Background

Mutations in isocitrate dehydrogenase-2 (IDH2) occur in around 5% of patients with myelodysplastic syndromes. Neomorphic activity of mutant IDH2 proteins results in hypermethylation of DNA and histones, leading to blocked haemopoietic differentiation. Enasidenib, an inhibitor of mutated IDH2 proteins, induces responses in patients with IDH2-mutated, relapsed or refractory acute myeloid leukaemia. We aimed to establish the clinical outcomes of enasidenib monotherapy in a subgroup of patients with myelodysplastic syndromes harbouring mutations in IDH2 from the AG221-C-001 trial.

Methods

The multicentre, open-label, phase 1–2 AG221-C-001 trial enrolled patients with advanced haematological malignancies (2008 WHO criteria) harbouring an IDH2 mutation. The present study is a subgroup analysis of patients with IDH2-mutated myelodysplastic syndromes in the phase 1 dose-escalation and expansion portions of the trial. Patients with myelodysplastic syndromes were aged 18 years or older with an ECOG performance status score of 2 or lower, and were relapsed or refractory to, or ineligible for, standard treatments. Patients received oral doses of enasidenib at 60–300 mg per day in repeated 28-day treatment cycles. In this subgroup analysis, we focused on the safety and activity of enasidenib as main outcomes. Overall response rate, duration of response, and overall and event-free survival analyses were by intention-to-treat. Safety was assessed in all participants who received at least one dose of study drug in terms of treatment-emergent adverse events. The AG221-C-001 trial is registered on ClinicalTrials.gov, NCT01915498, status ongoing but closed to recruitment.

Findings

17 patients with myelodysplastic syndromes harbouring an IDH2 mutation (median age, 67·0 years [IQR 60·5–73·0]) were enrolled between Feb 18, 2014, and Sept 1, 2015. At data cutoff (Oct 1, 2018), after a median follow-up of 11·0 months (IQR 6·8–23·0), all patients had discontinued enasidenib, with a median of 3 treatment cycles (2–15) for all patients (five [29%] received ≥12 cycles). At entry, three (18%) patients had relapsed after allogeneic stem-cell transplants, 13 (76%) had previously received therapy with hypomethylating agents, and ten (59%) had received at least two previous therapies. No dose-limiting toxicities were reported. The most common treatment-emergent adverse events were diarrhoea and nausea (in nine [53%] patients each). Most common grade 3–4 treatment-emergent adverse events were indirect hyperbilirubinaemia (in six [35%] patients), pneumonia (in five [29%] patients), and thrombocytopaenia (in four [24%] patients). Serious treatment-emergent adverse events in more than one patient were pneumonia (in five [29% patients); tumor lysis syndrome (in three [18%] patients); and sepsis, atrial flutter, indirect hyperbilirubinaemia, cerebral hemorrhage, and mental status change (in two [12%] patients each). No treatment-related deaths occurred. An overall response was achieved in 9 patients (53% [95% CI 28–77]), with a median duration of response of 9·2 months (95% CI 1·0–not reached). Six (46%) of 13 patients previously treated with hypomethylating agents responded. Median overall survival was 16·9 months (95% CI 1·5–32·3), and median event-free survival was 11·0 months (1·5–16·7).

Interpretation

Enasidenib is generally well tolerated and can induce responses in patients with mutant IDH2 myelodysplastic syndromes, including in those who have had previous therapy with hypomethylating agents. Testing for IDH2 mutations in myelodysplastic syndromes is essential for identifying patients who might benefit from enasidenib therapy, including those patients in whom conventional treatments have been unsuccessful.

Funding

Celgene and Agios Pharmaceuticals.

中文翻译：

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Enasidenib 治疗突变 IDH2 骨髓增生异常综合征患者：多中心 AG221-C-001 试验的 1 期亚组分析。

背景

大约 5% 的骨髓增生异常综合征患者发生异柠檬酸脱氢酶 2 ( IDH2 ) 突变。突变 IDH2 蛋白的新形态活性导致 DNA 和组蛋白的高甲基化，导致造血分化受阻。Enasidenib 是一种突变 IDH2 蛋白的抑制剂，可在 IDH2 突变、复发或难治性急性髓性白血病患者中诱导反应。我们旨在确定 enasidenib 单药治疗在AG221-C-001 试验中携带IDH2突变的骨髓增生异常综合征患者亚组的临床结果。

