Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children's Hospital experience.
接受替莫唑胺、伊立替康和贝伐单抗治疗的 DIPG 和高级别胶质瘤患儿: 西雅图儿童医院的经验。
- 作者列表："Crotty EE","Leary SES","Geyer JR","Olson JM","Millard NE","Sato AA","Ermoian RP","Cole BL","Lockwood CM","Paulson VA","Browd SR","Ellenbogen RG","Hauptman JS","Lee A","Ojemann JG","Vitanza NA
INTRODUCTION:Beyond focal radiation, there is no consensus standard therapy for pediatric high-grade glioma (pHGG) and outcomes remain dismal. We describe the largest molecularly-characterized cohort of children with pHGG treated with a 3-drug maintenance regimen of temozolomide, irinotecan, and bevacizumab (TIB) following radiation. METHODS:We retrospectively reviewed 36 pediatric patients treated with TIB at Seattle Children's Hospital from 2009 to 2018 and analyzed survival using the Kaplan-Meier method. Molecular profiling was performed by targeted DNA sequencing and toxicities, steroid use, and palliative care utilization were evaluated. RESULTS:Median age at diagnosis was 10.9 years (18 months-18 years). Genetic alterations were detected in 26 genes and aligned with recognized molecular subgroups including H3 K27M-mutant (12), H3F3A G34-mutant (2), IDH-mutant (4), and hypermutator profiles (4). Fifteen patients (42%) completed 12 planned cycles of maintenance. Side effects associated with chemotherapy delays or modifications included thrombocytopenia (28%) and nausea/vomiting (19%), with temozolomide dosing most frequently modified. Median event-free survival (EFS) and overall survival (OS) was 16.2 and 20.1 months, with shorter survival seen in DIPG (9.3 and 13.3 months, respectively). Survival at 1, 2, and 5 years was 80%, 10% and 0% for DIPG and 85%, 38%, and 16% for other pHGG. CONCLUSION:Our single-center experience demonstrates tolerability of this 3-drug regimen, with prolonged survival in DIPG compared to historical single-agent temozolomide. pHGG survival was comparable to analogous 3-drug regimens and superior to historical agents; however, cure was rare. Children with pHGG remain excellent candidates for the study of novel therapeutics combined with standard therapy.
简介: 除了局灶性辐射，儿童高级别胶质瘤 (pHGG) 的标准治疗还没有达成共识，结局仍然令人沮丧。我们描述了最大的 pHGG 儿童分子特征队列，接受替莫唑胺、伊立替康和贝伐单抗 (TIB) 放疗后 3 种药物维持方案治疗。 方法: 我们回顾性分析了 2009 年至 2018 年在西雅图儿童医院接受 TIB 治疗的 36 例儿童患者，并使用 Kaplan-Meier 方法分析了生存率。通过靶向 DNA 测序进行分子分析，并评估毒性、类固醇使用和姑息治疗利用情况。 结果: 诊断时的中位年龄为 10.9 岁 (18 个月-18 岁)。在 26 个基因中检测到遗传改变，并与公认的分子亚组对齐，包括 H3 K27M-mutant (12) 、 H3F3A G34-mutant (2) 、 IDH 突变体 (4) 和超突变谱 (4)。15 例患者 (42%) 完成了 12 个计划周期的维持。与化疗延迟或改变相关的副作用包括血小板减少症 (28%) 和恶心/呕吐 (19%)，替莫唑胺给药最常改变。中位无事件生存期 (EFS) 和总生存期 (OS) 分别为 16.2 和 20.1 个月，其中 DIPG 的生存期较短 (分别为 9.3 和 13.3 个月)。DIPG 和其他 pHGG 的 1 、 2 和 5 年生存率分别为 80% 、 10% 和 0%，85% 、 38% 和 16%。 结论: 我们的单中心经验证明了这 3 种药物方案的耐受性，与历史单药替莫唑胺相比，DIPG 的生存期延长。PHGG 生存率与类似的 3-药物方案相当，优于历史药物; 然而，治愈罕见。PHGG 患儿仍然是新型疗法联合标准疗法研究的优秀候选者。
METHODS:PURPOSE:To generate a preclinical model of isocitrate dehydrogenase (IDH) mutant gliomas from glioma patients and design a MRS method to test the compatibility of 2-hydroxyglutarate (2HG) production between the preclinical model and patients. METHODS:Five patient-derived xenograft (PDX) mice were generated from two glioma patients with IDH1 R132H mutation. A PRESS sequence was tailored at 9.4 T, with computer simulation and phantom analyses, for improving 2HG detection in mice. 2HG and other metabolites in the PDX mice were measured using the optimized MRS at 9.4 T and compared with 3 T MRS measurements of the metabolites in the parental-tumor patients. Spectral fitting was performed with LCModel using in-house basis spectra. Metabolite levels were quantified with reference to water. RESULTS:The PRESS TE was optimized to be 96 ms, at which the 2HG 2.25 ppm signal was narrow and inverted, thereby leading to unequivocal separation of the 2HG resonance from adjacent signals from other metabolites. The optimized MRS provided precise detection of 2HG in mice compared to short-TE MRS at 9.4 T. The 2HG estimates in PDX mice were in excellent agreement with the 2HG measurements in the patients. CONCLUSION:The similarity of 2HG production between PDX models and parental-tumor patients indicates that PDX tumors retain the parental IDH metabolic fingerprint and can serve as a preclinical model for improving our understanding of the IDH-mutation associated metabolic reprogramming.
