Dermatologic Effects of Selumetinib in Pediatric Patients with Neurofibromatosis Type 1: Clinical Challenges and Therapeutic Management.

Background : Plexiform neurofibromas (pNFs) are benign neoplasms, primarily originating from Schwann cells, posing challenges in patients with type 1 neurofibromatosis (NF1) due to pain, disfigurement, compression of vital structures and potential for malignancy. Selumetinib, a MEK1/2 inhibitor, has shown promising results in treating inoperable pNFs, with clinical trials demonstrating tumor volume reduction and improved patient-reported outcomes. Despite its efficacy, dermatologic toxicities may impact the quality of life and treatment adherence. Evaluating the frequency and spectrum of such effects is crucial for effective management. Methods : In a four-year retrospective and prospective study, pediatric NF1 patients with symptomatic, inoperable plexiform neurofibromas (pNFs) were treated with selumetinib. Eligibility criteria included significant morbidity, pNF size exceeding 3 cm or surgical inoperability, and performance status >70%. Hematological, liver, lung and cardiac assessments established baseline health. Selumetinib, orally administered at 25 mg/m 2 twice, was administered for two years unless a response warranting extension occurred. Cutaneous AEs were documented and graded by severity according to CTCAE v5.0, with evaluations every three to six months. The impact on symptoms and pNF size was systematically recorded, and biopsies characterized histopathological features in those patients requiring surgery. Results : Twenty patients were enrolled, with an average age at therapy initiation of 11.6 years. Cutaneous side effects were common, with all patients experiencing at least one and a median of two per patient. Xerosis, paronychia and acneiform rash were prevalent. Notably, pre-pubertal individuals were more susceptible to xerosis. Acneiform rash had a higher incidence in older patients and those with skin phototypes II and III. Successful management involved tailored approaches, such as clindamycin for acneiform rash and topical agents for paronychia. Hair abnormalities, including color changes and thinning, occurred, with female patients at higher risk for the latter. Paronychia presented challenges, necessitating various interventions, including surgical approaches. AEs led to treatment suspension in 20% of patients, with tumor rebound observed in 75%. Conclusions : According to our experience, successful management of selumetinib-induced cutaneous AEs requires tailored strategies including surgery. AEs might indirectly determine pNF regrowth due to therapy suspension. We thus emphasize the pivotal role of addressing cutaneous reactions for effective selumetinib management in pediatric patients.