Introduction Mitogen-activated protein kinase pathway inhibitors (MAPKi) are an important therapeutic option for patients with unresectable, symptomatic or progressive pediatric low-grade gliomas (pLGGs). Despite high disease control rates during treatment, tumor regrowth following MAPKi discontinuation has been reported. This phenomenon, termed rebound regrowth (RR), appears biologically and clinically distinct from classic off-therapy progression or acquired resistance to MAPKi. However, the incidence, timing, and predictors of RR remain poorly defined. This systematic review synthesizes evidence on RR following MAPKi discontinuation in pLGG. Methods A systematic literature review was conducted according to PRISMA 2020 guidelines. Eligible studies included clinical trials, cohort studies, and case reports/series, involving patients aged 0–25 years with NF1-associated or sporadic pLGG, who experienced RR after MAPKi dose reduction or discontinuation. RR was defined as radiological progression within 6 months after treatment cessation. Cohort-level and individual patient-level data were extracted. Results Twenty publications met inclusion criteria. Among ten studies involving ≥10 patients, RR was documented in at least 23 of 131 evaluable individuals. Additionally, individual-level data of 21 patients were analyzed. Most RR events occurred early after MAPKi cessation, were detected radiologically and clinically asymptomatic. RR was reported most frequently in tumors harboring the BRAF V600E variant. Most patients responded to MAPKi rechallenge, suggesting preserved drug sensitivity. Conclusion RR is a reproducible and clinically relevant phenomenon following MAPKi discontinuation in pLGG. Standardized definitions, structured post-discontinuation surveillance, and prospective evaluation of treatment duration and dose-tapering strategies are needed to optimize MAPKi discontinuation and long-term disease management in patients with pLGG.
Styczewska et al. (2026) studied this question.