New Treatments Cut NF1 Morbidity by 50%

Neurofibromatosis type 1 (NF1) is a common genetic disorder marked by a range of manifestations, including plexiform neurofibromas (PNs) that cause significant morbidity and require lifelong management. In a recent The American Journal of Managed Care® (AJMC) Stakeholder Summit moderated by Ryan Haumschild, PharmD, MS, MBA, vice president of ambulatory pharmacy services at Emory Healthcare and Winship Cancer Institute, a panel of experts discussed the evolving NF1-PN treatment landscape. They highlighted the transformative impact of newly FDA-approved mirdametinib alongside selumetinib and underscored the importance of multidisciplinary teams, proactive surveillance, and whole-body MRI to track disease burden and tailor care, particularly during the transition from pediatric to adult case management.

Epidemiology, Burden, and Current Management of NF1-PN

NF1 is a common autosomal dominant genetic disorder that affects approximately 1 in 2500 to 3000 individuals worldwide and is caused by mutations in the NF1 gene, which encodes the tumor suppressor protein neurofibromin.1,2 NF1 is inherited in an autosomal dominant pattern, with about half of cases due to de novo mutations. Each child of an affected individual has a 50% chance of inheriting the disease, and penetrance is nearly 100%, though clinical severity varies widely.3

Approximately 25% to 30% of patients with NF1 develop PNs, benign nerve sheath tumors that can be congenital and grow throughout life.2,4,5 PNs are typically found in the craniofacial region, neck, pelvis, and lower extremities.4 These tumors can cause significant morbidity due to disfigurement, pain, functional impairment, and a risk of malignant transformation to malignant peripheral nerve sheath tumors (MPNSTs).4

Beyond physical symptoms, about one-third of children and adolescents with NF1-PN experience social-emotional difficulties, including anxiety, depression, and social withdrawal, with worse disease severity linked to poorer quality of life (QOL).4 Patient-reported outcomes from pediatric and adult trials show that larger tumor volumes correlate with worse QOL in adults.4 These psychosocial impacts vary by age, underscoring the need for lifelong assessment and support.4

Whole-body MRI is the preferred imaging modality to identify and characterize PNs, particularly during the transition from pediatric to adult care. It helps assess size and involvement with critical structures, informs management decisions, and highlights the link between total body PN burden and lifetime risk of malignant transformation.4 Treatment decisions should involve a multidisciplinary team to determine whether surgery or medical management is most appropriate. Although surgery has historically been the mainstay of treatment, complete resection is often impossible due to the infiltrative and complex nature of these tumors.4

Pathophysiology, Epidemiology, and Diagnosis

Lionel Chow, MD, PhD, pediatric hematologist oncologist at Dayton Children’s Hospital and associate professor of medicine at Wright State University Boonshoft School of Medicine, provided an overview of the genetic and molecular mechanisms driving NF1 pathophysiology, describing it as a classic tumor suppressor condition due to NF1 mutations that disrupt neurofibromin. “Neurofibromin regulates the RAS-MAP-kinase pathway, and it’s…one of the major brakes of this pathway,” Chow explained. “When neurofibromin or the NF1 gene is mutated and inactivated, it can no longer catalyze GTP to GDP and so RAS is kept in the GTP-bound form…[leading] to sustained activation of this downstream series of events...which ultimately leads to [uncontrolled] cell growth…[and] different tumors.”

Mina Lobbous, MD, MSPH, staff neuro-oncologist at the Cleveland Clinic Foundation and medical director of the Adult Neurofibromatosis Clinic, described NF1 as “the most common tumor suppressor syndrome,” usually diagnosed in early childhood, with about 80% of individuals diagnosed before they were aged 6 years and 95% before they were aged 8 years. Diagnosis is typically clinical, based on meeting 2 of the key criteria, including café au lait spots, Lisch nodules, optic pathway gliomas, neurofibromas, bony lesions, or family history.

