Clinical efficacy/effectiveness, safety, and health-related quality of life associated with relapsed/refractory pediatric low-grade glioma treatments: systematic literature review

Abstract Background Patients with relapsed/refractory pediatric low-grade glioma (R/R pLGG) face considerable long-term morbidity. Most cases are driven by mitogen-activated protein kinase (MAPK) pathway alterations, for which several targeted agents have been evaluated. Systematic literature reviews (SLRs) were performed to deepen understanding of efficacy/effectiveness, safety/tolerability, health-related quality of life (HRQoL), and functional outcomes of systemic drug therapies used in R/R pLGG. Methods In two SLRs, bibliographic databases and gray literature were last searched in July 2025 for eligible clinical trials and real-world studies, respectively, in patients with R/R pLGG (excluding neurofibromatosis type 1) aged 0.5–25 years (no date restrictions; PROSPERO registration, CRD420250648339). Results Twenty-nine clinical trials were included: 19 single-arm, seven non-randomized, three randomized. Eleven trials investigated 10 MAPK inhibitor regimens; 13 trials investigated 12 chemotherapy-based regimens. Of 16 real-world studies included, 14 were retrospective; four evaluated MAPK inhibitors, 10 evaluated 18 chemotherapy-based regimens. In MAPK pathway-altered clinical trial cohorts, MAPK inhibitor overall response rates (ORRs) were 9%–93%; in chemotherapy-based regimen clinical trial populations without molecular selection, ORRs were 0%–52%. Safety/tolerability reporting was limited. Substantial population and methodological heterogeneity complicated between-study comparisons. HRQoL and functional outcome data were notably sparse. Conclusions The therapeutic diversity and assessment heterogeneity highlight the ongoing evolution of R/R pLGG treatment and study standardization. MAPK inhibitors demonstrate encouraging tumor responses and safety profiles. Robust evidence of effective, well-tolerated therapies from studies incorporating molecular stratification (e.g. by BRAF alteration), consistent assessment methodologies, and long-term HRQoL and functional outcomes, is needed to inform R/R pLGG treatment. Clinical efficacy/effectiveness, safety, and health-related quality of life associated with relapsed/refractory pediatric low-grade glioma treatments: systematic literature review Olaf Witt, Rikke Brandt, Aude Houchard, Nadia Kelkouli, Ben Mayer, Lydia Vinals, Angela Mastronuzzi, Darren Hargrave