Pharmacotherapy of plexiform neurofibromas in patients with neurofibromatosis type 1. Possible adverse events and their management

Neurofibromatosis type 1 is a multisystem genetic disorder associated with an increased risk of benign and malignant tumors due to mutations in the NF1 gene. Clinical manifestations of the disease vary and depend on the patient’s age. One of the most common complications of neurofibromatosis type 1 is plexiform neurofibroma – a benign tumor affecting peripheral nerves. For a long time, there had been no standard care for such patients in the Russian Federation; treatment of plexiform neurofibromas was usually limited to symptomatic therapy and repeated surgical interventions. In the last few years, treatment approach to patients with neurofibromatosis type 1 complicated by plexiform neurofibromas changed, since a targeted drug, selumetinib became available. In clinical trials, 65 % of children receiving selumetinib demonstrated a partial response (reduction in the volume of plexiform neurofibromas by 20 % or more) for more than 3 cycles (months), 56 % of children demonstrated a long-term response (a year or more) without traumatic surgical interventions. In our country, more than 200 children have already received selumetinib under the early access program after its registration in the Russian Federation (January 2021). In Yu.E. Veltischev Research and Clinical Institute for Pediatrics and Pediatric Surgery, the drug was prescribed to 104 patients; of them, 54 patients were followed up between April 2021 and October 2023. The most common adverse events associated with selumetinib in our patients included skin rash (acne/maculopapular rash or eczema), dry skin, hair discoloration and hair loss, paronychia, and an asymptomatic elevation of creatine phosphokinase. This article provides information on the most common adverse events of selumetinib therapy, preventive measures, and recommendations for patient follow-up.

1. Instructions for medical use of the drug Koselugo® (selumetinib) LP-007563 dated November 1, 2021.

2. 2. Blakeley J., Plotkin S. Therapeutic advances for the tumors associated with neurofibromatosis type 1, type 2, and schwan-nomatosis. Neuro Oncol 2016;18(5):624–38. DOI: 10.1093/neuonc/nov200

3. Carton С., Gareth Evans D., Blanco I. et al. ERN GENTURIS tumour surveillance guidelines for individuals with neurofibromatosis type 1. E Clin Med 2023;56:101818. DOI: 10.1016/j.eclinm.2022.101818

4. Cimino P., Gutmann D. Neurofibromatosis type 1. Handb Clin Neurol 2018;148:799–811. DOI: 10.1016/B978-0-444-64076-5.00051-X

5. Dagher S., Blom A., Chabanol H. et al. Cutaneous toxicities from targeted therapies used in oncology: Literature review of clinical presentation and management. Int J Womens Dermatology 2021;7(5):615–24. DOI: 10.1016/j.ijwd.2021.09.009

6. Dombi E., Andrea Baldwin A., Marcus L. et al. Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Engl J Med 2016;375(26):2550–60. DOI: 10.1056/NEJMoa1605943

7. Farschtschi S., Mautner V., Lawson A. et al. The neurofibromatoses. Deutsches Arzteblatt Int 2020;117(20):354. DOI: 10.3238/arztebl.2020.0354

8. Gross A.M., Wolters P.L., Dombi E. et al. Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas. Neuro Oncol 2023;25(10):1883–94. DOI: 10.1093/neuonc/noad086

9. Gross A.M., Wolters P.L., Dombi E. et al. Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med 2020;382:1430–42. DOI: 10.1056/NEJMoa1912735

10. Gutmann D., Ferner R., Listernick R. et al. Neurofibromatosis type 1. Nat Rev Dis Primers 2017;3:17004. DOI: 10.1038/nrdp.2017.4

11. Hirbe A., Gutmann D. et al. Neurofibromatosis type 1: A multidisciplinary approach to care. Lancet Neurol 2014;13(8):834–43. DOI: 10.1016/S1474-4422(14)70063-8

12. Klesse L., Jordan J., Radtke H. et al. The use of MEK inhibitors in neurofibromatosis type 1-associated tumors and management of toxicities. Oncologist 2020;25(7):e1109–16. DOI: 10.1634/theoncologist.2020-0069

13. Koczkowska M., Chen Y., Callens T. Genotype-phenotype correlation in NF1: Evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844–848. Am J Hum Genet 2018;102(1):69–87. DOI: 10.1016/j.ajhg.2017.12.001

14. NCI CTCAE v. 5.0. Available at: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0/Archive/CTCAE_5.0_2009-05-29_QuickReference_8.5x11.pdf.

15. Needle M.N., Cnaan A., Dattilo J. et al. Prognostic signs in the surgical management of plexiform neurofibroma: The Children’s Hospital of Philadelphia experience, 1974–1994. J Pediatr 1997; 131:678–8. DOI: 10.1016/s0022-3476(97)70092-1

16. Nguyen R., Ibrahim С., Friedrich R. et al. Growth behavior of plexiform neurofibromas after surgery. Genet Med 2013;15:691–7. DOI: 10.1038/gim.2013.30

17. Nishio M., Kato T., Toyozawa R. et al. Management of peripheral edema in patients with MET exon 14-mutated non-small cell lung cancer treated with small molecule MET inhibitors. Target Oncol 2022;17(5):597–604. DOI: 10.1007/s11523-022-00912-y

18. Prudner B., Ball T., Rathore R. et al. Diagnosis and management of malignant peripheral nerve sheath tumors: Current practice and future perspectives. Neurooncol Adv 2019;2(Suppl 1):i40–9. DOI: 10.1093/noajnl/vdz047

19. Scheer M., Leisz, S., Sorge E. et al. Neurofibromatosis type 1 gene alterations define specific features of a subset of glioblastomas. Int J Mol Sci 2022;23(1):352. DOI: 10.3390/ijms23010352

20. Volonte M., Esoletta E., Gordon S. et al. Acneiform rash as a side effect of selumetinib in a child with neurofibromatosis type 1 treated for inoperable plexiform neurofibromas: Good results with doxycycline. Dermatol Ther 2022;35:e15607. DOI: 10.1111/dth.15607

21. Yang Y., Liu Y., Sun X. et al. Risk of peripheral edema in cancer patients treated with MEK inhibitors: A systematic review and meta-analysis of clinical trials. Curr Med Res Opin 2017;33(9):1663–75. DOI: 10.1080/03007995.2017.1349657

22. Yap Y.-S., McPherson J.R., Ong C.-K. et al. The NF1 gene revisited – from bench to bedside. Oncotarget 2014;5(15):5873–92. DOI: 10.18632/oncotarget.2194