Persistent IDH mutations are not associated with increased relapse or death in patients with IDH-mutated acute myeloid leukemia undergoing allogeneic hematopoietic cell transplant with post-transplant cyclophosphamide.
Persistent IDH mutations are not associated with increased relapse or death in patients with IDH-mutated acute myeloid leukemia undergoing allogeneic hematopoietic cell transplant with post-transplant cyclophosphamide.
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对于接受移植后环磷酰胺的同种异体造血细胞移植的 IDH 突变急性髓系白血病患者，持续 IDH 突变与复发或死亡增加无关。
DOI：
10.1101/2023.08.14.23294087
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Ambinder,AlexanderJ
中科院分区：
文献类型：
--
作者：
Ravindra,Niveditha;Dillon,LauraW;Gui,Gege;Smith,Matthew;Gondek,LukaszP;Jones,RichardJ;Corner,Adam;Hourigan,ChristopherS;Ambinder,AlexanderJ
在急性髓性白血病（AML）患者中，有大量证据表明，在治疗期间和之后，特别是在同种异体造血细胞移植（alloHCT）之前，可测量的残留病（MRD）检测可预测随后的复发和较差的生存结果[2,3]。ELN指南建议在可用的情况下使用经过验证的AML MRD分子检测，但这种监测的适当靶点尚未完全确定[10]。表观遗传调控因子异柠檬酸脱氢酶（IDH）基因突变在大约20%的AML[5]患者中被观察到。同种异体ct可以改善这类患者的预后[6,7]。为了进一步研究IDH1和IDH2突变作为AML MRD标志物的效用，我们在接受同种异体hct的AML患者队列中筛选了移植前和移植后缓解时间点检测到的这些变异。2015年至2020年期间，在约翰霍普金斯大学西德尼·基梅尔综合癌症中心接受了基于环磷酰胺的移植物抗宿主病预防的非清髓性同种异体hct治疗的idh突变AML患者获得了完全缓解（CR），并被纳入本研究。该队列的患者特征和结果之前已经报道过，但由于无法获得样本，有5名患者被排除在外（补充图1）。获得了所有患者的书面和知情同意，该研究由内部伦理委员会根据赫尔辛基宣言批准。患者在同种异体hct后随访中位数为1048天（范围：96-2413天）。基线和复发骨髓DNA样本使用75个基因的VariantPlex髓系面板（ArcherDx, Boulder, CO .）进行测序。使用液滴数字PCR （ddPCR）或定制的错误纠正靶向下一代测序面板（ecNGS）对同种异体hct缓解前和缓解后的样本进行持续IDH突变评估。补充数据1-5提供了其他临床和测试细节。55例患者可获得用于测序的基线DNA样本。临床特征见补充表1。在26例患者中分别鉴定出IDH1或IDH2突变，而其余3例患者在两个基因中都检测到突变。IDH1组（20%和17%）和IDH2组（38%和28%）的少数患者在同种异体hct后接受了IDH抑制剂。只有2例患者在移植后出现非复发死亡率。在idh1突变队列中，诊断时的中位变异等位基因频率（VAF）为35%（范围：3-49%）。我们在44.8%的样品中分别鉴定出R132H和R132C，其次是R132G（10%）和R132L（3.4%）。其中一个样本携带R132L和R132C双突变。NPM1、DNMT3A、FLT3、SRSF2和PTPN11最常与IDH1共突变（Supplementary Fig. 2）。在idh2突变队列中，R140Q突变最为常见（72.4%），其次是R172K（20.6%）和R140W（7%）。R140和R172热点诊断时的中位VAF分别为38%和31% (p= 0.65)（范围：0.4-49%和0.4-47%）。DNMT3A、FLT3、SRSF2、NPM1和BCOR是IDH2计算最多的基因（Supplementary Fig. 2）。先前有报道称，缓解期IDH1 R132和IDH2 R172突变的持续存在可能与移植后复发有关[9,10]。我们通过ddPCR和/或ecNGS对49/55例在同种异体ct前时间点有足够DNA可用的患者进行了靶向评估。
In patients with acute myeloid leukemia (AML) there is considerable evidence that suggests that measurable residual disease (MRD) detection during and after treatment [1], and particularly before allogeneic hematopoietic cell transplantation (alloHCT), predicts subsequent relapse and inferior survival outcomes [2, 3]. ELN guidelines recommend the use of validated molecular tests for AML MRD where available, but the appropriate targets for such monitoring are incompletely defined [4]. Mutations in the epigenetic regulator Isocitrate Dehydrogenase (IDH) genes are observed in approximately 20% of patients diagnosed with AML [5]. AlloHCT may improve outcomes for such patients [6, 7]. To further investigate the utility of persistent IDH1 and IDH2 mutations as AML MRD markers, we screened for the detection of these variants at pre-and post-transplant remission timepoints in a cohort of AML patients undergoing alloHCT. Consecutive adult patients between 2015 and 2020 with IDH-mutated AML who achieved complete remission (CR) and underwent non-myeloablative alloHCT with cyclophosphamidebased graft versus host disease prophylaxis at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center were included in this study. Patient characteristics and outcomes for this cohort have been previously reported [8], although five