University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
Lancet Oncol. 2018 Feb;19(2):216-228. doi: 10.1016/S1470-2045(18)30010-X. Epub 2018 Jan 12.
BACKGROUND: Elderly patients (aged ≥65 years) with acute myeloid leukaemia have poor outcomes and no effective standard-of-care therapy exists. Treatment with hypomethylating agents such as azacitidine and decitabine is common, but responses are modest and typically short-lived. The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor, venetoclax, has shown promising single-agent activity in patients with relapsed or refractory acute myeloid leukaemia and preclinical data suggested synergy between hypomethylating agents and venetoclax, which led to this combination phase 1b study. METHODS: Previously untreated patients aged 65 years and over with acute myeloid leukaemia who were ineligible for standard induction therapy were enrolled into this non-randomised, open-label, phase 1b study. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0-2 and either intermediate-risk or poor-risk cytogenetics. Patients were enrolled into one of three groups for the dose-escalation phase of this study: group A (venetoclax and intravenous decitabine 20 mg/m [days 1-5 of each 28-day cycle]), group B (venetoclax and subcutaneous or intravenous azacitidine 75 mg/m [days 1-7 of each 28-day cycle]), and group C (a venetoclax and decitabine substudy with the oral CYP3A inhibitor posaconazole, 300 mg twice on cycle 1, day 21, and 300 mg once daily from cycle 1, days 22-28, to assess its effect on venetoclax pharmacokinetics). Dose escalation followed a standard 3 + 3 design with at least three evaluable patients enrolled per cohort; daily target doses of venetoclax for groups A and B were 400 mg (cohort 1), 800 mg (cohorts 2 and 3), and 1200 mg (cohort 4), and 400 mg for group C. The primary endpoints were the safety and pharmacokinetics of venetoclax plus decitabine or azacitidine, and to determine the maximum tolerated dose and recommended phase 2 dose. Secondary endpoints included the preliminary anti-leukaemic activity of venetoclax with decitabine or azacitidine through the analysis of overall response, duration of response, and overall survival. We analysed safety, pharmacokinetics, and anti-leukaemic activity in all patients who received one or more venetoclax doses. The expansion phase of the study is ongoing but is closed to accrual. This trial is registered with ClinicalTrials.gov, number NCT02203773. FINDINGS: 57 patients were enrolled in the study. 23 patients in group A and 22 patients in group B were enrolled between Nov 19, 2014, and Dec 15, 2015, and 12 patients in group C were enrolled between June 14, 2015, and Jan 16, 2016. As of data cutoff on June 15, 2016, the most common grade 3-4 treatment-emergent adverse events were thrombocytopenia (27 [47%] of 57 patients; nine in group A, 13 in group B, and five in group C), febrile neutropenia (24 [42%] of 57; 11 in group A, ten in group B, and three in group C), and neutropenia (23 [40%] of 57; 12 in group A, eight in group B, and three in group C). The most common serious treatment-emergent adverse event in groups A and B was febrile neutropenia (seven [30%] of 23 patients vs seven [32%] of 22), whereas in group C it was lung infection (four [33%] of 12 patients). 49 (86%) of 57 patients had treatment-related adverse events; the most common in groups A and B included nausea (12 [52%] patients vs seven [32%] patients), fatigue (six [26%] patients vs seven [32%]), and decreased neutrophil count (six [26%] patients vs six [27%]), whereas in group C the most common were nausea (seven [58%] of 12 patients), leucopenia (six [50%]), vomiting (five [42%]), and decreased platelet count (five [42%]). The maximum tolerated dose was not reached. The recommended phase 2 dose was 400 mg once a day or 800 mg with an interrupted dosing schedule (safety expansion). In total, four (7%) of 57 patients had died within 30 days of the first venetoclax dose caused by sepsis (group B), bacteraemia (group A), lung infection (group C), and respiratory failure (group A). Tumour lysis syndrome was not observed. Decitabine and azacitidine did not substantially affect venetoclax exposures. Overall, 35 (61%; 95% CI 47·6-74·0) of 57 patients achieved complete remission or complete remission with incomplete marrow recovery. In groups A and B, 27 (60%; 95% CI 44·3-74·3) of 45 patients had complete remission or complete remission with incomplete marrow recovery. INTERPRETATION: Venetoclax plus hypomethylating agent therapy seems to be a novel, well-tolerated regimen with promising activity in this underserved patient population. Evaluation of expansion cohorts is ongoing at 400 mg and 800 mg doses using both hypomethylating agent combinations. FUNDING: AbbVie and Genentech.