方法

多中心、开放标签、1-2 期 AG221-C-001 试验招募了携带IDH2突变的晚期血液系统恶性肿瘤（2008 年 WHO 标准）患者。本研究是对IDH2患者的亚组分析-在试验的 1 期剂量递增和扩展部分中发生突变的骨髓增生异常综合征。患有骨髓增生异常综合征的患者年龄在 18 岁或以上，ECOG 体能状态评分为 2 或更低，并且复发或难治或不适合标准治疗。在重复的 28 天治疗周期中，患者每天接受 60-300 mg 的 enasidenib 口服剂量。在该亚组分析中，我们将依那西尼的安全性和活性作为主要结果。总体缓解率、缓解持续时间以及总体和无事件生存分析是通过意向治疗进行的。就治疗出现的不良事件而言，对所有接受至少一剂研究药物的参与者的安全性进行了评估。AG221-C-001 试验已在 ClinicalTrials.gov 上注册，NCT01915498，

发现

17 名携带IDH2的骨髓增生异常综合征患者突变（中位年龄，67·0 岁 [IQR 60·5–73·0]）在 2014 年 2 月 18 日至 2015 年 9 月 1 日期间入组。在数据截止（2018 年 10 月 1 日），中位随访后在 11·0 个月 (IQR 6·8–23·0) 中，所有患者都停用了 enasidenib，所有患者的中位治疗周期为 3 个治疗周期 (2–15)（5 [29%] 接受≥12 个周期）。入组时，3 名 (18%) 患者在异基因干细胞移植后复发，13 名 (76%) 之前接受过低甲基化药物治疗，10 名 (59%) 之前接受过至少两种治疗。没有报告剂量限制性毒性。最常见的治疗引起的不良事件是腹泻和恶心（各有 9 名 [53%] 患者发生）。最常见的 3-4 级治疗出现的不良事件是间接高胆红素血症（6 名 [35%] 患者）、肺炎（5 名 [29%] 患者）、和血小板减少症（四名 [24%] 患者）。不止一名患者出现严重的治疗相关不良事件是肺炎（5 名 [29% 患者）；肿瘤溶解综合征（三名 [18%] 患者）；和败血症、心房扑动、间接高胆红素血症、脑出血和精神状态改变（各有 2 名 [12%] 患者）。没有发生与治疗相关的死亡。9 名患者（53% [95% CI 28-77]）实现了总体缓解，中位缓解持续时间为 9·2 个月（95% CI 1·0–未达到）。之前接受过低甲基化药物治疗的 13 名患者中有 6 名（46%）有反应。中位总生存期为 16·9 个月 (95% CI 1·5–32·3)，中位无事件生存期为 11·0 个月 (1·5–16·7)。肿瘤溶解综合征（三名 [18%] 患者）；和败血症、心房扑动、间接高胆红素血症、脑出血和精神状态改变（各有 2 名 [12%] 患者）。没有发生与治疗相关的死亡。9 名患者（53% [95% CI 28-77]）实现了总体缓解，中位缓解持续时间为 9·2 个月（95% CI 1·0–未达到）。之前接受过低甲基化药物治疗的 13 名患者中有 6 名（46%）有反应。中位总生存期为 16·9 个月 (95% CI 1·5–32·3)，中位无事件生存期为 11·0 个月 (1·5–16·7)。肿瘤溶解综合征（三名 [18%] 患者）；和败血症、心房扑动、间接高胆红素血症、脑出血和精神状态改变（各有 2 名 [12%] 患者）。没有发生与治疗相关的死亡。9 名患者（53% [95% CI 28-77]）实现了总体缓解，中位缓解持续时间为 9·2 个月（95% CI 1·0–未达到）。之前接受过低甲基化药物治疗的 13 名患者中有 6 名（46%）有反应。中位总生存期为 16·9 个月 (95% CI 1·5–32·3)，中位无事件生存期为 11·0 个月 (1·5–16·7)。中位缓解持续时间为 9·2 个月（95% CI 1·0–未达到）。之前接受过低甲基化药物治疗的 13 名患者中有 6 名（46%）有反应。中位总生存期为 16·9 个月 (95% CI 1·5–32·3)，中位无事件生存期为 11·0 个月 (1·5–16·7)。中位缓解持续时间为 9·2 个月（95% CI 1·0–未达到）。之前接受过低甲基化药物治疗的 13 名患者中有 6 名（46%）有反应。中位总生存期为 16·9 个月 (95% CI 1·5–32·3)，中位无事件生存期为 11·0 个月 (1·5–16·7)。

解释

Enasidenib 通常具有良好的耐受性，并且可以在患有突变IDH2骨髓增生异常综合征的患者中诱导反应，包括之前接受过低甲基化药物治疗的患者。检测骨髓增生异常综合征中的IDH2突变对于识别可能从 enasidenib 治疗中受益的患者至关重要，包括那些常规治疗不成功的患者。

资金

Celgene 和 Agios 制药公司。