METHODS:BACKGROUND:Gliomas consist of a heterogeneous group of tumors. This study aimed to report the incidences of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, 1p19q co-deletion, isocitrate dehydrogenase (IDH) gene mutations, and inactivating mutations of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) in high-grade gliomas in an ethnically diverse population. METHODS:Records of patients who underwent surgery for high-grade gliomas from January 2013 to March 2017 at our institution were obtained. The patients' age, gender, ethnicity, Karnofsky Performance Scale (KPS) score, ability to perform activities of daily living (ADLs), tumor location and biomarkers status were recorded. Data were analyzed using chi-square and Mann-Whitney U tests, Kaplan-Meier estimates and log-rank test. RESULTS:181 patients were selected (56 with grade III gliomas, 125 with grade IV gliomas). In the grade III group, 55% had MGMT promoter methylation, 41% had 1p19q co-deletion, 35% had IDH1 mutation and none had ATRX loss. In the grade IV group, 30% had MGMT promoter methylation, 2% had 1p19q co-deletion, 15% had IDH1 mutation and 8% had ATRX loss. After adjusting for effects of age, surgery and pre-operative ADL statuses, only MGMT promoter methylation was found to be significantly associated with longer overall survival time in grade III (p = 0.024) and IV patients (p = 0.006). CONCLUSIONS:The incidences of MGMT promoter methylation and IDH1 mutation were found to be comparable to globally reported rates, but those of 1p19q co-deletion and ATRX loss seemed to be lower in our cohort. MGMT promoter methylation was associated with increased overall survival in our cohort and might serve as favorable prognostic factor.
METHODS:BACKGROUND:Glioblastoma multiforme is a CNS cancer characterized by diffuse infiltrative growth, aggressive clinical behavior and very poor prognosis. The state-of-art clinical approach to this disease consists of surgical resection followed by radiotherapy plus concurrent and adjuvant chemotherapy with temozolomide. Tumor recurrence occurs in virtually all cases, therefore, despite any treatment, the median survival is very low (14.6 months), which makes the approach to these patients a challenging clinical issue. MAIN BODY:The escalating costs and times required for new medications to reach the bedside make repurposing or repositioning of old drugs, when scientific bases allow their use in other pathologies, an appealing strategy. Here, we analyze a number of literature data concerning the antipsychotic chlorpromazine, the founder of the phenothiazines class of drugs, a medication widely used in the clinics for approximately 60 years. The drug exerts its effects on psychiatric patients by interfering with the dopamine receptor D2, although more recent pharmacodynamics studies ascribe chlorpromazine a series of biological effects on cancer cells, all converging in hindering also glioblastoma survival capabilities. SHORT CONCLUSIONS:On these bases, and assisted by the information on the well-established chlorpromazine toxicity and dosage in humans, we designed a Phase II clinical trial involving the combination of chlorpromazine with the standard treatment, temozolomide, in the adjuvant phase of the therapeutic protocol. Patients displaying hypo-methylation of the MGMT gene, and thus intrinsically resistant to temozolomide, will be enrolled. The endpoints of this study are the analysis of toxicity and clinical activity, as evaluated in terms of Progression-Free Survival, of the association of chlorpromazine with the first-line treatment for this very serious form of cancer.