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Page 4 of 9 Lightner. Rare Dis Orphan Drugs J. 2026;5:1

hearing remains functional; in such cases, it may be reserved only for individuals with brainstem
compression. Unfortunately, some patients may experience tumor recurrence or develop new tumors despite
gross total resection. Gamma knife radiosurgery has been used and has gained prominence for the treatment
of sporadic vestibular schwannomas; however, NF2-related schwannomas may not be as radiosensitive as
their sporadic counterparts. Studies report long-term tumor control rates of 60%-80%, with hearing
preservation in approximately 35% of patients. After treatment, patients have been noted to experience
hearing decline or worsening cranial neuropathy, raising the question of whether these are treatment-related
complications or disease progression despite therapy. Malignant transformation is uncommon but can occur
up to 15 years after exposure; the risk has been estimated at 5%-6%, compared to less than 1% in those not
treated with radiation [29-34] .

Pharmacological treatment
Bevacizumab (Genentech) is a recombinant humanized monoclonal antibody against VEGF and has been
used for years in cancer therapy . In 2009, Plotkin et al. reported improved hearing in individuals with
[35]
progressive vestibular schwannomas . This was later investigated in children and adolescents and was
[36]
found to be beneficial for both hearing and tumor growth . Studies have confirmed diminished signal on
[37]
diffusion tensor imaging and improved hearing with treatment. Bevacizumab has been associated with
partial tumor volume reduction of 20% or more in approximately 40% of patients and disease stabilization in
about half of cases. Only about 10% experience disease progression while on treatment. More importantly,
36% show hearing improvement, and 46% have hearing stabilization. Unfortunately, toxicity can occur,
including thrombosis, hemorrhage, hypertension, proteinuria, colonic perforation, and menstrual disorders.
To mitigate side effects, investigators have studied lower dosages; even regimens of 5 mg/kg or 2.5 mg/kg
administered biweekly or triweekly have shown sustained response. The treatment can be tolerated for years,
although rebound tumor growth has been reported once bevacizumab is withdrawn, despite good
radiographic and audiological responses. Furthermore, bevacizumab was found to be helpful in eight patients
with spinal ependymoma, all of whom experienced improvement in neurological symptoms, and half
demonstrated radiographic response to treatment [38-42] .

DNA methylation studies have been performed. Shi et al. demonstrated that NF2-related vestibular
schwannomas exhibit both hyper- and hypo-methylated sequences, corresponding to areas of over- and
under-expression. Highly expressed genes promoted innate immune responses, gene expression, and cell
migration. Low-expression genes appeared to regulate RNA polymerase II promoters, embryonic limb
morphogenesis, fat cell differentiation, and MAPK pathway upregulation. Significantly enriched pathways
included PI3K/Akt, MAPK, Ras, and cell adhesion molecule signaling . Tsuchiya et al. highlighted the wide
[43]
array of mutations across sporadic and NF2-related vestibular schwannomas. They emphasized the
importance of the tumor microenvironment, including inflammation and heterogeneity, and suggested that
a better understanding could provide insights into treatment and management . In summary, targeted
[44]
therapy may be beneficial for some patients, at least temporarily; however, it is not universally effective, and
cytotoxic regimens have generally been unsuccessful.

In 2013, tyrosine kinase inhibition through ALK-IN-1 appeared to be helpful in preclinical models of NF2-
deficient schwannomas and meningiomas. Subsequent trials of brigatinib showed inhibitory activity in
mouse models of NF2-related nonvestibular schwannomas and meningiomas . The drug was then
[45]
evaluated in a clinical trial through the Innovative Trial for Understanding the Impact of Targeted Therapies
in NF2 (INTUITT-NF2) Consortium. This phase 2 trial included patients aged 12 years and older, involved
40 participants, and had a 10-month follow-up. Brigatinib not only alleviated clinical symptoms but also
demonstrated radiographic responses in target tumors and other tumors. Interestingly, the meningiomas
appeared to respond best to the treatment. The study is ongoing to monitor response, but it is no longer
recruiting patients .
[46]