Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study.,The Lancet Oncology

当前位置： X-MOL 学术 › Lancet Oncol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study.
The Lancet Oncology ( IF 41.6 ) Pub Date : 2020-03-11 , DOI: 10.1016/s1470-2045(20)30060-7
Seth E Karol ₁ , Thomas B Alexander ₂ , Amit Budhraja ₃ , Stanley B Pounds ₄ , Kristin Canavera ₅ , Lei Wang ₄ , Joshua Wolf ₆ , Jeffery M Klco ₇ , Paul E Mead ₇ , Soumyasri Das Gupta ₃ , Su Y Kim ₈ , Ahmed Hamed Salem ₉ , Tammy Palenski ₈ , Norman J Lacayo ₁₀ , Ching-Hon Pui ₁ , Joseph T Opferman ₃ , Jeffrey E Rubnitz ₁

Affiliation

Background

Outcomes for children with relapsed or refractory acute myeloid leukaemia remain poor. The BCL-2 inhibitor, venetoclax, has shown promising activity in combination with hypomethylating agents and low-dose cytarabine in older adults for whom chemotherapy is not suitable with newly diagnosed acute myeloid leukaemia. We aimed to determine the safety and explore the activity of venetoclax in combination with standard and high-dose chemotherapy in paediatric patients with relapsed or refractory acute myeloid leukaemia.

Methods

We did a phase 1, dose-escalation study at three research hospitals in the USA. Eligible patients were aged 2–22 years with relapsed or refractory acute myeloid leukaemia or acute leukaemia of ambiguous lineage with adequate organ function and performance status. During dose escalation, participants received venetoclax orally once per day in continuous 28-day cycles at either 240 mg/m² or 360 mg/m², in combination with cytarabine received intravenously every 12 h at either 100 mg/m² for 20 doses or 1000 mg/m² for eight doses, with or without intravenous idarubicin (12 mg/m²) as a single dose, using a rolling-6 accrual strategy. The primary endpoint was the recommended phase 2 dose of venetoclax plus chemotherapy and the secondary endpoint was the proportion of patients treated at the recommended phase 2 dose who achieved complete remission or complete remission with incomplete haematological recovery. Analyses were done on patients who received combination therapy. The study is registered with ClinicalTrials.gov (NCT03194932) and is now enrolling to address secondary and exploratory objectives.

Findings

Between July 1, 2017, and July 2, 2019, 38 patients were enrolled (aged 3–22 years; median 10 [IQR 7–13]), 36 of whom received combination therapy with dose escalation, with a median follow-up of 7·1 months (IQR 5·1–11·2). The recommended phase 2 dose of venetoclax was found to be 360 mg/m² (maximum 600 mg) combined with cytarabine (1000 mg/m² per dose for eight doses), with or without idarubicin (12 mg/m² as a single dose). Overall responses were observed in 24 (69%) of the 35 patients who were evaluable after cycle 1. Among the 20 patients treated at the recommended phase 2 dose, 14 (70%, 95% CI 46–88) showed complete response with or without complete haematological recovery, and two (10%) showed partial response. The most common grade 3–4 adverse events were febrile neutropenia (22 [66%]), bloodstream infections (six [16%]), and invasive fungal infections (six [16%]). Treatment-related death occurred in one patient due to colitis and sepsis.

Interpretation

The safety and activity of venetoclax plus chemotherapy in paediatric patients with heavily relapsed and refractory acute myeloid leukaemia suggests that this combination should be tested in newly diagnosed paediatric patients with high-risk acute myeloid leukaemia.

Funding

US National Institutes of Health, American Lebanese Syrian Associated Charities, AbbVie, and Gateway for Cancer Research.

中文翻译：

Venetoclax 联合阿糖胞苷联合或不联合伊达比星治疗复发性或难治性急性髓性白血病儿童：一项 1 期剂量递增研究。

背景

复发性或难治性急性髓系白血病儿童的预后仍然很差。 BCL-2 抑制剂 Venetoclax 与低甲基化药物和低剂量阿糖胞苷联合使用，对新诊断的急性髓性白血病不适合化疗的老年人显示出良好的活性。我们的目的是确定维奈托克与标准和高剂量化疗联合治疗复发性或难治性急性髓系白血病儿科患者的安全性并探讨其活性。

方法

我们在美国的三家研究医院进行了第一阶段剂量递增研究。符合条件的患者年龄为2-22岁，患有复发性或难治性急性髓系白血病或谱系不明确的急性白血病，具有足够的器官功能和体能状态。在剂量递增过程中，参与者以 240 mg/m ²或 360 mg/m ²的剂量连续 28 天为一个周期，每天口服一次维奈托克，并与每 12 小时静脉注射一次 100 mg/m ²的阿糖胞苷联合使用，共 20 剂或 1000 mg/m ²八次剂量，有或没有静脉注射伊达比星 (12 mg/m ² ) 作为单剂量，使用滚动 6 应计策略。主要终点是推荐的 2 期 Venetoclax 剂量加化疗，次要终点是接受推荐的 2 期剂量治疗后实现完全缓解或完全缓解但血液学恢复不完全的患者比例。对接受联合治疗的患者进行了分析。该研究已在 ClinicalTrials.gov (NCT03194932) 注册，目前正在招募以解决次要和探索性目标。

发现

2017年7月1日至2019年7月2日期间，入组了38名患者（年龄3-22岁；中位数10[IQR 7-13]），其中36名接受剂量递增的联合治疗，中位随访时间为7·1 个月（IQR 5·1–11·2）。 Venetoclax 的推荐 2 期剂量为 360 mg/m ² （最大 600 mg）联合阿糖胞苷（每剂 1000 mg/m ² ，共八剂），联合或不联合伊达比星（单剂 12 mg/m ^2）剂量）。在第 1 周期后可评估的 35 名患者中，有 24 名 (69%) 观察到总体缓解。在接受推荐的 2 期剂量治疗的 20 名患者中，14 名 (70%, 95% CI 46-88) 显示完全缓解，或没有完全的血液学恢复，有两人 (10%) 显示部分缓解。最常见的 3-4 级不良事件是发热性中性粒细胞减少症（22 例 [66%]）、血流感染（6 例 [16%]）和侵袭性真菌感染（6 例 [16%]）。一名患者因结肠炎和败血症而发生治疗相关死亡。