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Trametinib for orbital plexiform neurofibromas in young children with neurofibromatosis type 1

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Abstract

Introduction

Plexiform neurofibromas (PNF) in neurofibromatosis type 1 (NF1) are usually diagnosed in childhood and can grow rapidly during this period. In 10% of patients, PNF involve the orbital-periorbital area and may cause visual problems including glaucoma, visual loss from amblyopia (deprivational, strabismic, or refractive), optic nerve compression, or keratopathy. Ptosis, proptosis, and facial disfigurement lead to social problems and decreased self-esteem. Complete surgical removal involves significant risks and mutilation, and regrowth after debulking is not uncommon. Inhibitors of the RAS/MAPK pathway have recently been investigated for their activity in PNF. We administered the oral MEK inhibitor trametinib to five young children with NF1 and PNF of the orbital area, with visual compromise and progressive tumor growth; and followed them clinically and by volumetric MRI.

Methods

Treatment was initiated at a mean age of 26.8 months (SD ± 12.8) and continued for a median 28 months (range 16–51). Doses were 0.025 mg/kg/day for children aged > 6 years and 0.032 mg/kg/day for those aged < 6 years.

Results

Volumetric MRI measurements showed a reduction of 2.9–33% at 1 year after treatment initiation, with maximal reductions of 44% and 49% in two patients, at 44 and 36 months, respectively. No change in visual function was recorded during treatment. One child reported decreased orbital pain after 2 weeks; and another, with involvement of the masseters, had increased ability to chew food. Toxicities were mostly to skin and nails, grades 1–2.

Conclusions

Trametinib can decrease tumor size in some young children with orbital PNF and may prevent progressive disfigurement.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Dept. of Pediatric Hematology-Oncology, Schneider Children’s Medical Center, Petah Tikva, Israel

    Helen Toledano

  2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Helen Toledano, Gad Dotan, Rivka Friedland, Rony Cohen, Hagit Toledano-Alhadef, Shlomi Constantini & Mika Shapira Rootman

  3. Dept. of Pediatric Ophthalmology, Schneider Children’s Medical Center, Petah Tikva, Israel

    Gad Dotan

  4. Dept. of Pediatric Dermatology, Schneider Children’s Medical Center, Petah Tikva, Israel

    Rivka Friedland

  5. Neurofibromatosis Clinic, Schneider Children’s Medical Center, Petah Tikva, Israel

    Rony Cohen

  6. Department of Ophthalmology, Rabin Medical Center, Petah Tikva, Israel

    Iftach Yassur

  7. The Gilbert Israeli Neurofibromatosis Center (GINFC), Tel Aviv, Israel

    Hagit Toledano-Alhadef & Shlomi Constantini

  8. Department of Pediatric Neurosurgery, Dana-Dwek Children’s Hospital, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel

    Shlomi Constantini

  9. Dept. of Pediatric Radiology, Schneider Children’s Medical Center, Petah Tikva, Israel

    Mika Shapira Rootman

Authors
  1. Helen Toledano
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  2. Gad Dotan
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  4. Rony Cohen
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  7. Shlomi Constantini
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Helen Toledano, Gad Dotan, and Mika Shapira Rootman. The first draft of the manuscript was written by Helen Toledano and Mika Shapira Rootman and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Helen Toledano.

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Ethics approval

The local institutional review board of the Rabin Medical Center and the Israeli Ministry of Health approved the study. We certify that the study was performed in accordance with the ethical standards as laid down in the Declaration of Helsinki.

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Written informed consent was obtained from all parents before treatment. Informed consent for publication of data and photographic material was obtained from all parents.

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The authors have no conflicts of interest to declare.

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Toledano, H., Dotan, G., Friedland, R. et al. Trametinib for orbital plexiform neurofibromas in young children with neurofibromatosis type 1. Childs Nerv Syst 37, 1909–1915 (2021). https://doi.org/10.1007/s00381-021-05127-6

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  • DOI: https://doi.org/10.1007/s00381-021-05127-6

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