Selumetinib side effects in children treated for plexiform neurofibromas: first case reports of peripheral edema and hair color change

Abstract

Background Plexiform neurofibromas (PNs) are congenital tumors that affect around 50 % of the subjects with neurofibromatosis type 1. Despite being histologically benign, PNs can grow rapidly, especially in the pediatric age, and cause severe morbidities. In the past, various therapeutic approaches have been proposed to treat these masses, none of which obtained valuable results. Selumetinib, an inhibitor of mitogen-activated protein kinase (MEK) 1 and 2, has been the first molecule to demonstrate the ability of tackling the growth of PNs. The drug’s most common side effects, which usually are mild or moderate, include gastrointestinal symptoms (diarrhea, abdominal pain), dermatologic manifestations (maculo-papular and acneiform rash, paronychia, mucositis), and various laboratory test abnormalities (elevation of creatine kinase and aminotransferase). Cases presentation We report two previously undescribed adverse events in pediatric patients: peripheral edema and hair color change. The first case of peripheral edema occurred in a 7-year-old boy affected by a severe form of NF1, after two years of treatment with selumetinib at the standard dose (25 mg/m2twice a day). The edema involved the right leg, and the patient did not complain of pain. The second case of peripheral edema occurred in a 12-year-old girl after six months of therapy with selumetinib at the standard dose, involving her lower left leg. The patient initially complained of pain in that area, but it gradually and spontaneously resolved. In both patients, all the radiological exams, including lymphoscintigraphy, pelvic and abdominal ultrasound, and doppler ultrasound of the affected limb, as well as blood tests, revealed no abnormalities. Hair color change appeared in a 4-year-old boy after six months of therapy at the standard dose. The boy’s hair, whose natural color was dark blonde, became lighter in some areas. Despite the appearance of these side effects, all the patients and their families decided to continue the treatment with selumetinib, in considerations of its clinical benefits. Conclusions Since the use of selumetinib to treat plexiform neurofibromas is increasing in the pediatric population, clinicians should be aware of its side effects, so to decide whether continuing the treatment, reducing the dose or even interrupting it, when appropriate.

Selumetinib for symptomatic, inoperable plexiform neurofibromas in children with neurofibromatosis type 1: A national real‐world case series

“…Of the rarer events, oedema has been reported in children on selumetinib. 15 Overall, selumetinib toxicities are acceptable, given the clinical benefits.…”

Analysis of patient-specific NF1 variants leads to functional insights for Ras signaling that can impact personalized medicine

“…Therapeutic interventions to date have focused on inhibition of upregulated Ras signaling (e.g., MEK inhibition with selumetinib (Figure 1, right)). While MEK inhibitors have demonstrated effectiveness, not all patients benefit, plexiform neurofibromas do not completely disappear, and there can be significant side effects (Baldo, Magnolato, Barbi, & Bruno, 2021). Therefore, additional treatments that can be used in conjunction with MEK inhibitors are needed.…”

Analysis of patient‐specific NF1 variants leads to functional insights for Ras signaling that can impact personalized medicine

“…Therapeutic interventions to date have focused on inhibition of upregulated Ras signaling (e.g., MEK inhibition with selumetinib (Figure 1a, right)). While MEK inhibitors have demonstrated effectiveness, not all patients benefit, plexiform neurofibromas do not completely disappear, and there can be significant side effects (Baldo et al, 2021). Therefore, additional treatments that can be used in conjunction with MEK inhibitors are needed.…”