Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML
Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML
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DOI：
10.1056/nejmoa1716984
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发表时间：
2018-06-21
影响因子：
158.5
通讯作者：
Kantarjian, H. M.
中科院分区：
文献类型：
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作者：
DiNardo, C. D.;Stein, E. M.;Kantarjian, H. M.
研究背景编码异柠檬酸脱氢酶1（IDH 1）的基因突变发生在6%至10%的急性髓性白血病（AML）患者中。Ivosidenib（AG-120）是一种口服、靶向、小分子IDH 1突变抑制剂。方法我们进行了一项Ivosidenib单药治疗IDH 1突变AML的I期剂量递增和剂量扩展研究。在所有接受治疗的患者中评估安全性和疗效。主要疗效人群包括复发性或难治性AML患者，每天接受500 mg伊沃西地尼治疗，至少随访6个月。结果总体而言，258名患者接受了伊沃西地尼治疗，并评估了安全性结局。在复发性或难治性AML患者中（179例患者），至少3例患者发生的3级或以上治疗相关不良事件为QT间期延长（7.8%的患者），IDH分化综合征（3.9%）、贫血（2.2%）、血小板减少或血小板计数减少（3.4%）和白细胞增多（1.7%）。主要疗效人群完全缓解或完全缓解伴部分血液学恢复者125例，占30.4%（95%可信区间[CI]，22.5至39.3），完全缓解率为21.6%（95%CI，14.7至29.8），总缓解率为41.6%（95%CI，32.9至50.8）。这些缓解的中位持续时间分别为8.2个月（95% CI，5.5 - 12.0）、9.3个月（95% CI，5.6 - 18.3）和6.5个月（95% CI，4.6 - 9.3）。84例患者中有29例（35%）实现了输血独立性，有反应的患者比无反应的患者感染和发热性中性粒细胞减少症发作较少。在34例完全缓解或完全缓解伴部分血液学恢复的患者中，7例（21%）在数字聚合酶链反应检测中没有残留可检测的IDH 1突变。没有预先存在的共存的单基因突变预测临床反应或对treatment.CONCLUSIONSIn晚期IDH 1突变复发或难治性AML患者，ivosidenib在500 mg每日剂量与低频率的3级或更高的治疗相关不良事件和输血独立性，持久缓解，和分子缓解在一些完全缓解的患者.
BACKGROUNDMutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1.METHODSWe conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up.RESULTSOverall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting cooccurring single gene mutation predicted clinical response or resistance to treatment.CONCLUSIONSIn patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment- related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission.