LGG-27. TARGETED THERAPY FOR PEDIATRIC LOW-GRADE GLIOMAS AND PLEXIFORM NEUROFIBROMAS WITH TRAMETINIB

Abstract BACKGROUND Targeted therapy aimed at modulating the RAS/RAF/MEK/ERK pathway is of increasing interest for patients with plexiform neurofibromas and low-grade gliomas. Trametinib is an FDA-approved MEK inhibitor that has little published pediatric experience to date. METHODS A retrospective chart review of patients treated with trametinib for low-grade gliomas (LGG) and/or plexiform neurofibromas (PN) between 2015–2018 was conducted at Children’s Hospital Colorado. Data collected included patient demographics, lesion location, Neurofibromatosis type 1 (NF1) status, best response of PN/LGG to trametinib, duration of trametinib therapy, and reported toxicities at least possibly attributed to trametinib. RESULTS Thirty (57% male; 73% NF1) patients were identified. Sixteen (53%) patients had PN only, 12 (40%) had LGG only, and two (7%) patients had both PN and LGG. The most common LGG location was the optic pathway/hypothalamus (72%). The most common location of PN was the face (63%). Two-thirds (8/12) of patients with LGG had a BRAF alteration or NF1 mutation. The median age at start of trametinib therapy was 9.9 years (range, 2.0 – 18.8 years). The median duration of trametinib therapy was 0.8 years (range 0.1 – 2.9 years). The most commonly reported adverse event was rash. No patients developed retinal toxicity or cardiotoxicity. Only two (7%) patients discontinued for toxicity and one (3%) for progressive disease. CONCLUSIONS Trametinib can be administered without significant toxicity to children with PN or LGG. Clinical benefit is noted in this cohort; however, prospective clinical trials are necessary to characterize efficacy formally.

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LGG-12. TRAMETINIB FOR PEDIATRIC LOW GRADE GLIOMAS: A SINGLE INSTITUTION EXPERIENCE

Neuro-Oncology ◽

10.1093/neuonc/noaa222.394 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii368-iii368

Author(s):

Mustafa Barbour ◽

Michael Angelo Huang

Keyword(s):

De Novo ◽

Mapk Pathway ◽

Neurofibromatosis Type ◽

Mek Inhibitor ◽

Pediatric Brain Tumors ◽

Mitogen Activated Protein Kinase ◽

Braf V600e ◽

Low Grade ◽

Low Grade Gliomas ◽

Best Response

Abstract INTRODUCTION Low grade gliomas (LGG) are the most common pediatric brain tumors. Tumors not amenable to resection can recur or progress despite treatment with chemotherapy and/or radiation. Recent discovery of the activation of the mitogen-activated-protein-kinase (MAPK) pathway as the primary oncogenic driver for this group of tumors has led to a shift towards the use of BRAF and MEK inhibitors. METHODS Herein we performed a chart review of seven pediatric LGG treated with trametinib, a MEK inhibitor. While most were treated in the relapse setting, one patient was treated for de novo LGG as a result of experiencing multiple severe adverse effects to conventional agents. RESULTS Median age was 14 years old (range: 5 to 17 years). Six of seven patients had tissue for molecular characterization. The 2 patients with Neurofibromatosis Type 1 (NF-1) carried no other molecular aberrations. Two had the BRAF V600e mutation (1 had a concurrent PTPN11 mutation) and 2 were positive for the KIAA1549-BRAF fusion. Average duration on treatment was 8 months (range: 3 to 31 months). Disease control was achieved in 6 of 7 subjects, with one PR as best response. One patient with concurrent BRAF V600e and PTPN11 mutations progressed on trametinib and was switched to dual BRAF and MEK inhibitor therapy. Most common toxicities were acne (57.1%), oral mucositis (42.9%), skin rash, and paronychia (both 28.6%). Three patients required dose reduction and/or intermittent dose interruption. CONCLUSION Our data supports the use of trametinib for both upfront and relapsed/refractory pediatric LGG.