Maciej M. Mrugala, MD, PhD, neuro-oncologist, professor of neurology and medicine, and codirector of the Neurofibromatosis Clinic at Mayo Clinic and Mayo Clinic Cancer Center, explained that PNs are a hallmark of NF1 and part of the National Institutes of Health diagnostic criteria. “In terms of the anatomical description, plexiform neurofibromas are typically soft, spongy lesions, very diffuse. In literature, they’re frequently compared to a bag of worms on palpation. They typically transgress multiple anatomical planes and can be located anywhere where peripheral nerves are,” Mrugala noted, adding that common sites include the head and neck, as well as the limbs. Some PNs can remain undetected for years. He highlighted 3 main symptoms: neurological issues (weakness or sensory problems), pain that can be debilitating, and disfigurement, especially in the face or limbs.

Mrugala noted that PNs are typically present by age 5 years, with faster growth in children and more chronic pain in adults. The risk of malignant transformation, he said, is about 15% to 20% in adults, adding, “It’s critically important to detect these tumors…[to] guide monitoring.” Haumschild emphasized Mrugala’s point. “It’s important to get that diagnosis done correctly and soon, not only for quality of life with pain and disfigurement, but…[also for] malignant transformation…[so] that clinicians have the right awareness…and the right access to the therapies early on,” he said.

Prognosis and Disease Burden

Lobbous described the prognosis for NF1-PN as variable, depending on tumor location and associated complications. “It’s ranging from disfigurement with the impact on psychosocial status and how patients feel and self-image, mobility, weakness, sensory changes.… With head and neck, tumors can affect swallowing and breathing as well,” he said. Regarding mortality, he noted that survival in patients with NF1 is “10 to 15 years younger than [the] general population, driven by…the transformation of these plexiform neurofibromas into very aggressive malignant tumors.... Even with aggressive treatment for the MPNST, the 5-year survival is less than 50%.”

Mrugala highlighted the profound impact of NF1-PN on patients’ quality of life, noting how symptoms vary by age, location, and size, with small tumors in critical areas impairing swallowing or breathing and large limb tumors severely limiting mobility and preventing normal clothing wear, greatly impacting daily life.

Beyond physical symptoms, Mrugala underscored the emotional toll. “These patients may isolate themselves because they feel stigmatized,” he said. “I think we need to change this perception of the disease and educate communities so patients don’t feel stigmatized by having this disease.… Social isolation and having NF1-related PN can lead to psychological conditions such as anxiety and depression,” which often go unaddressed.

Pain also requires individualized care. “Pain is truly one of the main symptoms…and management of the pain needs to be optimized for each patient,” he said. “These patients might be stigmatized as pain medication seeking.… We need to change the perception of this disease and how we as the medical community see these patients, treat these patients, and help them deal with not only the tumor itself, but also all the implications that come along with having the tumor.”

Risk Factors and the Need for Multidisciplinary Management

There are factors that predispose individuals to more severe NF1-PN symptoms. “Plexiform neurofibromas grow a little bit faster in children than in adults, so that definitely is a population that we need to be monitoring closely,” Chow said. “We also know that this is a very heterogeneous condition, so not all patients will have plexiform neurofibromas. It’s incumbent upon the provider to identify the patients, early on, who have a plexiform neurofibroma for follow-up.” Chow added, “This is a condition that screams for a multidisciplinary approach…including, potentially, neurologists, neuro-oncologists, oncologists, and various surgeons [depending on the tumor’s location].” Lobbous emphasized that managing NF1-PN “takes a village…[a] big team to make sure that the patient is well taken care of,” and stressed the critical importance of a seamless transition from pediatric to adult care to avoid complications later in life.

Chow also mentioned the risk of malignant transformation to MPNST. “Overall plexiform neurofibroma tumor burden in a patient is related to the propensity to transform,” he noted. Although whole-body MRIs aren’t currently recommended to identify high-risk patients, he suggested that “as we enter upon an age where we have multiple treatments available…we want to readdress…[the] recommendation for whole-body MRI to identify patients [who] are potentially at a higher risk for transformation to MPNST.” Haumschild emphasized that “if we don’t address this earlier with multidisciplinary care, I can see a high total cost of care, if we don’t get these patients treated. And that’s burdensome for the patient, it’s burdensome for the provider, and really for the payer as well, who’s [treating] these patients.” Lobbous added that “a lot of the tertiary centers now are adopting a whole-brain, whole-body MRI with PET to catch any early malignant transformation,” underscoring that “access to care, transition of care, and also the multidisciplinary [teams]” are essential for achieving the best outcomes for patients.

Current Unmet Needs and Gaps in Care