Leptomeningeal disease in histone-mutant gliomas

Abstract

Background: The 2016 WHO classification described a subtype of midline gliomas harboring histone 3 (H3) K27M alterations, and the 2021 edition added a new subtype of hemispheric diffuse gliomas with H3 G34R/V mutations. The incidence and clinical behavior of leptomeningeal disease (LMD) in these patients is not well defined.

Methods: Retrospective study of patients with H3-altered gliomas diagnosed from 01/2012 to 08/2021; histone mutations were identified through next-generation sequencing (NGS) of tumor biopsy and/or cerebrospinal fluid (CSF).

Results: We identified 42 patients harboring H3 mutations (K27M mutations in 33 patients, G34R/V in 8, and both in one). Median age was 21 (4-70); 27 were male. LMD was diagnosed in 21/42 (50%) patients, corresponding to a 3-year cumulative incidence of 44.7% (95% confidence interval (CI): 26.1%-63.4%) for the K27-mutant group and a 1-year cumulative incidence of 37.5% in the G34-mutant group (95% CI: 0.01%-74.4%; no events after 1 year). Median time from tumor diagnosis to LMD was 12.9 months for H3-K27 patients and 5.6 months for H3-G34 patients. H3 mutation was detected in CSF in all patients with LMD who had NGS (8 H3-K27-mutant patients). In the H3-K27-mutant group, modeled risk of death was increased in patients who developed LMD (hazard ratio: 7.37, 95% CI: 2.98-18.23, P < .0001).

Conclusions: In our cohort, 50% of patients developed LMD. Although further studies are needed, CSF ctDNA characterization may aid in identifying molecular tumor profiles in glioma patients with LMD, and neuroaxis imaging and CSF NGS should be considered for early LMD detection.

Keywords: cerebrospinal fluid; circulating tumor DNA; diffuse hemispheric glioma; diffuse midline histone mutations; glioma; leptomeningeal disease.

Figure 1.

Oncoplot detailing next-generation sequencing results and clinicopathological characteristics of all 42 patients, organized by histone mutation. Copy number variations are represented by coloring of the middle portion of the square (deletions in red, amplifications in blue). For patients with both CSF and tissue NGS available, tissue results are included here; for 4 patients only CSF NGS was available. *Denotes patient with both K27 and G34 mutations.

Figure 2.

Cumulative incidence of leptomeningeal disease for H3 K27 patients (left) and H3 G34 patients (right).

Figure 3.

Imaging signs of LMD. (A) MRI from patient in the H3 G34 group (patient 19 in Table 2) showing peritumoral sulcal enhancement in the right parasagittal frontal lobe. (B) and (C) MRI of the brain (B) and spine (C) from a patient from the H3 K27 group (corresponding to patient 1 in Table 2) showing diffuse leptomeningeal enhancement in the cerebellar folia and brainstem surface as well as along the lower spinal cord and cauda equina.

Figure 4.

Overall survival of H3 K27 group according to LMD status (LMD in orange, no LMD in blue), landmarked to median time of LMD diagnosis.