In this JCO Precision Oncology Article Insights episode, Jiasen He summarizes “Midline Low-Grade Gliomas of Early Childhood: Focus on Targeted Therapies.” by Dr. Ludmila Papusha et al. published on July 08, 2024.

TRANSCRIPT

Jiasen He: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host Jiasen He, a JCO Journal's Editorial Fellow. Today, I will provide a summary on “Midline Low-Grade Gliomas of Early Childhood: Focus on Targeted Therapies.” This is an observational study by Dr. Ludmila Papusha and colleagues that investigated the use of target therapies in early childhood with midline low grade glioma.

Low grade glioma located in the hypothalamic chiasmatic region, thalamus and the brain stem are classified as midline low grade gliomas. Due to their unique locations, complete surgical resection is usually not able to be achieved. In young children with low grade glioma, radiation therapy is generally not favored. Traditionally, chemotherapy regimens such as carboplatin and vincristine have been used. However, as Dr. Papusha noted, this population often exhibits poor response to chemotherapy. With a growing understanding of the RAS-RAF-MEK pathways in low grade glioma, targeted therapy has emerged as a promising treatment option for this group. However, limited data is available regarding the mutation status of midline low grade glioma in early childhood and real world evidence on their response to targeted therapy remains scarce.

Dr. Papusha's research aimed to address this critical gap by evaluating the effectiveness of targeted therapy in midline gliomas of early childhood. In this observational study, 40 patients under the age of three with midline low grade glioma were enrolled. Somatic genetic aberrations associated with activation of RAS-RAF signaling pathway were identified in 95% of the cohort with BRAF fusion being the most common aberration followed by the BRAF V600E mutation. These findings confirm the presence of targetable mutations in this specific population and provide a foundation for the use of targeted therapy.

Diencephalic syndrome is a rare neurologic disorder typically affecting infants and young children with tumors located in the diencephalon. In this cohort, 43% of the optic pathway and hypothalamic gliomas manifested diencephalic syndrome. Among 30 patients who received first line chemotherapy, primary carboplatin and vincristine, the two-year and five-year progression-free survival rate were only 24% and 6.4% respectively, indicating that most patients experience disease progression with chemotherapy. Targeted therapy was administered to 27 patients of whom 22 experienced disease progression during or after chemotherapy. A total of 26 patients were available for evaluation. Dr. Papusha reported that all patients benefited from targeted therapy with 12 achieving a partial response, 2 showing a minor response and 12 maintaining stable disease. The median duration of targeted therapy was 16 months. These findings demonstrate the efficacy of targeted therapy in this population.

Regarding toxicity from targeted therapy in this population, the most common adverse event was grade 1 to 2 skin toxicity observed in 52% of patients. Severe toxicity occurred in 36% of patients treated with trametinib including grade 3 skin toxicity, mucositis and hematuria. Additionally, grade 3 gastrointestinal toxicity was reported. Interestingly, all three patients who experienced grade 3 gastrointestinal toxicity had diencephalic syndrome at the time of targeted therapy initiation. The author also noted cases of disease progression during treatment breaks. However, tumor response was restored in all affected patients upon resumption of targeted therapy. The two-year progression-free survival rate was 59%.

In conclusion, Dr. Papusha states the unique characteristics of infantile midline low grade glioma, including the high prevalence of diencephalic syndrome and resistance to chemotherapy. The study contributes valuable information on the targetable mutation profile in this population and provides further evidence supporting the use of targeted therapy while emphasizing the need for low monitoring of severe adverse events. As the author notes, important questions remain regarding the long term side effects of kinase inhibitors in infants and children as well as optimal duration of therapy.

Thank you for listening to JCO Precision Oncology Article Insights and please tune in for the next topic. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

JCO PO Article Insights: Therapy of Infantile Midline Low-Grade Gliomas

JCO Precision Oncology Conversations