Differentiation Syndrome Associated With Enasidenib, a Selective Inhibitor of Mutant Isocitrate Dehydrogenase 2: Analysis of a Phase 1/2 Study.
与突变异柠檬酸脱氢酶 2 的选择性抑制剂 Enasidenib 相关的分化综合征: 1/2 期研究分析。


Importance:Enasidenib mesylate, a mutant isocitrate dehydrogenase 2 (IDH2) protein inhibitor that promotes differentiation of leukemic myeloblasts, was recently approved by the US Food and Drug Administration for use in relapsed/refractory (R/R) mutant IDH2 acute myeloid leukemia (AML). During the first study of enasidenib in humans, a minority of patients with advanced myeloid neoplasms experienced unexpected signs/symptoms of a differentiation syndrome (DS), a potentially lethal entity.
Objective:To characterize IDH-inhibitor-associated DS (IDH-DS) and its effective management.
Design, Setting, and Participants:Using data obtained from a multicenter, open-label, pivotal phase 1/2 study of enasidenib, a differentiation syndrome review committee retrospectively evaluated potential cases of IDH-DS in enasidenib-treated patients with R/R AML. Data were collected between August 27, 2013, and October 14, 2016. The committee identified and agreed on signs and symptoms characteristic of IDH-DS and developed an algorithm for identification and treatment. Among 281 patients with R/R AML enrolled in the trial, the committee identified 72 patients for review based on investigator-reported cases of DS (n = 33) or reported adverse events or signs and symptoms characteristic of IDH-DS.
Interventions:Treatment with enasidenib at a dosage of 50 to 650 mg/d was evaluated during the dose-escalation phase, and a dosage of 100 mg/d was used in the phase 1 expansion and phase 2, all in continual 28-day cycles.
Main Outcomes and Measures:Unexpected adverse events of IDH-DS during the phase 1/2 study.
Results:Thirty-three of the 281 patients (11.7%) were identified as having possible or probable IDH-DS. Median age of those 33 patients was 70 years (range, 38-80 years); 20 (60.6%) were male. The most frequent manifestations were dyspnea, fever, pulmonary infiltrates, and hypoxia. Median time to onset was 30 days (range, 7-129 days). Patients who experienced IDH-DS were less likely to have less than 20% bone marrow blasts (6% vs 22%, P = .04) and more likely to have undergone fewer previous anticancer regimens (median, 1.0 [range, 1-4] vs 2.0 [range, 1-14], P = .05) at study entry than those who did not. Thirteen patients (39.4%) had concomitant leukocytosis. Isocitrate dehydrogenase differentiation syndrome was effectively managed with systemic corticosteroids. The enasidenib regimen was interrupted for 15 patients (45.5%), but permanent discontinuation of treatment was not required.
Conclusions and Relevance:Isocitrate dehydrogenase differentiation syndrome is a recognizable and potentially lethal clinical entity, occurring in approximately 12% of enasidenib-treated patients with mutant-IDH2 R/R AML. It requires prompt recognition and management. As use of mutant IDH inhibitors increases, these findings and recommendations are increasingly germane to care of patients with mutant-IDH neoplasms.
Trial Registration:clinicaltrials.gov Identifier: NCT01915498.


重要性: 甲磺酸 Enasidenib,一种促进白血病成髓细胞分化的突变型异柠檬酸脱氢酶 2 (IDH2) 蛋白抑制剂, 最近被美国食品和药物管理局批准用于复发/难治 (R/R) 突变 IDH2 急性髓细胞白血病 (AML)。在对人类进行的第一次 enasidenib 研究中,少数晚期骨髓肿瘤患者经历了一种潜在致命实体 -- 分化综合征 (DS) 的意外迹象/症状。
目的: 描述 IDH 抑制剂相关的 DS (IDH-DS) 及其有效管理。
设计、设置和参与者: 使用从多中心、开放标签、关键的 enasidenib 1/2 阶段研究中获得的数据, 一个分化综合征审查委员会回顾性评估了伊纳西丁尼治疗的 R/R AML 患者中 IDH-DS 的潜在病例。数据收集于 2013年8月27日至 2016年10月14日。委员会确定并同意 IDH-DS 的症状和体征特征,并开发了识别和治疗的算法。在参与试验的 281 名 R/R AML 患者中,委员会根据研究者报告的 DS 病例确定了 72 名患者进行审查 (n = 33) 或报告的不良事件或 IDH-DS 特征的体征和症状。
干预: 在剂量递增阶段,使用 50 到 650 mg/d 剂量的 enasidenib 进行治疗, 在第一阶段和第二阶段中使用了 100 毫克/天的剂量,所有这些都持续 28 天的周期。
主要结果和措施: 1/2 期研究期间 IDH-DS 的意外不良事件。
结果: 281 名患者中的 33 名 (11.7%) 被确定为可能或可能患有 IDH-DS。这 33 名患者的平均年龄为 70 岁 (范围为 38-80 岁); 20 名 (60.6%) 是男性。最常见的表现是呼吸困难、发热、肺部浸润和缺氧。中位发病时间为 30 天 (范围 7-129 天)。经历 IDH-DS 的患者不太可能有少于 20% 的骨髓肿瘤 (6% vs 22%,p =  。 04) 并且更有可能经历过较少的先前抗癌方案 (中位数,1.0 [范围,1-4] vs 2.0 [范围,1-14],p = ¼。 05),在研究入口比那些没有。13 名患者 (39.4%) 伴有白细胞增多。异柠檬酸脱氢酶分化综合征采用全身皮质类固醇有效治疗。15 名患者 (45.5%) 中断了 enasidenib 方案,但不需要永久停止治疗。
结论和相关性: 异柠檬酸脱氢酶分化综合征是一种可识别的、潜在致命的临床实体,发生在大约 12% 的接受 enasidenib 治疗的 mutant-IDH2 R/R AML 患者中。它需要迅速的识别和管理。随着突变 IDH 抑制剂使用的增加,这些发现和建议越来越与突变 IDH 肿瘤患者的护理密切相关。
试验注册: clinicaltrials.gov 标识符: nct01915498。


肿瘤 白血病 药物
概述  :  

2017年8月1日,美国FDA批准了Celgene的Idhifa(Enasidenib,恩西地平)上市,成为第一个针对肿瘤代谢的抗癌药物。主要用于治疗携带异柠檬酸脱氢酶2(IDH2)基因突变的成人复发或难治性急性髓系白血病。 恩西地平属于异柠檬酸脱氢酶2抑制剂,可以抑制多种促进细胞增殖的酶的活性。如果患者血液或骨髓样本中检测到了IDH2突变,便适用于接受恩西地平治疗。AML患者中携带IDH2突变的比例大约为8%-19%。 恩西地平

释    义   n. 恩西地平

例    句   Here we describe two patients with IDH2-mutant AML who had a clinical response to enasidenib followed by clinical resistance, disease progression, and a recurrent increase in circulating levels of 2HG. 在此,我们描述了2例IDH2突变的AML患者,他们用恩西地平后有临床缓解,随后出现临床耐药性、病情进展,2HG循环水平在周期性升高。