Matthias A. Karajannis

Background: We analyzed whether changes in RB1 circulating tumor DNA (ctDNA) variant allele frequency (VAF) in plasma and/or cerebrospinal fluid (CSF) was associated with clinical outcomes in patients with retinoblastoma (RB). Methods: We reviewed all RB patients treated at MSKCC and SCEH who had serial plasma and CSF ctDNA analyses. Results: 4/33 intraocular RB patients developed extraocular RB, all associated with an increase in plasma RB1 ctDNA VAF. In the remaining 29 patients who did not develop extraocular disease, RB1 ctDNA remained undetectable. Plasma RB1 ctDNA was positive in 15 of 16 extraocular RB patients at diagnosis and became undetectable in 13 of 14 patients post treatment; the sole patient with rising RB1 ctDNA died of disease. Two stage 4a patients who developed CNS relapse had positive/rising levels of plasma RB1 ctDNA VAF at relapse. 11 patients in remission have undetectable RB1 ctDNA. Two stage 4a patients with residual bony lesions post-chemotherapy but negative ctDNA remain in remission. CSF ctDNA was positive in all 7 patients with central nervous system (CNS) disease at diagnosis and became undetectable post treatment in 3 of 4 patients; the only patient with rising ctDNA died of disease. Two suffered disease recurrence in the CNS post treatment associated with positive/rising levels of CSF RB1 ctDNA VAF. Two stage 4a RB patients had CSF ctDNA positivity at initial diagnosis and recurred in the CNS. Conclusions: Longitudinal ctDNA may predict risk of developing extraocular RB. Its use for monitoring and risk stratification deserves further study.

Map demonstrating the countries represented by contributing institutions.

Long-term survivors ≥ 5 years (n = 12)

Patients with G34V mutation subtype (n = 9)

Initial chemotherapy combinations

Kaplan-Meier survival plots demonstrating overall survival. (A). Initial chemotherapy (all ages): TMZ-based vs TMZ/CCNU. (B). Initial chemotherapy (under 18 years old): TMZ-based vs TMZ/CCNU. (C). Re-irradiation: yes vs no. (D). ATRX mutation: yes vs no. (E). PDGFRA amplification: yes vs no. (F) TP53 mutation: yes vs no. (G). PDGFRA mutation: yes vs no.

Purpose: Knowledge of prognostic factors and long-term survival in patients with diffuse hemispheric glioma, H3 G34–mutant (DHG, H3 G34), remains limited in this tumor with a poor prognosis.Experimental Design:This retrospective, multi-institutional study investigated prognostic variables for patients with DHG, H3 G34, and their association with progression-free survival (PFS) and overall survival (OS). Uni- and multivariable Cox proportional hazard models were applied with multiple imputed datasets.Results:A total of 153 patients (142 G34R, 9 G34V, 2 via DNA methylation) were included. The median age at diagnosis was 17 years (range, 2–45). Initial gross/near total resection (GTR/NTR) was achieved in 43% of patients. Radiation was given in 91% (85% focal irradiation), and initial chemotherapy was given in 87% [70% temozolomide-based (TMZ), 25% TMZ/lomustine, 5% non-TMZ]. Median OS was 24 months [interquartile range (IQR), 22–28] with a median PFS of 14 months (IQR, 12–19). Twelve patients (8%) were found to be long-term survivors (≥5 years). Exploratory multivariable analysis showed that adjuvant radiotherapy [HR, 0.076; 95% confidence interval (CI), 0.033–0.17] and achieving GTR/NTR compared with < NTR (HR, 0.51; 95% CI, 0.33–0.78) were associated with improved PFS. Multivariable analysis showed improved OS with increasing age at diagnosis (HR, 0.70; 95% CI, 0.57–0.87), initial radiotherapy (HR, 0.38; 95% CI, 0.15–0.96), and initial GTR/NTR compared with < NTR (HR, 0.60; 95% CI, 0.37–0.97).Conclusions:This cohort highlights prognostic factors for patients with DHG, H3 G34, and describes relapse patterns and therapy approaches. Clinical trials and prospective registries are needed to improve outcomes.