PATH-30. TARGETED THERAPIES FOR PEDIATRIC LOW-GRADE GLIOMAS: A CASE SERIES

Abstract Pediatric central nervous system (CNS) malignancies are the most common malignancies of childhood. The standard treatment plan for most CNS malignancies involves surgery, chemotherapy, radiation, and/or a combination of above therapies. Unresectable symptomatic low grade gliomas, such as pilocytic astrocytomas and gangliogliomas, are slow growing tumors that are typically responsive to a single course of intravenous chemotherapy, but in select patients these WHO grade I or II tumors can recur and be refractory to multiple courses. Molecular diagnostics can offer valuable insight into the tumor microenvironment, where targeted therapies can be offered for specific actionable mutations. Here we report a case series of 3 pediatric patients, with unique CNS malignancies, currently on targeted therapies for tumor-specific somatic mutations. Patient A is a 5 year old male with unresectable Neurofibromatosis-1 related plexiform neurofibroma of the nasopharyngeal space as well as optic pathway glioma, with a mutation of the MAPK/ERK pathway. Patient B is a 6 year old male with recurrent, refractory pilocytic astrocytoma of the optic pathway and hypothalamus, with progression through several courses of intravenous chemotherapy, noted to have somatic NACC2-NTRK mutation. Patient C is a 17 year old female with unresectable, pontomedullary ganglioglioma, noted to have BRAF-V600E mutation. Patient A is treated with Selumetinib, for about 6 months, with near resolution of nasopharyngeal mass. Patient B is treated with Larotrectinib, for about 3 months, with stability of clinical symptoms. Patient C is treated with Vemurafenib, for about 10 months, with stability of lesion size and patient-reported clinical improvement. No adverse events were noted for any of these patients and all medications were administered orally. Significant improvement in quality of life was reported, as they did not have central lines or bone marrow suppression. Targeted inhibitors provide a reasonable treatment option for relapsed, refractory CNS malignancies with actionable mutations.

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Resolving mystery behind autonomous retrogression of low-grade gliomas; a systematic review

Journal of the Pakistan Medical Association ◽

10.47391/jpma.581 ◽

2020 ◽

pp. 1-28

Author(s):

Syed Ijlal Ahmed ◽

Syeda Beenish Bareeqa ◽

Syeda Sana Samar ◽

Syed Daniyal Ahmed Jilanee

Keyword(s):

Systematic Review ◽

Therapeutic Intervention ◽

Spontaneous Regression ◽

Experimental Studies ◽

Optic Pathway Glioma ◽

Low Grade ◽

Evidence Based ◽

Optic Pathway ◽

Diffuse Astrocytoma ◽

Low Grade Gliomas

Abstract Objective: To review evidence-based data on spontaneous retrogression of low-grade gliomas with respect to interval till regression, type of glioma and patient outcome. Method: The systematic review comprised medical literature in English language published from January 1997 to January 2017 on Scopus, PubMed and Google Scholar databases to establish consensus about the possible mechanism of spontaneous regression, the role of therapeutic intervention and failure of management strategies in low-grade gliomas. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed during the review. Results: Of the 176 articles identified, 73(41.5%) were shortlisted for detailed assessment. Of them, 10(13.7%) were included; 5(50%) case reports and 5(50%) case series. There were 23 cases of spontaneous regression; 15(65.2%) males and 8(34.7%) females. The interval of regression varied from 3 months to 15.5 years, and the most commonly presenting low-grade glioma type was optic pathway glioma 11(47.4%). Conclusion: The phenomenon of regression was most evident in optic pathway glioma. Literature suggested that low-grade gliomas should undergo serial imaging before implying any therapeutic intervention. However, the evidence-based proof, large-scale experimental studies and ethical considerations are still required to standardise this strategy. Key Words: Pilocytic astrocytomas, Desmoplastic infantile ganglioglioma, DIG, Desmoplastic infantile astrocytomas, DIA, Diffuse astrocytoma, Spontaneous regression. Continuous...

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Postoperative hydrocephalus is a high-risk lethal factor for patients with low-grade optic pathway glioma

British Journal of Neurosurgery ◽

10.1080/02688697.2021.1947971 ◽

2021 ◽

pp. 1-7

Author(s):

Song Han ◽

Zuocheng Yang ◽

Liguo Wang ◽

Yakun Yang ◽

Xueling Qi ◽

...

Keyword(s):

High Risk ◽

Lethal Factor ◽

Optic Pathway Glioma ◽

Low Grade ◽

Optic Pathway ◽

Postoperative Hydrocephalus

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Molecular Alterations in Pediatric Low-Grade Gliomas That Led to Death

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlab097 ◽

2021 ◽

Author(s):

Jared T Ahrendsen ◽

Claire Sinai ◽

David M Meredith ◽

Seth W Malinowski ◽

Tabitha M Cooney ◽

...

Keyword(s):

Braf V600e ◽

Molecular Characteristics ◽

Low Grade ◽

Diffuse Astrocytoma ◽

Term Survival ◽

Pten Loss ◽

Low Grade Gliomas ◽

Molecular Alterations ◽

Idh1 R132h ◽

Poor Outcomes

Abstract Pediatric low-grade gliomas (PLGGs) have excellent long-term survival, but death can occasionally occur. We reviewed all PLGG-related deaths between 1975 and 2019 at our institution: 48 patients were identified; clinical data and histology were reviewed; targeted exome sequencing was performed on available material. The median age at diagnosis was 5.2 years (0.4–23.4 years), at death was 13.0 years (1.9–43.2 years), and the overall survival was 7.2 years (0.0–33.3 years). Tumors were located throughout CNS, but predominantly in the diencephalon. Diagnoses included low-grade glioma, not otherwise specified (n = 25), pilocytic astrocytoma (n = 15), diffuse astrocytoma (n = 3), ganglioglioma (n = 3), and pilomyxoid astrocytoma (n = 2). Recurrence occurred in 42/48 cases, whereas progression occurred in 10. The cause of death was direct tumor involvement in 31/48 cases. Recurrent drivers included KIAA1549-BRAF (n = 13), BRAF(V600E) (n = 3), NF1 mutation (n = 3), EGFR mutation (n = 3), and FGFR1-TACC1 fusion (n = 2). Single cases were identified with IDH1(R132H), FGFR1(K656E), FGFR1 ITD, FGFR3 gain, PDGFRA amplification, and mismatch repair alteration. CDKN2A/B, CDKN2C, and PTEN loss was recurrent. Patients who received only chemotherapy had worse survival compared with patients who received radiation and chemotherapy. This study demonstrates that PLGG that led to death have diverse molecular characteristics. Location and co-occurring molecular alterations with malignant potential can predict poor outcomes.

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Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas

Journal of Clinical Oncology ◽

10.1200/jco.2016.71.8726 ◽

2017 ◽

Vol 35 (25) ◽

pp. 2934-2941 ◽

Cited By ~ 106

Author(s):

Alvaro Lassaletta ◽

Michal Zapotocky ◽

Matthew Mistry ◽

Vijay Ramaswamy ◽

Marion Honnorat ◽

...

Keyword(s):

Quantitative Imaging ◽

Progression Free Survival ◽

Extent Of Resection ◽

Braf V600e ◽

Low Grade ◽

Low Grade Gliomas ◽

Molecular Stratification ◽

Treatment Data ◽

Poor Outcomes ◽

Independent Cohort

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

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A phase II prospective study of selumetinib in children with recurrent or refractory low-grade glioma (LGG): A Pediatric Brain Tumor Consortium (PBTC) study.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.10504 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 10504-10504 ◽

Cited By ~ 7

Author(s):

Jason R. Fangusaro ◽

Arzu Onar-Thomas ◽

Tina Young-Poussaint ◽

Shengjie Wu ◽

Azra H Ligon ◽

...

Keyword(s):

Phase Ii ◽

Pediatric Brain Tumor ◽

Braf V600e Mutation ◽

Low Grade Glioma ◽

Braf V600e ◽

Low Grade ◽

Optic Pathway ◽

Grade 3 ◽

Molecular Aberrations

10504 Background: A greater understanding of the Ras-MAP kinase-signaling pathway in pediatric low-grade glioma (LGG) paired with the availability of potent selective inhibitors has enhanced the ability to target this pathway with therapeutic intent. Methods: The PBTC conducted a multi-institutional phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/refractory LGG assigned to 6 strata and treated at 25 mg/m2/dose PO BID for up to two years. Here we present the data from three of these strata. The remaining strata are still accruing patients. Results: Stratum I included children with non-NF-1 and non-optic pathway recurrent/refractory pilocytic astrocytoma (PA) harboring BRAF aberrations (BRAF V600e mutation or the BRAF-KIAA 1549 fusion). Eight of 25 (32%) patients achieved a partial response (PR) with 2-year PFS of 66+/-11%. Two of 7 (29%) patient tumors with a BRAF V600e mutation and 6/18 (33%) with a BRAF KIAA-1549 fusion had a PR. Stratum 3 enrolled NF-1-associated LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Ten of 25 (40%) achieved PR with a 2-year PFS of 96+/-4%. Only one patient progressed while on treatment. Stratum 4 included children with non-NF-1 optic pathway/hypothalamic LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Two of 16 (12.5%) had a PR with a 2-year PFS of 65+/-13%. The BRAF aberration status of the responders in strata 3 and 4 is mostly unknown. All responses were confirmed centrally and seven patients remain on treatment. The most common toxicities were grade 1/2 CPK elevation, diarrhea, hypoalbuminemia, elevated AST and rash. Rare grade 3/4 toxicities included elevated CPK, rash, neutropenia, emesis and paronychia. Conclusions: Selumetinib was effective in treating children with recurrent/refractory LGG, including those with NF-1 associated LGG and PA harboring BRAF V600e mutation or BRAF-KIAA 1549 fusion. Larger prospective studies are necessary to determine the future, specific role of this agent in treating children with LGG harboring specific molecular aberrations. Clinical trial information: NCT01089101.