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LGG-11. INSTITUTIONAL EXPERIENCE OF BRAF TARGETING THERAPY

Neuro-Oncology ◽

10.1093/neuonc/noaa222.393 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii368-iii368

Author(s):

Gino Bardi Lola ◽

Mariko Sato

Keyword(s):

Targeted Therapy ◽

Adverse Events ◽

Retrospective Chart Review ◽

Mek Inhibitor ◽

Common Side Effect ◽

Low Grade ◽

Targeting Therapy ◽

Common Diagnosis ◽

Institutional Experience ◽

Severe Adverse Events

Abstract BACKGROUND The use of BRAF inhibitors is widely accepted in adult oncology as treatment for BRAF mutated cancers. BRAF alterations are frequently found in both pediatric low grade and high-grade gliomas, which has opened a new door to targeted therapies for pediatric gliomas. Targeted therapy drugs are associated with predictable patterns of adverse events. However treating in children may potentiate unique challenges. We present our institutional experience of targeted therapy with a focus on adverse events. METHODS We conducted a retrospective chart review of patients treated with BRAF and/or MEK inhibitors between 2015–2019. RESULTS There are nine patients treated with either MEK inhibitor(n=) or the combination therapy(n=). The most common diagnosis was Pilocytic astrocytoma. Targeted therapy was chosen as salvage therapy in all patients. The most common side effect was a pruritic erythematous rash, observed in 8 out of 9 patients. Cardiac toxicity (Grade 2, n=1) and GI toxicity (Grade 3, n=1) were found in patients treated with MEK inhibitor. Both cases resulted in cessation of therapy or significant decreased dose respectively. While two patients died due to progression of disease and two other continued to progress, 5 patients have demonstrated stable disease while on therapy. CONCLUSIONS Our study revealed the incidence of severe adverse events in two patients with BRAF targeted therapy. Due to the potential life-long use of targeted therapy, it is important to follow guidelines of adverse event monitoring and to develop a prevention and management strategy for severe adverse events.

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NFB-13. TRAMETINIB FOR PLEXIFORM NEUROFIBROMA AND RECURRENT LOW-GRADE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.616 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii420-iii420

Author(s):

Aimee Sato ◽

Nathan Millard ◽

Francisco Perez ◽

Nicholas Vitanza ◽

Sarah Leary

Keyword(s):

Plexiform Neurofibroma ◽

Retrospective Chart Review ◽

Neurofibromatosis Type ◽

Mek Inhibitor ◽

Tumor Location ◽

Low Grade Glioma ◽

Inhibitor Therapy ◽

Driver Mutations ◽

Low Grade ◽

Standard Clinical Practice

Abstract BACKGROUND Based on early clinical efficacy data, Seattle Children’s established a standard clinical practice for MEK inhibitor therapy for children with plexiform neurofibroma (PN) or recurrent low-grade glioma (LGG). METHODS Data were collected under an IRB-approved retrospective chart review. Trametinib was prescribed off-label at 0.025 mg/kg daily for up to two years. Physical exam and laboratory monitoring were monthly for 3 months, then every 3 months. Retinal examination, ECHO/ECG were every 3 months. Tumor response was evaluated by MRI every 3 months for LGG; imaging for PN was dependent on tumor location. RESULTS 30 patients received trametinib; 17 LGG, 16 PN (3 both); 22 with Neurofibromatosis, Type-1 (NF1); 16 female/15 male; median age 11 (range 4.1–22.6). Most common tumor location was optic pathway (n=11) and face/neck (n=10). Most common adverse events (AE) were dermatologic and gastrointestinal. Ten had dose interruption/reduction, only one discontinued therapy for AE. Six received dermatology specialty care for AE. With median follow-up of 12 months, only 3 patients had progression, one with NF1. One-year EFS was 100% for PN and 88%+7 for LGG. Driver mutations were identified in 9 of 10 tumors tested (5 BRAF fusion, 1 BRAFV600E, 1 FGFR1+NF1, 1 FGFR1+PTPN11, 1 NF1). Radiology review of response will be presented. CONCLUSIONS This real-world pediatric cohort supports efficacy and tolerability of MEK inhibitor therapy for short-term control of plexiform neurofibroma and low-grade glioma with and without NF1. Further studies are warranted to evaluate comparative efficacy, combination therapy and duration of therapy.

