Amatangelo Michael D, Quek Lynn, Shih Alan, Stein Eytan M, Roshal Mikhail, David Muriel D, Marteyn Benoit, Farnoud Noushin Rahnamay, de Botton Stephane, Bernard Olivier A, Wu Bin, Yen Katharine E, Tallman Martin S, Papaemmanuil Elli, Penard-Lacronique Virginie, Thakurta Anjan, Vyas Paresh, Levine Ross L
Celgene Corporation, Summit, NJ.
Medical Research Council Molecular Hematology Unit, Oxford Comprehensive Biomedical Research Centre, Weatherall Institute of Molecular Medicine, and Department of Hematology, Oxford University Hospital National Health Service Foundation Trust, University of Oxford, Oxford, United Kingdom.
Blood. 2017 Aug 10;130(6):732-741. doi: 10.1182/blood-2017-04-779447. Epub 2017 Jun 6.
Recurrent mutations at R140 and R172 in isocitrate dehydrogenase 2 () occur in many cancers, including ∼12% of acute myeloid leukemia (AML). In preclinical models these mutations cause accumulation of the oncogenic metabolite -2-hydroxyglutarate (2-HG) and induce hematopoietic differentiation block. Single-agent enasidenib (AG-221/CC-90007), a selective mutant IDH2 (mIDH2) inhibitor, produced an overall response rate of 40.3% in relapsed/refractory AML (rrAML) patients with m in a phase 1 trial. However, its mechanism of action and biomarkers associated with response remain unclear. Here, we measured 2-HG, m allele burden, and co-occurring somatic mutations in sequential patient samples from the clinical trial and correlated these with clinical response. Furthermore, we used flow cytometry to assess inhibition of mIDH2 on hematopoietic differentiation. We observed potent 2-HG suppression in both R140 and R172 m AML subtypes, with different kinetics, which preceded clinical response. Suppression of 2-HG alone did not predict response, because most nonresponding patients also exhibited 2-HG suppression. Complete remission (CR) with persistence of m and normalization of hematopoietic stem and progenitor compartments with emergence of functional m neutrophils were observed. In a subset of CR patients, m allele burden was reduced and remained undetectable with response. Co-occurring mutations in NRAS and other MAPK pathway effectors were enriched in nonresponding patients, consistent with RAS signaling contributing to primary therapeutic resistance. Together, these data support differentiation as the main mechanism of enasidenib efficacy in relapsed/refractory AML patients and provide insight into resistance mechanisms to inform future mechanism-based combination treatment studies.
异柠檬酸脱氢酶2（IDH2）的R140和R172位点反复发生的突变见于多种癌症，包括约12%的急性髓系白血病（AML）。在临床前模型中，这些突变导致致癌代谢物-2-羟基戊二酸（2-HG）蓄积，并诱导造血分化阻滞。单药enasidenib（AG-221/CC-90007）是一种选择性突变IDH2（mIDH2）抑制剂，在一项1期试验中，其在复发/难治性AML（rrAML）伴mIDH2突变的患者中产生的总缓解率为40.3%。然而，其作用机制以及与反应相关的生物标志物仍不清楚。在此，我们检测了来自该临床试验的连续患者样本中的2-HG、mIDH2等位基因负担和同时发生的体细胞突变，并将这些与临床反应相关联。此外，我们使用流式细胞术评估mIDH2对造血分化的抑制作用。我们观察到在R140和R172 mIDH2突变的AML亚型中均有强效的2-HG抑制，其动力学不同，且发生在临床反应之前。单独抑制2-HG并不能预测反应，因为大多数无反应的患者也表现出2-HG抑制。观察到有患者达到完全缓解（CR），mIDH2持续存在，造血干细胞和祖细胞区室正常化，出现功能性mIDH2野生型中性粒细胞。在部分CR患者中，mIDH2等位基因负担降低，且随着反应持续不可检测。NRAS和其他MAPK通路效应器中的同时发生的突变在无反应患者中富集，这与RAS信号传导导致原发性治疗耐药一致。总之，这些数据支持分化是enasidenib在复发/难治性AML患者中发挥疗效的主要机制，并为耐药机制提供了见解，为未来基于机制的联合治疗研究提供参考。
