Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial.
Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial.
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DOI：
10.1182/blood.2021014901
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发表时间：
2023-01-12
期刊：
影响因子：
20.3
通讯作者：
DiNardo, Courtney D.
中科院分区：
文献类型：
--
作者：
de Botton, Stephane;Montesinos, Pau;Schuh, Andre C.;Papayannidis, Cristina;Vyas, Paresh;Wei, Andrew H.;Ommen, Hans;Semochkin, Sergey;Kim, Hee-Je;Larson, Richard A.;Koprivnikar, Jaime;Frankfurt, Olga;Thol, Felicitas;Chromik, Joerg;Byrne, Jenny;Pigneux, Arnaud;Thomas, Xavier;Salamero, Olga;Vidriales, Maria Belen;Doronin, Vadim;Doehner, Hartmut;Fathi, Amir T.;Laille, Eric;Yu, Xin;Hasan, Maroof;Martin-Regueira, Patricia;DiNardo, Courtney D.
与CCR相比，enasidenib显著改善了EFS; OS受到早期脱落和后续AML治疗的混淆。与CCR相比，Enasidenib在这个接受过大量预治疗的老年R/R突变体-IDH 2 AML人群中提供了有意义的形态学和血液学缓解。这项开放标签、随机化、III期试验（NCT 02577406）在年龄≥60岁的晚期、复发/难治性（R/R）的MUH 2-IDH 2急性髓性白血病（AML）患者中比较了恩昔地尼（一种口服IDH 2（异柠檬酸脱氢酶2）抑制剂）与传统治疗方案（CCR）与2种或3种既往AML定向治疗。患者首先被预先选择接受CCR（阿扎胞苷、中等剂量阿糖胞苷、低剂量阿糖胞苷或支持性治疗），然后随机（1：1）接受enasidenib 100 mg/d或CCR。主要终点是总生存期（OS）。次要终点包括无事件生存期（EFS）、至治疗失败时间（TTF）、总缓解率（ORR）、血液学改善（HI）和输血独立性（TI）。总体而言，319例患者被随机分配至enasidenib组（n = 158）或CCR组（n = 161）。中位年龄为71岁，中位（范围）enasidenib暴露为142天（3至1270），CCR为36天（1至1166）。1例enasidenib（0.6%）和20例CCR（12%）患者未接受随机治疗，分别有30%和43%的患者在随访期间接受了随后的AML导向治疗。Enasidenib与CCR的中位OS分别为6.5个月与6.2个月（HR [风险比]，0.86; P = 0.23）; 1年生存率分别为37.5%与26.1%。Enasidenib显著改善EFS（中位数，CCR组为4.9 vs 2.6个月; HR，0.68; P = .008），TTF（中位数，4.9 vs 1.9个月; HR，0.53; P < .001），ORR（40.5% vs 9.9%; P <.001），HI（42.4% vs 11.2%）和红细胞（RBC）-TI（31.7% vs 9.3%）。Enasidenib的安全性与之前的报告一致。未达到主要研究终点，但OS受到早期脱落和随后AML导向治疗的混淆。Enasidenib在这种经过大量预治疗的老年mu-IDH 2 R/R AML人群中提供了有意义的EFS、TTF、ORR、HI和RBC-TI获益。de Botton及其同事报告了一项随机化3期研究的结果，该研究评估了IDH 2靶向治疗enasidenib与传统疗法相比在复发性IDH 2突变急性髓性白血病（AML）中的获益。与传统治疗相比，这项开放标签研究证明了enasidenib在多个次要终点（无事件生存期、缓解率、不依赖输血）方面的临床重要改善。然而，没有明显的生存获益，可能反映了与设计和挽救治疗相关的混杂因素。
EFS was meaningfully improved with enasidenib vs CCR; OS was confounded by early dropout and use of subsequent AML therapies. Enasidenib provided meaningful morphologic and hematologic responses vs CCR in this heavily pretreated older R/R mutant-IDH2 AML population. This open-label, randomized, phase 3 trial (NCT02577406) compared enasidenib, an oral IDH2 (isocitrate dehydrogenase 2) inhibitor, with conventional care regimens (CCRs) in patients aged ≥60 years with late-stage, mutant-IDH2 acute myeloid leukemia (AML) relapsed/refractory (R/R) to 2 or 3 prior AML-directed therapies. Patients were first preselected to a CCR (azacitidine, intermediate-dose cytarabine, low-dose cytarabine, or supportive care) and then randomized (1:1) to enasidenib 100 mg per day or CCR. The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), time to treatment failure (TTF), overall response rate (ORR), hematologic improvement (HI), and transfusion independence (TI). Overall, 319 patients were randomized to enasidenib (n = 158) or CCR (n = 161). The median age was 71 years, median (range) enasidenib exposure was 142 days (3 to 1270), and CCR was 36 days (1 to 1166). One enasidenib (0.6%) and 20 CCR (12%) patients received no randomized treatment, and 30% and 43%, respectively, received subsequent AML-directed therapies during follow-up. The median OS with enasidenib vs CCR was 6.5 vs 6.2 months (HR [hazard ratio], 0.86; P = .23); 1-year survival was 37.5% vs 26.1%. Enasidenib meaningfully improved EFS (median, 4.9 vs 2.6 months with CCR; HR, 0.68; P = .008), TTF (median, 4.9 vs 1.9 months; HR, 0.53; P < .001), ORR (40.5% vs 9.9%; P <.001), HI (42.4% vs 11.2%), and red blood cell (RBC)-TI (31.7% vs 9.3%). Enasidenib safety was consistent with prior reports. The primary study endpoint was not met, but OS was confounded by early dropout and subsequent AML-directed therapies. Enasidenib provided meaningful benefits in EFS, TTF, ORR, HI, and RBC-TI in this heavily pretreated older mutant-IDH2 R/R AML population. de Botton and colleagues report on results of a randomized phase 3 study evaluating the benefit of the IDH2-targeted therapy enasidenib vs conventional therapies in relapsed IDH2-mutated acute myeloid leukemia (AML). Compared with conventional care, this open-label study demonstrates clinically important improvements in multiple secondary endpoints (event-free survival, response rates, transfusion independent) with enasidenib. However, no survival benefit is evident, likely reflecting confounding factors related to design and salvage therapies.
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影响因子：
20.3
作者：
Vardiman, James W.;Thiele, Juergen;Bloomfield, Clara D.
通讯作者：
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