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LGG-05. MOLECULAR GUIDED THERAPY FOR A PEDIATRIC LOW GRADE GLIOMA: A CASE REPORT

Neuro-Oncology ◽

10.1093/neuonc/noaa222.390 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii367-iii367

Author(s):

Jayne VonBergen ◽

Beth Armstrong ◽

Morgan Schmitt

Keyword(s):

Targeted Therapy ◽

Standard Treatment ◽

Head Tilt ◽

Study Patient ◽

Low Grade ◽

Temporal Region ◽

Low Grade Gliomas ◽

Leptomeningeal Involvement ◽

The Right ◽

Guided Therapy

Abstract Low grade gliomas are the most common type of central nervous system tumors among children. Despite the fact that they are not typically life threatening, low grade gliomas remain a significant clinical challenge. Case Study: Patient is a 4-year-old male who presented at 20 months of age with several weeks of ataxia, emesis, and head tilt. Imaging revealed a right temporal lobe lesion; he was subsequently taken to surgery, where a gross total resection was achieved. Imaging 9 months post resection revealed recurrent disease within the right temporal region with leptomeningeal involvement. Four months later imaging revealed progression of multifocal disease and new growth within the sella. At this time the patient started standard treatment, Carboplatin and Vincristine, per CCG 9952A. Persistent slow progression was observed despite receiving standard therapy. The patient developed a grade 3 reaction to carboplatin, worsening with each subsequent dose. At this time, he was referred to our Precision Genomics Neuro Oncology program for tumor molecular characterization. Somatic tumor testing revealed an ETV6-NTRK3 fusion, at which time standard treatment was stopped, and patient began targeted therapy, Larotrectinib. Imaging was preformed 2 months post start of targeted therapy and revealed interval decrease in size of previously enhancing nodular lesions; findings consistent with treatment response. Disease burden continues to decrease with therapy. This case illustrates a clear benefit of using molecular guided therapy in low grade gliomas.

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Trametinib Induces Neurofibroma Shrinkage and Enables Surgery

Neuropediatrics ◽

10.1055/s-0039-1691830 ◽

2019 ◽

Vol 50 (05) ◽

pp. 300-303 ◽

Cited By ~ 9

Author(s):

Pia Vaassen ◽

Nikola Dürr ◽

Andreas Röhrig ◽

Rainer Willing ◽

Thorsten Rosenbaum

Keyword(s):

Vertebral Column ◽

Plexiform Neurofibroma ◽

Neurofibromatosis Type ◽

Mek Inhibitor ◽

Suppressor Gene ◽

Complete Disappearance ◽

Therapeutic Success ◽

Mek Inhibitors ◽

Plexiform Neurofibromas ◽

Peripheral Nerve Sheath Tumors

AbstractPlexiform neurofibromas are congenital peripheral nerve sheath tumors characteristic of neurofibromatosis type 1 (NF1)—a frequent neurocutaneous disorder caused by mutations of the NF1 tumor suppressor gene. Since plexiform neurofibromas are a major cause of the burden of disease and may also progress to malignancy, many efforts have been undertaken to find a cure for these tumors. However, neither surgery nor medication has so far produced a breakthrough therapeutic success. Recently, a clinical phase I study reported significant shrinkage of plexiform neurofibromas following treatment with the MEK inhibitor selumetinib. Here, we report an 11-year-old NF1 patient with a large plexiform neurofibroma of the neck that had led to a sharp-angled kinking of the cervical spine and subsequent myelopathy. Although surgical stabilization of the cervical vertebral column was urgently recommended, the vertebral column was inaccessible due to extensive tumor growth. In this situation, treatment with the MEK inhibitor trametinib was initiated which resulted in a 22% reduction in tumor volume after 6 months of therapy and finally enabled surgery. These data show that MEK inhibitors may not lead to complete disappearance of NF1-associated plexiform neurofibromas but can be an essential step in a multimodal therapeutic approach for these tumors. The course of our patient suggests that MEK inhibitors are likely to play a significant role in providing a cure for one of the most devastating manifestations of NF1.

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LGG-06. COMPREHENSIVE GENOMIC CHARACTERIZATION AND INTEGRATED CLINICAL ANALYSIS OF LOW-GRADE GLIOMAS IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1

Neuro-Oncology ◽

10.1093/neuonc/noab090.130 ◽

2021 ◽

Vol 23 (Supplement_1) ◽

pp. i32-i32

Author(s):

Michael Fisher ◽

David Jones ◽

Yimei Li ◽

Xiaofan Guo ◽

Poonam Sonawane ◽

...