背景：老年（≥65 岁）急性髓系白血病患者的预后较差，目前尚无有效的标准治疗方法。阿扎胞苷和地西他滨等低甲基化剂的治疗较为常见，但反应较为温和，通常持续时间较短。口服抗凋亡 B 细胞淋巴瘤 2 蛋白抑制剂维奈托克在复发或难治性急性髓系白血病患者中表现出良好的单药活性，临床前数据表明低甲基化剂与维奈托克具有协同作用，这导致了这项联合 1b 期研究。
方法：我们纳入了这项非随机、开放标签、1b 期研究的之前未经治疗、年龄在 65 岁及以上且不符合标准诱导治疗条件的急性髓系白血病患者。患者需要有东部肿瘤协作组（ECOG）体能状态 0-2 级，且具有中危或高危细胞遗传学特征。患者被纳入研究的剂量递增阶段，共分为三组：A 组（维奈托克联合静脉用去甲胞苷 20 mg/m[每个 28 天周期的第 1-5 天]）、B 组（维奈托克联合皮下或静脉用阿扎胞苷 75 mg/m[每个 28 天周期的第 1-7 天]）和 C 组（维奈托克联合去甲胞苷亚组研究，同时给予口服 CYP3A 抑制剂泊沙康唑，第 1 周期第 21 天和第 30 天各 300mg，第 1 周期第 22-28 天每天 300mg，以评估其对维奈托克药代动力学的影响）。剂量递增遵循标准的 3+3 设计，每个队列至少纳入 3 例可评估患者；A 组和 B 组的每日目标剂量为 400mg（第 1 队列）、800mg（第 2 队列和第 3 队列）和 1200mg（第 4 队列），C 组为 400mg。主要终点是评估维奈托克联合去甲胞苷或阿扎胞苷的安全性和药代动力学，确定最大耐受剂量和推荐的 2 期剂量。次要终点包括通过分析总缓解率、缓解持续时间和总生存期，评估维奈托克联合去甲胞苷或阿扎胞苷的初步抗白血病活性。我们分析了所有接受过维奈托克治疗的患者的安全性、药代动力学和抗白血病活性。该研究的扩展阶段仍在进行中，但已停止入组。本试验在 ClinicalTrials.gov 注册，编号为 NCT02203773。
结果：57 例患者入组研究。A 组 23 例，B 组 22 例，于 2014 年 11 月 19 日至 2015 年 12 月 15 日入组，C 组 12 例，于 2015 年 6 月 14 日至 2016 年 1 月 16 日入组。截至 2016 年 6 月 15 日数据截止时，最常见的 3-4 级治疗相关不良事件是血小板减少症（57 例患者中有 27 例[47%]；A 组 9 例，B 组 13 例，C 组 5 例）、发热性中性粒细胞减少症（57 例患者中有 24 例[42%]；A 组 11 例，B 组 10 例，C 组 3 例）和中性粒细胞减少症（57 例患者中有 23 例[40%]；A 组 12 例，B 组 8 例，C 组 3 例）。A 组和 B 组最常见的严重治疗相关不良事件是发热性中性粒细胞减少症（23 例患者中各有 7 例[30%]），而 C 组则是肺部感染（12 例患者中有 4 例[33%]）。57 例患者中有 49 例（86%）发生与治疗相关的不良事件；A 组和 B 组中最常见的不良事件包括恶心（12 例患者中有 12 例[52%]，12 例患者中有 7 例[32%]）、疲劳（6 例患者中有 6 例[26%]，12 例患者中有 7 例[32%]）和中性粒细胞计数减少（6 例患者中有 6 例[26%]，12 例患者中有 6 例[27%]），而 C 组中最常见的是恶心（12 例患者中有 7 例[58%]）、白细胞减少症（6 例患者中有 6 例[50%]）、呕吐（5 例患者中有 5 例[42%]）和血小板计数减少症（5 例患者中有 5 例[42%]）。未达到最大耐受剂量。推荐的 2 期剂量为每天 400mg 或 800mg 时中断剂量方案（安全性扩展）。共有 57 例患者中有 4 例（7%）在接受维奈托克首次治疗后 30 天内死亡，死亡原因分别为败血症（B 组）、菌血症（A 组）、肺部感染（C 组）和呼吸衰竭（A 组）。未观察到肿瘤溶解综合征。去甲胞苷和阿扎胞苷未显著影响维奈托克的暴露量。总的来说，57 例患者中有 35 例（61%；95%CI 47.6-74.0）达到完全缓解或不完全骨髓恢复的完全缓解。在 A 组和 B 组中，45 例患者中有 27 例（60%；95%CI 44.3-74.3）达到完全缓解或不完全骨髓恢复的完全缓解。
结论：维奈托克联合低甲基化剂治疗似乎是一种新的、耐受良好的方案，在这一未满足需求的患者群体中具有有前景的活性。目前正在 400mg 和 800mg 剂量组使用两种低甲基化剂组合对扩展队列进行评估。
资金来源：艾伯维（AbbVie）和基因泰克（Genentech）。
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