Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial
Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial
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DOI：
10.1016/s1470-2045(15)00362-9
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发表时间：
2015-12-01
期刊：
影响因子：
51.1
通讯作者：
Ehninger, Gerhard
中科院分区：
文献类型：
--
作者：
Rollig, Christoph;Serve, Hubert;Ehninger, Gerhard
背景 临床前数据和非随机试验结果表明，多激酶抑制剂索拉非尼可能是治疗急性髓系白血病的有效药物。我们在 60 岁或以下的急性髓系白血病患者中研究了索拉非尼与安慰剂加标准化疗的疗效和耐受性。方法 这项随机、双盲、安慰剂对照 2 期试验在德国 25 个地点进行。我们招募了年龄为 18-60 岁的新诊断、既往未经治疗的急性髓系白血病患者，他们的 WHO 临床表现评分为 0-2，肾功能和肝功能良好，无心脏合并症，近期没有外伤或手术。患者被随机分配（1:1）接受两个周期的柔红霉素诱导治疗（第 3-5 天 60 mg/m(2)）加阿糖胞苷（第 1-7 天 100 mg/m(2)），随后接受三个周期的高剂量阿糖胞苷巩固治疗（第 1、3 和 5 天每天两次 3 g/m(2)）加索拉非尼（400 mg 每天两次）或在诱导周期 1 和 2 的第 10-19 天、每次巩固的第 8 天开始服用安慰剂，并维持 12 个月。计划对所有有兄弟姐妹供体的中危患者和首次缓解期有匹配供体的所有高风险患者进行同种异体干细胞移植。计算机生成的随机化是分批进行的。主要终点是无事件生存期，事件定义为主要治疗失败或复发或死亡，在接受至少一剂研究治疗的所有随机患者中进行评估。我们报告最终分析。该试验已在临床试验中注册。 gov，编号NCT00893373和欧盟临床试验登记册（2008-004968-40）。调查结果2009年3月27日至2011年11月28日期间，招募并随机分组了276名患者，其中9人未接受研究药物治疗。主要分析包括 267 名患者（安慰剂，n=133；索拉非尼，n=134）。中位随访时间为 36 个月 (IQR 35.5-38.1)，安慰剂组中位无事件生存期为 9 个月 (95% CI 4-15)，而索拉非尼组为 21 个月 (9-32)，相当于安慰剂组的 3 年无事件生存率为 22% (95% CI 13-32)，而索拉非尼组为 40% (29-51)。索拉非尼组（风险比 [HR] 0.64，95% CI；0.45-0.91；p=0.013）。两组中最常见的3-4级不良事件是发烧（安慰剂组71例[53%] vs 索拉非尼组73例[54%]）、感染（55例[41%] vs 46例[34%]）、肺炎（21例[16%] vs 20例[14%]）和疼痛（13例[10%] vs 15例[11%]）。索拉非尼组比安慰剂组更常见的 3 级或更严重不良事件包括发烧（相对风险 [RR] 1.54，95% CI 1.04-2.28）、腹泻（RR 7.89、2.94-25.2）、出血（RR 3.75、1.5-10.0）、心脏事件（RR 3.46、 1.15-11.8）、手足皮肤反应（仅在索拉非尼组）和皮疹（RR 4.06、1.25-15.7）。 解释 对于60岁或以下的急性髓系白血病患者，在标准化疗中加入索拉非尼具有抗白血病功效，但也增加了毒性。我们的研究结果表明，激酶抑制剂可能是急性髓系白血病治疗的有效补充。需要长期随访后的总生存率和降低毒性的策略来确定索拉非尼在治疗这种疾病中的未来作用。
Background Preclinical data and results from non-randomised trials suggest that the multikinase inhibitor sorafenib might be an effective drug for the treatment of acute myeloid leukaemia. We investigated the efficacy and tolerability of sorafenib versus placebo in addition to standard chemotherapy in patients with acute myeloid leukaemia aged 60 years or younger.Methods This randomised, double-blind, placebo-controlled, phase 2 trial was done at 25 sites in Germany. We enrolled patients aged 18-60 years with newly diagnosed, previously untreated acute myeloid leukaemia who had a WHO clinical performance score 0-2, adequate renal and liver function, no cardiac comorbidities, and no recent trauma or operation. Patients were randomly assigned (1: 1) to receive two cycles of induction therapy with daunorubicin (60 mg/m(2) on days 3-5) plus cytarabine (100 mg/m(2) on days 1-7), followed by three cycles of high-dose cytarabine consolidation therapy (3 g/m(2) twice daily on days 1, 3, and 5) plus either sorafenib (400 mg twice daily) or placebo on days 10-19 of induction cycles 1 and 2, from day 8 of each consolidation, and as maintenance for 12 months. Allogeneic stem-cell transplantation was scheduled for all intermediate-risk patients with a sibling donor and for all high-risk patients with a matched donor in first remission. Computer-generated randomisation was done in blocks. The primary endpoint was event-free survival, with an event defined as either primary treatment failure or relapse or death, assessed in all randomised patients who received at least one dose of study treatment. We report the final analysis. This trial is registered with ClinicalTrials. gov, number NCT00893373, and the EU Clinical Trials Register (2008-004968-40).Findings Between March 27, 2009, and Nov 28, 2011, 276 patients were enrolled and randomised, of whom nine did not receive study medication. 267 patients were included in the primary analysis (placebo, n=133; sorafenib, n=134). With a median follow-up of 36 months (IQR 35.5-38.1), median event-free survival was 9 months (95% CI 4-15) in the placebo group versus 21 months (9-32) in the sorafenib group, corresponding to a 3-year event-free survival of 22% (95% CI 13-32) in the placebo group versus 40% (29-51) in the sorafenib group (hazard ratio [HR] 0.64, 95% CI; 0.45-0.91; p=0.013). The most common grade 3-4 adverse events in both groups were fever (71 [53%] in the placebo group vs 73 [54%] in the sorafenib group), infections (55 [41%] vs 46 [34%]), pneumonia (21 [16%] vs 20 [14%]), and pain (13 [10%] vs 15 [11%]). Grade 3 or worse adverse events that were significantly more common in the sorafenib group than the placebo group were fever (relative risk [RR] 1.54, 95% CI 1.04-2.28), diarrhoea (RR 7.89, 2.94-25.2), bleeding (RR 3.75, 1.5-10.0), cardiac events (RR 3.46, 1.15-11.8), hand-foot-skin reaction (only in sorafenib group), and rash (RR 4.06, 1.25-15.7).Interpretation In patients with acute myeloid leukaemia aged 60 years or younger, the addition of sorafenib to standard chemotherapy has antileukaemic efficacy but also increased toxicity. Our findings suggest that kinase inhibitors could be a useful addition to curative treatment for acute myeloid leukaemia. Overall survival after long-term follow-up and strategies to reduce toxicity are needed to determine the future role of sorafenib in treatment of this disease.