少症（5[5%]）。11 例患者在最后一次维奈托克治疗后 30 天内死亡；7 例死于疾病进展，4 例死于不良事件（均非治疗相关）。
本研究结果表明，维奈托克单药治疗复发或难治性 del(17p)慢性淋巴细胞白血病具有活性且耐受性良好，为这一预后极差的患者群体提供了新的治疗选择。此外，鉴于维奈托克的独特作用机制，应研究与其他新型靶向药物的联合或序贯治疗，以进一步推进 del(17p)慢性淋巴细胞白血病的治疗。
艾伯维和基因泰克。