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The management of incidental low-grade gliomas using magnetic resonance imaging: systematic review and optimal treatment paradigm

Neurosurgical FOCUS ◽

10.3171/2011.9.focus11219 ◽

2011 ◽

Vol 31 (6) ◽

pp. E12 ◽

Cited By ~ 14

Author(s):

Ashish H. Shah ◽

Karthik Madhavan ◽

Deborah Heros ◽

Daniel M. S. Raper ◽

J. Bryan Iorgulescu ◽

...

Keyword(s):

Systematic Review ◽

Mr Imaging ◽

Active Surveillance ◽

Case Series ◽

Treatment Decisions ◽

Low Grade ◽

Management Options ◽

Low Grade Gliomas ◽

Presenting Symptoms ◽

Radiological Evidence

Object The discovery of incidental low-grade gliomas (LGGs) on MR imaging is rare, and currently there is no existing protocol for management of these lesions. Various studies have approached the dilemma of managing patients with incidental LGGs. While some advocate surgery and radiotherapy, others reserve surgery until there is radiological evidence of growth. For neurosurgeons and radiologists, determining the course of action after routine brain imaging poses not only a medical but also an ethical dilemma. The authors conducted a systematic review of case reports and case series in hopes of enhancing the current understanding of the management options for these rare lesions. Methods A PubMed search was performed to include all relevant MR imaging studies in which management of suspected incidental LGG was reported. Comparisons were made between the surgical treatment arm and the active surveillance arm in terms of outcome, mode of discovery, reasons for treatment, and histology. Results Nine studies with 72 patients were included in this study (56 in the surgical arm and 16 in the active surveillance arm). Within the surgical arm, 49% remained deficit free after treatment, 25% showed evidence of tumor progression, 13% underwent a second treatment, and 7% died. The active surveillance group resulted in no unanticipated adverse events, with serial imaging revealing no tumor growth in all cases. Lesion regression was reported in 31% of this group. The surgical arm's mortality rate was 7% compared with 0% in the active surveillance arm. Conclusions Treatment decisions for incidental LGG should be individualized based on presenting symptoms and radiological evidence of growth. The asymptomatic patient may be monitored safely with serial MR imaging and occasionally PET scanning before treatment is initiated. In patients presenting with nonspecific symptoms or concurrent symptomatic lesions, treatment may be initiated earlier to reduce potential morbidity. All treatment decisions must be tempered by patient factors and expectations of anticipated benefit.

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Single-Agent Oral Vinorelbine in the Treatment of Pediatric Progressive Optic Pathway Glioma: A Single Institutional Experience

Clinical Oncology and Research ◽

10.31487/j.cor.2021.07.05 ◽

2021 ◽

pp. 1-6

Author(s):

Natalia Dassi ◽

N.S. Silva ◽

F.A. Silva ◽

D.B. Almeida ◽

...

Keyword(s):

Single Agent ◽

Drug Acquisition ◽

Gastrointestinal Toxicity ◽

Optic Pathway Glioma ◽

Oral Drug ◽

Low Grade ◽

Optic Pathway ◽

Oral Vinorelbine ◽

Minor Response ◽

Response To Chemotherapy

Purpose: The vinca alkaloids’ activity against pediatric low-grade glioma (PLGG) is well established. The goal of the present study is to describe our experience with oral vinorelbine in patients with progressive optic pathway glioma (OPG), not only regarding the clinical response, but also the cost benefit using an oral medication. Methods: Patients under 21 years of age with unresectable and/or progressive OPG were eligible. Oral vinorelbine was administered at a dose of 90mg/m2 daily on days 0, 8 and 22, in a scheme of 4 weekly cycles for a total of 18 cycles (54 doses). Results: From 2013 to 2018, sixteen patients were enrolled onto the study, with a median age of 9,1 years (range 4,6-17,8y). The most common histology was pilocytic astrocytoma (88,8%). Best response to chemotherapy was reviewed with a response rate (complete, partial, or minor response) of 30% for the patients treated exclusively with the oral drug. Five-year event-free survival (EFS) rate was 43.4%. Six patients had to change to intravenous vinorelbine due to gastrointestinal toxicity, vomiting grade III. None of the patients showed neurotoxicity. The total cost including drug acquisition, administration and toxicity management was lower with the oral formulation comparing to IV one. Conclusion: Single-agent oral vinorelbine seems to have some clinical activity in the management of recurrent or refractory pediatric OPG, being an interesting and cost-effective option, minding that gastrointestinal toxicity may be limiting and a combination of antiemetics should be considered in this treatment regimen.

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