Eltrombopag treatment during induction chemotherapy for acute myeloid leukaemia: a randomised, double-blind, phase 2 study
Eltrombopag treatment during induction chemotherapy for acute myeloid leukaemia: a randomised, double-blind, phase 2 study
复制标题
DOI：
10.1016/s2352-3026(18)30231-x
复制
发表时间：
2019-03-01
影响因子：
24.7
通讯作者：
Strickland, Stephen
中科院分区：
文献类型：
--
作者：
Frey, Noelle;Jang, Jun Ho;Strickland, Stephen
背景急性髓系白血病患者在诱导化疗过程中经常出现血小板减少症。ELTROMBOPG是一种口服血小板生成素受体激动剂，其刺激血小板生成的机制与内源性血小板生成素相似。本研究采用随机、双盲、2期研究方法，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急性髓系白血病患者。除M3和M7外的任何亚型的急性髓系白血病患者根据既往恶性血液病(是或否)和年龄(18-60岁或>；60岁)进行分层，然后使用自动交互语音应答系统随机时间表进行随机分配(1：1)。研究人员和患者都是盲目研究治疗方法。从第4天开始，患者接受标准诱导化疗(柔红霉素团注第1~3天[18~60岁患者90 mg/m(2)，高龄患者60 mg/m(2)]，加阿糖胞苷持续静脉滴注第1~7天[100 mg/m(2)])，厄曲贝克200 mg(东亚人100 mg)或安慰剂每日1次，直至血小板达到200×10(9)/L或以上，直至病情缓解，或自诱导化疗开始42天后。这项研究的主要目的是通过不良事件、左心室射血分数(LVEF)的变化和所有接受治疗的患者的临床实验室参数来评估安全性和耐受性。这项研究已经完成，并在ClinicalTrials.gov注册，编号为NCT01890746。研究结果在2013年9月7日至2015年1月30日期间，149名患者接受了资格评估，148名患者随后被随机分配接受eltrombopg(n=74)和安慰剂(n=74)。两组患者的平均(SD)年龄(电凝组为56.7岁[12.3岁]比安慰剂组的56.6岁[11.6岁])、初始血小板计数(59.5×10(9)/L[43.3]比63.7×10(9)/L[48.0])和低危险核型(16例[22%])在两组患者中是匹配的。最常见的3-4级不良事件(两组均为10%)是发热性中性粒细胞减少(31[42%]比28[39%])，白细胞计数下降(8[11%]比5[7%])，以及低磷血症(3[4%]比9[13%])。与安慰剂组的14名患者(20%)相比，电疗组中有24名患者(32%)发生了严重的不良事件。电疗组有39名患者(53%)死亡，而安慰剂组有29名患者(41%)死亡。血栓栓塞事件(5[7%]比4[6%])和平均(SD)变化(-2.5%[7.8]比-4.3%[8.5])相似。这项试验的解释数据不支持在急性髓系白血病患者中联合使用电疗和诱导化疗。版权所有(C)2019爱思唯尔有限公司。保留所有权利。
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/m(2) for patients aged 18-60 years or 60 mg/m(2) for patients aged >60 years], plus cytarabine continuous intravenous infusion on days 1-7 [100 mg/m(2)]), with eltrombopag 200 mg (100 mg for east Asians) or placebo once daily, until platelet counts were 200 x 10(9)/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 x 10(9)/L [43.3] vs 63.7 x 10(9)/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. Copyright (C) 2019 Elsevier Ltd. All rights reserved.