BACKGROUND Outcomes for younger patients with acute myeloid leukaemia have moderately improved over the past two decades owing to better supportive care and recent introduction of novel targeted agents. Blocking PD-1 and its ligand's pathways enhances antileukaemia responses by enabling T cells in murine models. We aimed to assess the addition of nivolumab to frontline therapy with idarubicin and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome. METHODS This single-arm, phase 2 part of the phase 1-2 study of nivolumab in combination with idarubicin and cytarabine was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible patients were aged 18-60 years (or >60 years if suitable for intensive chemotherapy), and had newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, and an Eastern Cooperative Oncology Group performance status of 0-2. Induction included cytarabine 1·5 g/m2 by 24-h continuous infusion daily on days 1-4 (3 days in patients >60 years) and idarubicin 12 mg/m2 daily on days 1-3. Nivolumab 3 mg/kg was started on day 24 (range 22-26) and continued every 2 weeks for up to a year in responders. Responders received either up to five consolidation cycles of attenuated doses of idarubicin and cytarabine, or allogeneic stem cell transplantation if eligible. The primary endpoint was event-free survival. Efficacy and safety analyses were done in all patients who received at least one dose of study treatment. Secondary endpoints were relapse-free survival and overall survival. This ongoing trial is registered with ClinicalTrials.gov, number NCT02464657. FINDINGS Between Aug 7, 2015, and June 2, 2018, 44 patients were enrolled of whom 22 (50%) had adverse genetic risk by European Leukaemia Network classification. All patients were evaluable for safety and efficacy. At a median follow-up of 17·25 months (IQR 0·50-30·40), median event-free survival was not reached (95% CI 7·93-NR). Median relapse-free survival of responders was 18·54 months (95% CI 8·20-23·22). The median overall survival was 18·54 months (95% CI 10·81-28·81). Six patients had seven grade 3-4 immune-related adverse events with two cases of rash, two of colitis, and one each of transaminitis, pancreatitis, and cholecystitis. 19 (43%) of 44 patients achieved a response and proceeded to allogeneic stem cell transplantation, with grade 3-4 graft-versus-host disease observed in five (26%). No treatment related deaths were attributed to nivolumab. INTERPRETATION Addition of nivolumab to induction chemotherapy with idarubicin and cytarabine is feasible in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome. Post-transplant severe graft-versus-host disease could be improved, and earlier initiation of checkpoint inhibitor therapy is warranted in future studies. FUNDING The MD Anderson Cancer Center Support Grant CA016672, and the MD Anderson Cancer Center Leukaemia SPORE CA100632 from the National Cancer Institute, Bristol Myers Squibb.

中文翻译：

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新诊断为急性髓细胞性白血病或高危骨髓增生异常综合症的患者中的依达比星，阿糖胞苷和尼古拉单抗：一项单臂，2期研究。

背景技术由于更好的支持治疗和新近引入的新型靶向药物，在过去的二十年中，年轻的急性髓细胞性白血病患者的治疗效果已有一定程度的改善。通过在鼠模型中启用T细胞，阻断PD-1及其配体的途径可增强抗白血病反应。我们的目的是评估新诊断为急性髓细胞性白血病或高危骨髓增生异常综合征的患者，在依达比星和阿糖胞苷的一线治疗中加用诺和单抗。方法在美国德克萨斯州大学MD安德森癌症中心（美国德克萨斯州休斯顿），完成了纳武单抗联合伊达比星和阿糖胞苷的1-2期研究的单臂2期研究。符合条件的患者年龄为18-60岁（如果适合强化化疗，则为60岁以上），并且新诊断为急性髓细胞性白血病或高危骨髓增生异常综合症，并且东部合作肿瘤小组的工作状态为0-2。诱导包括在第1-4天每天24小时连续输注阿糖胞苷1·5 g / m2（> 60岁的患者为3天）和在第1-3天每天每天使用阿达比星12 mg / m2。Nivolumab 3 mg / kg从第24天开始服用（范围22-26），在应答者中每2周持续服用长达一年。响应者接受减毒剂量达达比星和阿糖胞苷的多达五个巩固周期，或接受同种异体干细胞移植（如果符合条件）。主要终点是无事件生存。对接受至少一剂研究治疗药物的所有患者进行疗效和安全性分析。次要终点是无复发生存期和总体生存期。该正在进行的试验已在ClinicalTrials.gov上注册，编号为NCT02464657。结果在2015年8月7日至2018年6月2日之间，根据欧洲白血病网络分类，入组44例患者，其中22例（50％）有不良遗传风险。所有患者的安全性和有效性均可以评估。在中位随访17·25个月（IQR 0·50-30·40）时，未达到中位无事件生存期（95％CI 7·93-NR）。应答者的无复发中位生存期为18·54个月（95％CI 8·20-23·22）。中位总生存期为18·54个月（95％CI 10·81-28·81）。6例患者发生7例3-4级免疫相关不良事件，其中2例出现皮疹，2例是结肠炎，而每例分别是转氨酶，胰腺炎和胆囊炎。44例患者中有19例（43％）达到了应答并进行了同种异体干细胞移植，在5例（26％）中观察到3-4级移植物抗宿主病。没有与治疗有关的死亡归因于nivolumab。解释对于新诊断为急性髓性白血病或高危骨髓增生异常综合征的患者，在依达比星和阿糖胞苷的诱导化疗中加用纳武单抗是可行的。移植后严重的移植物抗宿主病可以得到改善，在未来的研究中有必要提早开始检查点抑制剂治疗。资金来自美国国家癌症研究所布里斯托尔·迈尔斯·斯奎布（Bristol Myers Squibb）的MD安德森癌症中心支持Grant CA016672和MD安德森癌症中心白血病SPORE CA100632。解释对于新诊断为急性髓性白血病或高危骨髓增生异常综合征的患者，在依达比星和阿糖胞苷的诱导化疗中加用纳武单抗是可行的。移植后严重的移植物抗宿主病可以得到改善，在未来的研究中有必要提早开始检查点抑制剂治疗。资金来自美国国家癌症研究所布里斯托尔·迈尔斯·斯奎布（Bristol Myers Squibb）的MD安德森癌症中心支持Grant CA016672和MD安德森癌症中心白血病SPORE CA100632。解释对于新诊断为急性髓性白血病或高危骨髓增生异常综合征的患者，在依达比星和阿糖胞苷的诱导化疗中加用纳武单抗是可行的。移植后严重的移植物抗宿主病可以得到改善，并且在未来的研究中有必要提早开始检查点抑制剂治疗。资金来自美国国家癌症研究所布里斯托尔·迈尔斯·斯奎布（Bristol Myers Squibb）的MD安德森癌症中心支持Grant CA016672和MD安德森癌症中心白血病SPORE CA100632。