Natural History of Neurofibromatosis Type 1-Associated Non-Optic Pathway Glioma to Support the Development of Evidence-Based Criteria for Surveillance and Initiation of Treatment

This prospective observational study will enroll at least 270 children with neurofibromatosis type 1 (NF-1) who have a newly diagnosed treatment-naïve low-grade non-optic pathway glioma and high-grade glioma.

Children with NF1 are at increased risk of developing low- and high-grade gliomas. Up to one-third of NF1-associated low-grade glioma (LGG) occurs extrinsic to the optic pathway. These non-optic pathway gliomas are generally associated with favorable outcomes, but consistent guidelines for surveillance or initiation of therapy are lacking. There are also no evidence-based guidelines for the treatment of high-grade glioma (HGG) in NF1.

This study will supply crucial data about the natural history of non-optic pathway gliomas in young patients with NF-1, including prognostic features to help identify progressive disease and factors influencing which tumors are likely to respond to chemotherapy. This knowledge will provide a foundation for designing evidence-based guidelines for disease management and future clinical trials. The longitudinal evaluation of quality of life and functional evaluations will provide a true understanding of the psychosocial and functional burden of disease in both NF1-LGG and NF1-HGG.

In addition, this study will provide necessary information about the risk of malignant transformation of NF1-LGG to HGG, including the prevalence of NF1- HGG in patients with pre-existing LGG and the potential identification of pre-malignant findings on either imaging or comprehensive tumor profiling that may predict subsequent development of NF1-HGG.

Inclusion Criteria

For all subjects

NF1: All subjects must have EITHER the clinical diagnosis of NF1 using the NIH Consensus Conference criteria OR have a constitutional NF1 mutation documented in a CLIA/CAP certified lab.
Age: ≤18 years of age at the time of study enrollment.
Tumor:
1. Newly diagnosed treatment-naïve non-optic pathway NF1-LGG (biopsy not required).
  1. Diagnosis of probable glioma within 90 days (3 months) of enrollment.
  2. Baseline MRI study documenting disease status is required within 90 days (3 months) prior to date of study enrollment
  3. Subjects with multiple target tumors (up to three) may be enrolled
  4. Subjects may be enrolled if previously/concurrently enrolled on NF1- Optic Pathway Glioma Natural History Study
  5. Treatment-naïve, i.e., no prior target (NF1-LGG) tumor directed therapy
  6. The baseline MRI must be sent to the study chairs within 14 days of enrollment for central review. If central review determines that NF1-glioma is not present, then the subject will be taken off-study and deemed ineligible.
2. Newly diagnosed NF1-HGG (WHO grade 2-4) or high-grade astrocytoma with piloid features (pathologic diagnosis required)
  1. Date of biopsy/surgical intervention resulting in pathologic diagnosis of NF1-HGG must be within 60 days of enrollment
  2. Baseline MRI study documenting disease status is required within 90 days (3 months) prior to date of study enrollment
  3. Must be biopsy-confirmed.

Additional neurocognitive and social skills enrollment criteria

Patients must have receptive and expressive language skills in English to complete the neurocognitive and social skills assessments.
Diagnosis of NF1-LGG

Additional biological specimen enrollment criteria

None.

Exclusion Criteria

NF1-LGG Cohort:

Prior therapy for the target non-optic pathway NF1-glioma (e.g. surgery [including biopsy], radiotherapy, chemotherapy, etc.)
All other prior tumor-directed therapies (e.g., MEK inhibition for PN) must be discussed with one of the study chairs to determine potential eligibility.