patients were excluded because samples were not available (Supplementary Fig. 1). Written and informed consent was obtained from all patients and the study was approved by the internal ethics committee in accordance with the Declaration of Helsinki. Patients were followed up for a median of 1048 days post-alloHCT (range: 96-2413 days). Baseline and relapse bone marrow DNA samples were sequenced using the 75-gene VariantPlex myeloid panel (ArcherDx, Boulder, CO). Assessment for persistent IDH mutations was performed on pre-and post-alloHCT remission samples using droplet digital PCR (ddPCR) or a custom error-corrected targeted next-generation sequencing panel (ecNGS). Additional clinical and testing details are provided in Supplementary Data 1-5. Baseline DNA samples for sequencing were available for 55 patients. Clinical characteristics are described in Supplementary Table 1. An exclusive IDH1 or IDH2 mutation was identified in 26 patients each, while the remaining 3 patients had a mutation detected in both genes. A minority of patients in the IDH1 (20 and 17%) and IDH2 cohorts (38 and 28%) received an IDH inhibitor preor post-alloHCT. Only two patients experienced non-relapse mortality after transplantation. In the IDH1-mutated cohort, the median variant allele frequency (VAF) at diagnosis was 35%(range: 3-49%). We identified R132H and R132C in 44.8% of samples each followed by R132G in 10%, and R132L in 3.4% of samples. One sample harbored double mutations with R132L and R132C. NPM1, DNMT3A, FLT3, SRSF2 and PTPN11 were most commonly co-mutated with IDH1 (Supplementary Fig. 2). In the IDH2-mutated cohort, the R140Q mutation was the most common (72.4%), followed by R172K (20.6%) and R140W (7%). The median VAF at diagnosis for the R140 and R172 hotspots were 38 and 31%, respectively (p= 0.65)(range: 0.4-49% and 0.4-47%). DNMT3A, FLT3, SRSF2, NPM1, and BCOR were the top comutated genes with IDH2 (Supplementary Fig. 2). It has previously been reported that the persistence of IDH1 R132 and IDH2 R172 mutations in remission may be associated with post-transplant relapse [9, 10]. We performed targeted assessment by ddPCR and/or ecNGS on 49/55 patients who had sufficient DNA available at the pre-alloHCT timepoint …
影响因子：
7.5
作者：
Bill, Marius;Jentzsch, Madlen;Bischof, Lara;Kohlschmidt, Jessica;Grimm, Juliane;Schmalbrock, Laura Katharina;Backhaus, Donata;Brauer, Dominic;Goldmann, Karoline;Franke, Georg -Nikolaus;Vucinic, Vladan;Niederwieser, Dietger;Mims, Alice S.;Platzbecker, Uwe;Eisfeld, Ann-Kathrin;Schwind, Sebastian
通讯作者：
Schwind, Sebastian
影响因子：
28.5
作者：
Kunadt, Desiree;Stasik, Sebastian;Metzeler, Klaus H.;Roellig, Christoph;Schliemann, Christoph;Greif, Philipp A.;Spiekermann, Karsten;Rothenberg-Thurley, Maja;Krug, Utz;Braess, Jan;Kraemer, Alwin;Hochhaus, Andreas;Scholl, Sebastian;Hilgendorf, Inken;Bruemmendorf, Tim H.;Jost, Edgar;Steffen, Bjoern;Bug, Gesine;Einsele, Hermann;Goerlich, Dennis;Sauerland, Cristina;Schaefer-Eckart, Kerstin;Krause, Stefan W.;Haenel, Mathias;Hanoun, Maher;Kaufmann, Martin;Woermann, Bernhard;Kramer, Michael;Sockel, Katja;Egger-Heidrich, Katharina;Herold, Tobias;Ehninger, Gerhard;Burchert, Andreas;Platzbecker, Uwe;Berdel, Wolfgang E.;Mueller-Tidow, Carsten;Hiddemann, Wolfgang;Serve, Hubert;Stelljes, Matthias;Baldus, Claudia D.;Neubauer, Andreas;Schetelig, Johannes;Thiede, Christian;Bornhaeuser, Martin;Middeke, Jan M.;Stoelzel, Friedrich
通讯作者：
Stoelzel, Friedrich