Response to trametinib treatment in progressive pediatric low-grade glioma patients.
Response to trametinib treatment in progressive pediatric low-grade glioma patients.
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对进行性小儿低度神经胶质瘤患者的曲敏尼治疗的反应。
DOI：
10.1007/s11060-020-03640-3
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发表时间：
2020-09
影响因子：
3.9
通讯作者：
Milde T
中科院分区：
文献类型：
--
作者：
Selt F;van Tilburg CM;Bison B;Sievers P;Harting I;Ecker J;Pajtler KW;Sahm F;Bahr A;Simon M;Jones DTW;Well L;Mautner VF;Capper D;Hernáiz Driever P;Gnekow A;Pfister SM;Witt O;Milde T
儿童低级别胶质瘤(PLGG)的一个特征是丝裂原活化蛋白激酶(MAPK)通路的信号异常。因此，使用小分子抑制剂如MEK抑制剂(Meki)来抑制MAPK信号转导可能是一种很有前途的策略。在这项多中心回顾性集中回顾研究中，我们分析了2015至2019年间18名接受Meki曲美替尼治疗进展性pLGG的患者作为个人治疗决定。我们根据中心放射学综述、分子分类和研究者观察到的毒性来研究放射反应。我们观察到6个部分应答(PR)、2个轻微应答(MR)和10个稳定疾病(SD)是最好的总体应答。治疗后疾病控制率(DCR)为100%。在KIAA1549：BRAF-以及神经纤维瘤病1型(NF1)驱动的肿瘤中观察到了反应。中位治疗时间为12.5个月(范围：2~27个月)。有3名患者在曲美替尼停止治疗后的中位时间为3(2-4)个月内观察到疾病进展。16/18例患者发生了与治疗相关的不良事件(89%)。18例患者中有8例(44%)出现严重不良反应(CTCAE III和/或IV；最常见的是皮疹和甲皱)，6/18例患者(33%)需要减少剂量，2/18例患者(11%)停止治疗。曲美替尼是治疗进展性pLGG的一种积极和可行的治疗方法，可使所有患者的疾病得到控制。然而，治疗相关的毒性干扰了个别患者的治疗，并且在Meki停药后的疾病控制在一小部分患者中没有持续。我们的数据支持Meki在pLGGs中的类内疗效，以及曲美替尼与当前标准化疗方案进行预先随机试验的必要性。
A hallmark of pediatric low-grade glioma (pLGG) is aberrant signaling of the mitogen activated protein kinase (MAPK) pathway. Hence, inhibition of MAPK signaling using small molecule inhibitors such as MEK inhibitors (MEKi) may be a promising strategy. In this multi-center retrospective centrally reviewed study, we analyzed 18 patients treated with the MEKi trametinib for progressive pLGG as an individual treatment decision between 2015 and 2019. We have investigated radiological response as per central radiology review, molecular classification and investigator observed toxicity. We observed 6 partial responses (PR), 2 minor responses (MR), and 10 stable diseases (SD) as best overall responses. Disease control rate (DCR) was 100% under therapy. Responses were observed in KIAA1549:BRAF- as well as neurofibromatosis type 1 (NF1)-driven tumors. Median treatment time was 12.5 months (range: 2 to 27 months). Progressive disease was observed in three patients after cessation of trametinib treatment within a median time of 3 (2–4) months. Therapy related adverse events occurred in 16/18 patients (89%). Eight of 18 patients (44%) experienced severe adverse events (CTCAE III and/or IV; most commonly skin rash and paronychia) requiring dose reduction in 6/18 patients (33%), and discontinuation of treatment in 2/18 patients (11%). Trametinib was an active and feasible treatment for progressive pLGG leading to disease control in all patients. However, treatment related toxicity interfered with treatment in individual patients, and disease control after MEKi withdrawal was not sustained in a fraction of patients. Our data support in-class efficacy of MEKi in pLGGs and necessity for upfront randomized testing of trametinib against current standard chemotherapy regimens.
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影响因子：
64.8
作者：
Capper D;Jones DTW;Sill M;Hovestadt V;Schrimpf D;Sturm D;Koelsche C;Sahm F;Chavez L;Reuss DE;Kratz A;Wefers AK;Huang K;Pajtler KW;Schweizer L;Stichel D;Olar A;Engel NW;Lindenberg K;Harter PN;Braczynski AK;Plate KH;Dohmen H;Garvalov BK;Coras R;Hölsken A;Hewer E;Bewerunge-Hudler M;Schick M;Fischer R;Beschorner R;Schittenhelm J;Staszewski O;Wani K;Varlet P;Pages M;Temming P;Lohmann D;Selt F;Witt H;Milde T;Witt O;Aronica E;Giangaspero F;Rushing E;Scheurlen W;Geisenberger C;Rodriguez FJ;Becker A;Preusser M;Haberler C;Bjerkvig R;Cryan J;Farrell M;Deckert M;Hench J;Frank S;Serrano J;Kannan K;Tsirigos A;Brück W;Hofer S;Brehmer S;Seiz-Rosenhagen M;Hänggi D;Hans V;Rozsnoki S;Hansford JR;Kohlhof P;Kristensen BW;Lechner M;Lopes B;Mawrin C;Ketter R;Kulozik A;Khatib Z;Heppner F;Koch A;Jouvet A;Keohane C;Mühleisen H;Mueller W;Pohl U;Prinz M;Benner A;Zapatka M;Gottardo NG;Driever PH;Kramm CM;Müller HL;Rutkowski S;von Hoff K;Frühwald MC;Gnekow A;Fleischhack G;Tippelt S;Calaminus G;Monoranu CM;Perry A;Jones C;Jacques TS;Radlwimmer B;Gessi M;Pietsch T;Schramm J;Schackert G;Westphal M;Reifenberger G;Wesseling P;Weller M;Collins VP;Blümcke I;Bendszus M;Debus J;Huang A;Jabado N;Northcott PA;Paulus W;Gajjar A;Robinson GW;Taylor MD;Jaunmuktane Z;Ryzhova M;Platten M;Unterberg A;Wick W;Karajannis MA;Mittelbronn M;Acker T;Hartmann C;Aldape K;Schüller U;Buslei R;Lichter P;Kool M;Herold-Mende C;Ellison DW;Hasselblatt M;Snuderl M;Brandner S;Korshunov A;von Deimling A;Pfister SM
通讯作者：
Pfister SM
影响因子：
3.9
作者：
Driever, Pablo Hernaiz;von Hornstein, Stephan;Gnekow, Astrid K.
通讯作者：
Gnekow, Astrid K.
影响因子：
15.9
作者：
Gnekow, Astrid K.;Falkenstein, Fabian;Faldum, Andreas
通讯作者：
Faldum, Andreas
DOI：
10.1056/nejmoa1605943
发表时间：
2016-12-29
期刊：
The New England journal of medicine
影响因子：
--
作者：
Dombi E;Baldwin A;Marcus LJ;Fisher MJ;Weiss B;Kim A;Whitcomb P;Martin S;Aschbacher-Smith LE;Rizvi TA;Wu J;Ershler R;Wolters P;Therrien J;Glod J;Belasco JB;Schorry E;Brofferio A;Starosta AJ;Gillespie A;Doyle AL;Ratner N;Widemann BC
通讯作者：
Widemann BC
影响因子：
51.1
作者：
Infante, Jeffrey R.;Fecher, Leslie A.;Messersmith, Wells A.
通讯作者：
Messersmith, Wells A.