Impact of trametinib on the neuropsychological profile of NF1 patients

Eve Lalancette¹, Édith Cantin², Marie-Ève Routhier², Chantal Mailloux³, Marie-Claude Bertrand³, Dorsa Sadat Kiaei⁴, Valérie Larouche⁵, Uri Tabori⁶, Cynthia Hawkins⁷, Benjamin Ellezam⁸, Jean-Claude Décarie⁹, Yves Théoret¹⁰, Marie-Élaine Métras¹⁰, Tara McKeown⁶, Luis H Ospina¹¹, Stéphanie Vairy¹², Vijay Ramaswamy⁶, Hallie Coltin¹³, Serge Sultan⁴, Geneviève Legault¹⁴, Éric Bouffet⁶, Lucie Lafay-Cousin¹⁵, Juliette Hukin¹⁶, Craig Erker¹⁷, Maxime Caru¹⁸, Mathieu Dehaes^{4

19}, Nada Jabado²⁰, Sébastien Perreault²¹, Sarah Lippé^{4

22}

Affiliations

¹ CHU Sainte-Justine Research Center, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada. eve.lalancette.1@umontreal.ca.
² Division of Neuropsychology, Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, QC, Canada.
³ Division of Neuropsychology, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
⁴ CHU Sainte-Justine Research Center, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
⁵ Division of Hemato-Oncology, Department of Pediatrics, Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, QC, Canada.
⁶ Division of Hemato-Oncology, Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada.
⁷ Department of Pathology, Hospital for Sick Children, Toronto, ON, Canada.
⁸ Department of Pathology, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
⁹ Department of Radiology, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
¹⁰ Department of Pharmacology, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
¹¹ Department of Ophthalmology, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
¹² Division of Hemato-Oncology, CHU Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada.
¹³ Department of Hemato-Oncology, CHU Sainte Justine, Université de Montréal, Montréal, QC, Canada.
¹⁴ Division of Neurology, Department of Pediatrics, McGill University Health Center, Montreal Children's Hospital, Montréal, QC, Canada.
¹⁵ Departments of Oncology and Pediatrics, Alberta Children's Hospital, University of Calgary, Cumming School of Medicine, Calgary, AB, Canada.
¹⁶ Department of Pediatrics, Divisions of Neurology and Oncology, BC Children's Hospital, University of British Columbia, Vancouver, BCBC, Canada.
¹⁷ Division of Hemato-Oncology, Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, NS, Canada.
¹⁸ Department of Pediatrics, Division of Hematology and Oncology, Pennsylvania State Health Children's Hospital, Hershey, PA, USA.
¹⁹ Department of Radiology, Radio-Oncology and Nuclear Medicine, University of Montréal, Montréal, Canada.
²⁰ Division of Hemato-Oncology, Department of Pediatrics, McGill University Health Center, Montreal Children's Hospital, Montréal, QC, Canada.
²¹ Division of Child Neurology, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
²² Department of Psychology, Faculty of Arts and Sciences, University of Montréal, Montréal, Canada.

PMID: 38443693
DOI: 10.1007/s11060-024-04624-3

Clinical Trial

Impact of trametinib on the neuropsychological profile of NF1 patients

Eve Lalancette et al. J Neurooncol. 2024 May.

. 2024 May;167(3):447-454.

doi: 10.1007/s11060-024-04624-3. Epub 2024 Mar 5.

Authors

Affiliations

¹ CHU Sainte-Justine Research Center, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada. eve.lalancette.1@umontreal.ca.
² Division of Neuropsychology, Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, QC, Canada.
³ Division of Neuropsychology, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
⁴ CHU Sainte-Justine Research Center, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
⁵ Division of Hemato-Oncology, Department of Pediatrics, Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, QC, Canada.
⁶ Division of Hemato-Oncology, Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada.
⁷ Department of Pathology, Hospital for Sick Children, Toronto, ON, Canada.
⁸ Department of Pathology, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
⁹ Department of Radiology, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
¹⁰ Department of Pharmacology, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
¹¹ Department of Ophthalmology, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
¹² Division of Hemato-Oncology, CHU Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada.
¹³ Department of Hemato-Oncology, CHU Sainte Justine, Université de Montréal, Montréal, QC, Canada.
¹⁴ Division of Neurology, Department of Pediatrics, McGill University Health Center, Montreal Children's Hospital, Montréal, QC, Canada.
¹⁵ Departments of Oncology and Pediatrics, Alberta Children's Hospital, University of Calgary, Cumming School of Medicine, Calgary, AB, Canada.
¹⁶ Department of Pediatrics, Divisions of Neurology and Oncology, BC Children's Hospital, University of British Columbia, Vancouver, BCBC, Canada.
¹⁷ Division of Hemato-Oncology, Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, NS, Canada.
¹⁸ Department of Pediatrics, Division of Hematology and Oncology, Pennsylvania State Health Children's Hospital, Hershey, PA, USA.
¹⁹ Department of Radiology, Radio-Oncology and Nuclear Medicine, University of Montréal, Montréal, Canada.
²⁰ Division of Hemato-Oncology, Department of Pediatrics, McGill University Health Center, Montreal Children's Hospital, Montréal, QC, Canada.
²¹ Division of Child Neurology, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
²² Department of Psychology, Faculty of Arts and Sciences, University of Montréal, Montréal, Canada.

PMID: 38443693
DOI: 10.1007/s11060-024-04624-3

Abstract

Purpose: The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation.

Methods: Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change.

Results: Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes.

Conclusion: These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.

Keywords: MEK inhibitor; Neurofibromatosis type 1; Neuropsychological profile; Trametinib.

PubMed Disclaimer

References

1. Lammert M et al (2005) Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol 141(1):71–74 - DOI - PubMed
1. Wang Y et al (2012) ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities. Cell 150(4):816–830 - DOI - PubMed - PMC
1. Hyman SL, Shores A, North KN (2005) The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Neurology 65(7):1037–1044 - DOI - PubMed
1. Payne JM et al (2013) Paired associate learning in children with neurofibromatosis type 1: implications for clinical trials. J Neurol 260(1):214–220 - DOI - PubMed
1. Sweatt JD (2004) Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol 14(3):311–317 - DOI - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
- Springer
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Impact of trametinib on the neuropsychological profile of NF1 patients

Affiliations

Impact of trametinib on the neuropsychological profile of NF1 patients

Authors

Affiliations

Abstract

References

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous