Exploring Novel Treatment Options for Neurofibromatosis Type 1 with Plexiform Neurofibromas

Panelists discuss how mutations in the NF1 gene lead to loss of neurofibromin function, resulting in hyperactivation of the RAS/MAPK and PI3K/AKT/mTOR pathways, and how this molecular dysregulation drives abnormal cell proliferation and tumor development in NF1.

Panelists discuss how neurofibromatosis type 1 (NF1) is typically diagnosed in early childhood using National Institutes of Health (NIH) clinical criteria, with genetic testing supporting unclear cases, and highlight the global prevalence of NF1 and the high incidence of plexiform neurofibromas, which affect up to 50% of patients regardless of racial or geographic background.

Panelists discuss how plexiform neurofibromas in NF1 often emerge in early childhood with progressive growth and symptoms such as disfigurement, pain, and neurologic deficits, noting that rapid enlargement may indicate malignant transformation, and that presentation and complications differ between pediatric and adult patients.

Panelists discuss how NF1-associated plexiform neurofibromas can cause significant morbidity, including disfigurement, pain, and neurologic impairment, with the risk of malignant transformation, and emphasize the impact of these tumors on quality of life, daily functioning, and prognosis based on tumor characteristics and access to care.

Panelists discuss how severe symptoms in NF1-associated plexiform neurofibromas are influenced by tumor size, location, growth rate, and genetic factors, and emphasize the importance of early intervention, regular imaging, and a multidisciplinary approach for monitoring and managing risks, including malignant transformation and complications.

Panelists discuss the unmet needs in NF1-associated plexiform neurofibromas, highlighting gaps in effective treatment, pain management, psychosocial support, and prevention of malignant transformation, while emphasizing the importance of early intervention, multidisciplinary care, and ongoing research into targeted therapies and improved surveillance protocols.

Panelists discuss the current management goals for NF1-associated plexiform neurofibromas, focusing on tumor control, symptom management, and prevention of malignant transformation, while highlighting the evolving future goals of targeted therapies, personalized treatment plans, and enhanced early detection to improve outcomes.

Panelists discuss how MEK inhibitors, such as trametinib and selumetinib, are emerging as first-line treatments for symptomatic NF1-associated plexiform neurofibromas, especially in progressive or inoperable cases, while emphasizing the importance of surgical resection, pain management, physical therapy, and psychosocial support for improving quality of life.

Panelists discuss key findings supporting the use of MEK inhibitors, such as selumetinib, in treating NF1-associated plexiform neurofibromas, emphasizing its impact on clinical decision-making, particularly for pediatric patients with progressive, symptomatic tumors who are not surgical candidates, and review current guidelines recommending its use to control tumor growth and improve quality of life.

Panelists discuss the exploration of combination therapies in treating complex or refractory NF1-associated plexiform neurofibromas, including MEK inhibitors combined with PI3K inhibitors, anti-angiogenic agents, and chemotherapies, and review early clinical findings suggesting potential synergistic effects, while highlighting concerns about toxicity and the need for careful patient monitoring.