Somatic gene mutation patterns and burden influence outcomes with enasidenib in relapsed/refractory IDH2-mutated AML

IF 2.1 4区 医学 Q3 HEMATOLOGY Leukemia research Pub Date : 2024-03-27 DOI:10.1016/j.leukres.2024.107497
Alberto Risueño , Wendy L. See , Iryna Bluemmert , Stéphane de Botton , Courtney D. DiNardo , Amir T. Fathi , Andre C. Schuh , Pau Montesinos , Paresh Vyas , Thomas Prebet , Anita Gandhi , Maroof Hasan
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Abstract

Limited treatment options are available for patients with relapsed/refractory acute myeloid leukemia (R/R AML). We recently reported results from the phase 3 IDHENTIFY trial (NCT02577406) showing improved response rates and event-free survival with enasidenib monotherapy compared with conventional care regimens (CCR) in heavily pretreated, older patients with late-stage R/R AML bearing IDH2 mutations. Here we investigated the prognostic impact of mutational burden and different co-mutation patterns at study entry within the predominant IDH2 variant subclasses, IDH2-R140 and IDH2-R172. The prognostic relevance of these variants is well documented in newly diagnosed AML, but data are lacking in R/R AML. In this large R/R AML patient cohort, targeted next-generation sequencing at baseline (screening) revealed distinct co-mutation patterns and mutational burden between subgroups bearing different IDH2 variants: variant IDH2-R140 was associated with greater mutational burden and was enriched predominantly with poor-risk mutations, including FLT3, RUNX1, and NRAS, while variant IDH2-R172 was associated with lower mutational burden and was preferentially co-mutated with DNMT3A. In multivariable analyses, RAS and RTK pathway mutations were significantly associated with decreased overall survival, after adjusting for treatment arm, IDH2 variant, and mutational burden. Importantly, enasidenib-mediated survival benefit was more pronounced in patients with IDH2-R172 variants.

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体细胞基因突变模式和负担影响依那西尼治疗复发/难治性IDH2突变急性髓细胞白血病的疗效
复发/难治性急性髓性白血病(R/R AML)患者的治疗方案有限。我们最近报告了3期IDHENTIFY试验(NCT02577406)的结果,显示与常规治疗方案(CCR)相比,依那西尼单药治疗重度预处理、年龄较大、携带IDH2突变的晚期R/R AML患者的反应率和无事件生存期均有所提高。在此,我们研究了突变负荷的预后影响,以及研究开始时在主要的IDH2变异亚类(IDH2-R140和IDH2-R172)中不同的共突变模式。在新诊断的急性髓细胞性白血病中,这些变异的预后相关性已得到充分证实,但在R/R急性髓细胞性白血病中却缺乏相关数据。在这一大型R/R AML患者队列中,基线(筛查)定向下一代测序揭示了携带不同IDH2变体的亚组之间不同的共突变模式和突变负荷:变体IDH2-R140与更大的突变负荷相关,并主要富集于低风险突变,包括FLT3、RUNX1和NRAS;而变体IDH2-R172与较低的突变负荷相关,并优先与DNMT3A共突变。在多变量分析中,在调整治疗方案、IDH2变异体和突变负荷后,RAS和RTK通路突变与总生存率下降显著相关。重要的是,依那西尼介导的生存获益在IDH2-R172变异患者中更为明显。
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来源期刊
Leukemia research
Leukemia research 医学-血液学
CiteScore
4.00
自引率
3.70%
发文量
259
审稿时长
1 months
期刊介绍: Leukemia Research an international journal which brings comprehensive and current information to all health care professionals involved in basic and applied clinical research in hematological malignancies. The editors encourage the submission of articles relevant to hematological malignancies. The Journal scope includes reporting studies of cellular and molecular biology, genetics, immunology, epidemiology, clinical evaluation, and therapy of these diseases.
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