Keyword(s):

Neurofibromatosis Type 1 ◽

Pik3ca Mutation ◽

Neurofibromatosis Type ◽

Clinical Analysis ◽

Genetic Alterations ◽

Low Grade ◽

Low Grade Gliomas ◽

Fgfr1 Mutation ◽

Glioneuronal Tumors

Abstract Background Low-grade gliomas (LGGs) arising in children with neurofibromatosis type 1 (NF1) are usually not biopsied. To identify secondary genetic alterations or molecular features that may contribute to pathogenesis and correlate with clinical behavior, we initiated a comprehensive molecular and clinical analysis of pediatric NF1-LGGs. Methods NF1-LGGs were analysed by whole-genome sequencing (31), targeted gene panel sequencing (9), RNAseq transcriptomal profiling (33) and genome-wide DNA methylation analysis (67). Clinical annotation was available for 48 subjects. Results Most LGGs harbored bi-allelic NF1 inactivation as the sole genetic abnormality, but 11% had additional alterations (FGFR1 mutation, n=3; PIK3CA mutation, n=2; homozygous 9p21 deletion, n=2; MYB:QKI fusion, n=1; SETD2 mutation, n=1; EGFR amplification, n=1). FGFR1 mutation conferred additional growth advantage in multiple complementary murine Nf1 models. 88% of NF1-LGGs resembled sporadic pilocytic astrocytoma (PA) by methylation, higher than that based on histology. Non-PA methylation patterns included low-grade glial/glioneuronal tumors, rosette-forming glioneuronal tumors, MYB/MYBL1-altered glioma, and high-grade astrocytoma with piloid features (2 tumors histologically diagnosed as LGG). In total, 18% of samples were classified as non-PA and/or harbored an additional non-NF1 mutation. Non-PA methylation class tumors were more likely to harbor an additional non-NF1 mutation (p=0.005). 7.7% of optic pathway hypothalamic gliomas (OPHGs) had other mutations or were not classified by methylation as PA, compared with 20.6% of NF1-LGGs arising elsewhere. There was no difference based on age for the presence of an additional non-NF1 mutation or non-PA methylation class. Conclusions Given the overall low occurrence of non-NF1 mutations or non-PA methylation class tumors in this series, routine clinical biopsy of typically-appearing NF1-LGG may not be indicated, particularly for children with OPHG. Biopsy should be considered for non-OPHG tumors refractory to conventional treatment. As additional agents are developed and treatment strategies evolve, the rationale for biopsy of NF1-LGG may become stronger.

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Clinical Management of Diffuse Low-Grade Gliomas

Cancers ◽

10.3390/cancers12103008 ◽

2020 ◽

Vol 12 (10) ◽

pp. 3008

Author(s):

Giuseppe Lombardi ◽

Valeria Barresi ◽

Antonella Castellano ◽

Emeline Tabouret ◽

Francesco Pasqualetti ◽

...

Keyword(s):

Radiation Therapy ◽

Targeted Therapy ◽

Operative Management ◽

Molecular Profile ◽

Low Grade ◽

Low Grade Gliomas ◽

Therapeutic Modalities ◽

Molecular Features ◽

Prognostic Stratification

Diffuse low-grade gliomas (LGG) represent a heterogeneous group of primary brain tumors arising from supporting glial cells and usually affecting young adults. Advances in the knowledge of molecular profile of these tumors, including mutations in the isocitrate dehydrogenase genes, or 1p/19q codeletion, and in neuroradiological techniques have contributed to the diagnosis, prognostic stratification, and follow-up of these tumors. Optimal post-operative management of LGG is still controversial, though radiation therapy and chemotherapy remain the optimal treatments after surgical resection in selected patients. In this review, we report the most important and recent research on clinical and molecular features, new neuroradiological techniques, the different therapeutic modalities, and new opportunities for personalized targeted therapy and supportive care.

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Weekly vinblastine in chemotherapy-naive children with unresectable or progressive low grade glioma: A Canadian cooperative study.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.10029 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 10029-10029 ◽

Cited By ~ 2

Author(s):

Eric Bouffet ◽

Katrin Scheinemann ◽

Shayna M. Zelcer ◽

Juliette Hukin ◽

Beverley Wilson ◽

...

