BACKGROUND Daunorubicin and cytarabine are used as standard induction chemotherapy for patients with acute myeloid leukaemia. CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. Primary analysis of the phase 3 trial in adults aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia provided support for approval of CPX-351 by the US Food and Drug Administration and European Medicines Agency. We describe the prospectively planned final 5-year follow-up results. METHODS This randomised, open-label, multicentre, phase 3 trial was done across 39 academic and regional cancer centres in the USA and Canada. Eligible patients were aged 60-75 years and had a pathological diagnosis of acute myeloid leukaemia according to WHO 2008 criteria, no previous induction therapy for acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned 1:1 (stratified by age and acute myeloid leukaemia subtype) to receive up to two induction cycles of CPX-351 (100 units/m2 administered as a 90-min intravenous infusion on days 1, 3, and 5; on days 1 and 3 for the second induction) or standard chemotherapy (cytarabine 100 mg/m2 per day continuous intravenous infusion for 7 days plus intravenous daunorubicin 60 mg/m2 on days 1, 2, and 3 [7+3]; cytarabine for 5 days and daunorubicin on days 1 and 2 for the second induction [5+2]). Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery could receive up to tw cycles of consolidation therapy with CPX-351 (65 units/m2 90-min infusion on days 1 and 3) or chemotherapy (5+2, same dosage as in the second induction cycle). The primary outcome was overall survival analysed in all randomly assigned patients. No additional adverse events were collected with long-term follow-up, except data for deaths. This trial is registered with ClinicalTrials.gov, NCT01696084, and is complete. FINDINGS Between Dec 20, 2012, and Nov 11, 2014, 309 patients with newly diagnosed high-risk or secondary acute myeloid leukaemia were enrolled and randomly assigned to receive CPX-351 (153 patients) or 7+3 (156 patients). At a median follow-up of 60·91 months (IQR 60·06-62·98) in the CPX-351 group and 59·93 months (59·73-60·50) in the 7+3 group, median overall survival was 9·33 months (95% CI 6·37-11·86) with CPX-351 and 5·95 months (4·99-7·75) with 7+3 (HR 0·70, 95% CI 0·55-0·91). 5-year overall survival was 18% (95% CI 12-25%) in the CPX-351 group and 8% (4-13%) in the 7+3 group. The most common cause of death in both groups was progressive leukaemia (70 [56%] of 124 deaths in the CPX-351 group and 74 [53%] of 140 deaths in the 7+3 group). Six (5%) of 124 deaths in the CPX-351 group and seven (5%) of 140 deaths in the 7+3 group were considered related to study treatment. INTERPRETATION After 5 years of follow-up, the improved overall survival with CPX-351 versus 7+3 was maintained, which supports the previous evidence that CPX-351 can contribute to long-term remission and improved overall survival in patients aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia. FUNDING Jazz Pharmaceuticals.

中文翻译：

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CPX-351 与 7+3 阿糖胞苷和柔红霉素化疗在新诊断的高危或继发性急性髓系白血病老年人中的比较：一项随机、开放标签、多中心、3 期试验的 5 年结果。

背景柔红霉素和阿糖胞苷被用作急性髓系白血病患者的标准诱导化疗。CPX-351 是柔红霉素和阿糖胞苷以 1:5 摩尔比协同包封的双药脂质体。对 60-75 岁新诊断高危或继发性急性髓系白血病成人的 3 期试验的初步分析为美国食品药品监督管理局和欧洲药品管理局批准 CPX-351 提供了支持。我们描述了前瞻性计划的最终 5 年随访结果。方法 这项随机、开放标签、多中心、3 期试验在美国和加拿大的 39 个学术和地区癌症中心进行。符合条件的患者年龄为 60-75 岁，根据 WHO 2008 标准病理诊断为急性髓系白血病，之前没有急性髓系白血病的诱导治疗，并且东部肿瘤合作小组的体能状态为 0-2。患者按 1:1（按年龄和急性髓系白血病亚型分层）随机分配接受最多两个 CPX-351 诱导周期（100 单位/平方米，在第 1、3 和 5 天静脉输注 90 分钟；在第二次诱导的第 1 天和第 3 天）或标准化疗（阿糖胞苷 100 mg/m2 每天连续静脉输注 7 天，加上第 1、2 和 3 天静脉注射柔红霉素 60 mg/m2 [7+3]；阿糖胞苷用于5 天，柔红霉素在第 1 天和第 2 天进行第二次诱导 [5+2]）。完全缓解或完全缓解且中性粒细胞或血小板恢复不完全的患者可以接受最多 2 个周期的 CPX-351（第 1 天和第 3 天输注 65 单位/平方米 90 分钟）或化疗（5+2，相同剂量）的巩固治疗如在第二个诱导循环中）。主要结果是在所有随机分配的患者中分析的总生存期。除了死亡数据外，没有在长期随访中收集到额外的不良事件。该试验已在 ClinicalTrials.gov 注册，NCT01696084，并且已经完成。结果 2012 年 12 月 20 日至 2014 年 11 月 11 日期间，309 名新诊断的高危或继发性急性髓系白血病患者被纳入并随机分配接受 CPX-351（153 名患者）或 7+3（156 名患者）。CPX-351 组中位随访时间为 60·91 个月（IQR 60·06-62·98），7+3 组中位随访时间为 59·93 个月（59·73-60·50），总体中位数CPX-351 的生存期为 9·33 个月（95% CI 6·37-11·86），7+3 的生存期为 5·95 个月（4·99-7·75）（HR 0·70，95% CI 0 ·55-0·91）。CPX-351 组的 5 年总生存率为 18%（95% CI 12-25%），7+3 组为 8%（4-13%）。两组中最常见的死因是进行性白血病（CPX-351 组 124 例死亡中的 70 例 [56%] 和 7+3 组 140 例死亡中的 74 例 [53%]）。CPX-351 组 124 例死亡中有 6 例 (5%) 和 7+3 组 140 例死亡中有 7 例 (5%) 被认为与研究治疗有关。解释 经过 5 年的随访，与 7+3 相比，CPX-351 的总体生存率得以提高，这支持先前的证据，即 CPX-351 可以促进 60-75 岁新诊断的高危或继发性急性髓系白血病患者的长期缓解和改善总体生存率。资助爵士制药。