Background

Patients with acute myeloid leukaemia frequently have thrombocytopenia during induction chemotherapy. Eltrombopag, an oral thrombopoietin receptor agonist, stimulates platelet production by a similar mechanism to endogenous thrombopoietin. This study investigated safety and efficacy of eltrombopag versus placebo during anthracycline-based induction treatment of patients with acute myeloid leukaemia.

Methods

In this randomised, double-blind, phase 2 study, treatment-naive patients were recruited from clinical centres across 10 countries (Australia, Belgium, Canada, Greece, Hungary, Israel, South Korea, Poland, Russia, and the USA). Patients with acute myeloid leukaemia of any subtype except M3 and M7 were stratified by antecedent malignant haematological disorder (yes or no) and age (18–60 years or >60 years) and were then randomly assigned (1:1) using an automated interactive voice–response system randomisation schedule. Investigators and patients were blinded to study treatment. Starting on day 4, patients received standard induction chemotherapy (daunorubicin bolus intravenous infusion on days 1–3 [90 mg/m² for patients aged 18–60 years or 60 mg/m² for patients aged >60 years], plus cytarabine continuous intravenous infusion on days 1–7 [100 mg/m²]), with eltrombopag 200 mg (100 mg for east Asians) or placebo once daily, until platelet counts were 200 × 10⁹/L or higher, until remission, or after 42 days from the start of induction chemotherapy. The primary objective of the study was safety and tolerability assessed by adverse events, changes in left ventricular ejection fraction (LVEF), and clinical laboratory parameters in all treated patients. This study has been completed and is registered with ClinicalTrials.gov, number NCT01890746.

Findings

Between Sept 7, 2013, and Jan 30, 2015, 149 patients were assessed for eligibility and 148 were then randomly assigned to receive eltrombopag (n=74) and placebo (n=74). Groups were matched in mean (SD) age (56·7 years [12·3] in the eltrombopag group vs 56·6 years [11·6] in the placebo group), mean (SD) initial platelet count (59·5 × 10⁹/L [43·3] vs 63·7 × 10⁹/L [48·0]), and poor-risk karyotype (16 [22%] of 74 patients in both groups). The most common grade 3–4 adverse events (≥10% in either group) were febrile neutropenia (31 [42%] vs 28 [39%]), decreased white blood cell count (8 [11%] vs 5 [7%]), and hypophosphataemia (3 [4%] vs 9 [13%]). Serious adverse events occurred in 24 (32%) patients in the eltrombopag group compared with 14 (20%) patients in the placebo group. 39 (53%) patients in the eltrombopag group died versus 29 (41%) patients in the placebo group. Thromboembolic events (5 [7%] vs 4 [6%]) and mean (SD) change in LVEF (−2·5% [7·8] vs −4·3% [8·5]) were similar.

Interpretation

Data from this trial do not support combining eltrombopag with induction chemotherapy in patients with acute myeloid leukaemia.

Funding

Novartis Pharma AG.

中文翻译：

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急性骨髓性白血病的诱导化疗期间Eltrombopag的治疗：一项随机，双盲，2期研究

背景

急性髓细胞性白血病患者在诱导化疗期间经常有血小板减少症。口服血小板生成素受体激动剂Eltrombopag通过与内源性血小板生成素相似的机制刺激血小板生成。这项研究调查了在以蒽环类为基础的急性髓细胞性白血病患者诱导治疗中，Eltrombopag与安慰剂的安全性和有效性。

方法

在这项随机，双盲，2期研究中，从10个国家（澳大利亚，比利时，加拿大，希腊，匈牙利，以色列，韩国，波兰，俄罗斯和美国）的临床中心招募了未接受治疗的患者。除M3和M7以外的任何亚型的急性髓细胞性白血病患者均按先前的恶性血液病（是或否）和年龄（18–60岁或> 60岁）进行分层，然后使用自动互动系统随机分配（1：1）语音响应系统随机化时间表。研究者和患者不愿接受研究治疗。从第4天开始，患者接受标准的诱导化学疗法（柔红霉素推注静脉滴注在1-3天[对于18-60岁的患者为90 mg / m ²或60 mg / m ²对于> 60岁的患者]，再加上阿糖胞苷在第1-7天连续静脉输注[100 mg / m ² ]），每天服用Eltrombopag 200 mg（东亚为100 mg）或安慰剂，直到血小板计数为200×10 ⁹ / L或更高，直到缓解，或从开始诱导化疗开始的42天后。这项研究的主要目的是通过不良事件，所有治疗患者的左心室射血分数（LVEF）的变化和临床实验室参数评估安全性和耐受性。该研究已完成，并已在ClinicalTrials.gov上注册，编号为NCT01890746。

发现

在2013年9月7日至2015年1月30日之间，评估了149例患者的资格，然后随机分配148例患者接受Eltrombopag（n = 74）和安慰剂（n = 74）。各组的平均年龄（SD）相匹配（Eltrombopag组为56·7岁[12·3]，而安慰剂组为56·6岁[11·6]），平均（SD）初始血小板计数（59·5 ）相匹配×10 ⁹ / L [43·3]与63·7×10 ⁹ / L [48·0]）和低风险核型（两组中74例患者中的16例[22％]）。最常见的3-4级不良事件（两组均≥10％）是发热性中性粒细胞减少（31 [42％] vs 28 [39％]），白细胞计数降低（8 [11％] vs 5 [7％] ]）和低磷血症（3 [4％] vs9 [13％]）。Eltrombopag组的严重不良事件发生在24名（32％）患者中，而安慰剂组的严重不良事件发生在14名（20％）患者中。Eltrombopag组中有39例患者死亡（53％），而安慰剂组中有29例（41％）患者死亡。血栓栓塞事件（5 [7％]对4 [6％]）和LVEF的平均（SD）变化（-2·5％[7·8]对-4·3％[8·5]）相似。

解释

该试验的数据不支持在急性髓细胞性白血病患者中将Eltrombopag与诱导化疗联合使用。

资金

诺华制药公司。