Keyword(s):

Response Rate ◽

Previous Treatment ◽

Progression Free Survival ◽

Neurofibromatosis Type ◽

Low Grade ◽

Free Survival ◽

Best Response ◽

Response To Chemotherapy ◽

Grade 3

10029 Background: Vinblastine has shown promising activity in a phase II study in children with recurrent/refractory LGG. The aim of this study was to assess the activity of vinblastine in chemotherapy naïve children. Methods: Patients < 18 years old with unresectable or progressive LGG were eligible if they had not received any previous treatment with chemotherapy or radiation. Vinblastine was administered weekly at a dose of 6 mg/m2over a period of 70 weeks. Patients who showed progression on 2 consecutive imaging studies or evidence of clinical progression were removed from treatment. Results: 54 patients (23 female) were enrolled between 2007 and 2010. Median age at inclusion was 7 years, 13 patients were < 3 years. 32 had chiasmatic/hypothalamic tumours, 6 had evidence of dissemination. 13 had neurofibromatosis type 1. Histology was pilocytic astrocytoma (25), pilomyxoid astrocytoma (4), low grade astrocytoma variant (8); 17 patients had no histological diagnosis. Treatment was well tolerated; however, only 14 patients received full dose for the duration of the study. Most common toxicity was haematological: 40 patients who experienced grade 3+ neutropenia. There were only 6 episodes of febrile neutropenia, 3 RBC transfusions and no toxic death. Best response to chemotherapy was assessed centrally by an independent radiologist: 1 CR, 10 PR, 3 MR, 28 SD, 12 PD, for a response rate of 24.5%. With a median follow-up of 2 years (9-48 months), progression-free survival at 2 years was 72.1% (95%CI: 58.1-82.2). One patient died of progression. Conclusions: Weekly vinblastine is well tolerated in paediatric LGG patients. Although the response rate appears inferior to other common LGG regimens, progression free survival at 2 years favourably compares to most currently used regimens. Supported by a grant from the Ontario Institute Cancer Research. Clinical trial information: 1000011227.

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Individualized Dosing of Fludarabine (FLU) for Low Grade Lymphoproliferative Disorders Results in Administration of Less Medication with Fewer Infections and Equivalent Survival.

Blood ◽

10.1182/blood.v108.11.4977.4977 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4977-4977

Author(s):

Donald Pasquale ◽

Nalini Ramanathan ◽

Sarah L. Scarpace ◽

Hung Nguyen ◽

Amy I. Jackson ◽

...

Keyword(s):

Overall Survival ◽

Medical Center ◽

Retrospective Chart Review ◽

Lymphoproliferative Disorders ◽

Time Interval ◽

Low Grade ◽

Chi Square ◽

Best Response ◽

Individualized Dosing ◽

Number Of Treatment

Abstract When used in the treatment of low-grade lymphoproliferative disorders, common practice is to administer 6 monthly cycles of FLU 25-mg/m2 daily × 5. This practice is reported to cause infections (including opportunistic such as PCP and Listeria) in over 50% of patients. It has been our practice to individualize the number of monthly cycles of FLU per treatment course based on response in general administering 1 cycle of therapy when rapid and substantial response is obtained, or 1 cycle past best response. Our objective is to describe our experience with this dosing schema - incidence of infections in relation to the number of cycles of FLU administered per treatment course and overall survival. We conducted a retrospective chart review of medical records of all patients who received FLU at the Stratton VA Medical Center. We defined one treatment course as the number of five day monthly FLU doses received. Any time interval of 3 or more months between FLU was considered to indicate a new treatment course. All infectious episodes of NCI grades 3 or higher that occurred within 6 months of the last FLU treatment course were attributed to that prior treatment course. Survival was estimated by Kaplan-Meier analysis from date of diagnosis to death or last known alive. There were 15 patients treated for CLL, 9 for low-grade lymphoma, and 4 for macroglobulinemia. Three individuals treated with FLAG for ANLL were excluded. These 28 patients received a total of 44 treatment courses (each treatment course with 1 to 6 monthly cycles) of FLU. Fifty-four (54) percent of the treatment courses were with ≤2 cycles. Mean ± SD age of the patients was 65 ± 11 years. Number of FLU cycles per treatment course Number of treatment courses with infection Number of treatment courses without infection % treatment courses with infection 1 3 12 20 2 1 8 11 3 6 3 67 4 3 1 75 5 3 1 75 6 2 1 67 The overall incidence of NCI grade 3 or higher infections was significantly increased with increased numbers of FLU cycles per treatment course (complex Chi-square = 0.0193). Treatment cycles with ≤2 compared with 3 or more cycles per treatment course (Chi-square with Yate’s correction = 0.0008) had significantly fewer infections. Median overall survival was 158 months with 78 ± 44 months of follow-up. Our data indicates that individualized dosing of FLU based on response results in using lower numbers of monthly cycles per treatment course, lower incidence of severe infections, and equivalent (based on historical controls) overall survival.

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