Selumetinib in the Treatment of Symptomatic Intractable Plexiform Neurofibromas in Neurofibromatosis Type 1: A Prospective Case Series with Emphasis on Side Effects

Baldo, Francesco; Grasso, A.; Wiel, Luisa Cortellazzo; Maestro, Alessandra; Trojniak, Marta Paulina; Murru, Flora Maria; Basso, Luca; Magnolato, Andrea; Bruno, Irene; Barbi, Egidio

doi:10.1007/s40272-020-00399-y

Cited by 24 publications

(51 citation statements)

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“…The drug has already been used in adult oncology in different protocols, such as in non-small cell lung cell carcinoma and uveal melanoma, with positive results. Selumenitib showed the capacity to tackle plexiform neurofibromas' growth in pediatric patients, obtaining a reduction of the original size of the mass of at least 20 % in most of the patients [1][2][3][4]. A decrease in tumor-related pain, disfigurement, and functional impairment was also described.…”

Section: Introductionmentioning

confidence: 95%

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

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 95%

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

et al. 2021

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“…ACNS1831). Possible side effects of MEK inhibition include frequently skin toxicities (in about 60% of patients) like acne or paronychia that are most often manageable by local therapies, and less often fatigue, gastrointestinal symptoms, CK elevation as well as rare cases of retinal detachment or left ventricular dysfunction [12][13][14]. BRAF-V600E-mutated pediatric LGG may not be as chemotherapy sensitive as other LGG [15].…”

Section: Targeting the Pathway In Low Grade Glioma By Mek Inhibitionmentioning

confidence: 99%

Innovative therapy concepts for pediatric brain tumors

Azizi

Gojo

Peyrl

2021

memo

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SummaryIn recent years, novel insight into molecular mechanisms has allowed the identification of drug targets for various pediatric brain tumors. The aim of this article is to give an overview of new treatment options in neurofibromatosis type 1 (NF1), novel tyrosine kinase inhibitors that target oncogenic gene fusions in pediatric brain tumors, and antiangiogenesis as promising therapy especially in recurrent medulloblastoma.

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“…РОЛь МУТацИЙ В гЕНЕ NF1 В РазВИТИИ ХИМИОРЕзИСТЕНТНОСТИ ОПУХОЛЕЙ В фармакотерапии НФ1 наиболее перспективным считается патогенетическое лечение, направленное на подавление активности системы RAF / MEK / ERK. Из препаратов, прошедших клинические испытания и показавших эффективность в отношении плексиформных нейрофибром в ходе ряда исследований [36][37][38][39], наиболее результативным оказался ингибитор MEK селуметиниб. Полученные данные могут быть использованы для планирования комплексного лечения спорадических ЗНО, устойчивость к фармакоте-рапии которых обусловлена мутациями в гене NF1 (при отсутствии мутаций в протоонкогенах в ткани опухоли [25]).…”

Section: Fig 1 Comparison Of Clinical Manifestations Of Neurofibromatosis Type 1 and Sporadic Tumors With Somatic Mutations In The Nf1 Geunclassified

“…Сложность патогенеза НФ1 обусловливает особенности развития спорадических ЗНО, резистентных к химиотерапии вследствие соматических мутаций в NF1. Хотя ингибиторы MEK, воздействующие на систему RAF / MEK / ERK, показали свою эффективность в лечении опухолей при НФ1 [36][37][38][39], мутации в NF1 вызывают резистентность к ингибитору RAF вемурафенибу при лечении меланомы [40][41].…”

Section: Fig 1 Comparison Of Clinical Manifestations Of Neurofibromatosis Type 1 and Sporadic Tumors With Somatic Mutations In The Nf1 Geunclassified

“…В ходе эксперимента устойчивость рака легкого к эрлотинибу и гефитинибу устранялась за счет блокирования MEK [43]. Это свидетельствует о перспективности применения ингибиторов MEK, таких как селуметиниб, которые используются в клинической практике [36][37][38][39] для данных ЗНО. Помимо классических ингибиторов MEK в опухолях с мутациями в NF1 перспективно применение и других препаратов в соответствии с механизмами взаимодействий нейрофибромина.…”

Section: транскрипция / Transcriptionunclassified

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The role of mutations in <i>NF1</i> gene in sporadic carcinogenesis

Мустафин

2021

Usp. mol. onkol

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Selumetinib in the Treatment of Symptomatic Intractable Plexiform Neurofibromas in Neurofibromatosis Type 1: A Prospective Case Series with Emphasis on Side Effects

Cited by 24 publications

References 24 publications

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

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

Innovative therapy concepts for pediatric brain tumors

The role of mutations in <i>NF1</i> gene in sporadic carcinogenesis

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