Study Identifies Factors Linked to Long-Term Survival in Pediatric/Adolescent DIPG

Maryam Fouladi, MD

A number of biological factors, including age at diagnosis, symptom duration at diagnosis, and HIST1H3B mutation status, are associated with survival ≥2 years in children and young adults with diffuse intrinsic pontine glioma (DIPG), a brainstem malignancy with a median survival <1 year.

Investigators with the Pediatric Oncology DIPG registries analyzed data collected from 1008 patients in Austria, Australia, Croatia, France, Germany, Italy, the Netherlands, North America, Switzerland, and the United Kingdom. Eligible patients in North America and Australia were aged 0 to 27 years (n = 409), while those in Europe and the United Kingdom were aged 0 to 21 years (n = 721). The median patient age was 6.8 years (range, 0-26.8).

All patients were diagnosed with radiographically-confirmed DIPG from 1990 to 2015. The median overall survival (OS) for the entire 1008-patient cohort was 11 months (IQR, 7.5-16). The 1-year OS rate was 42.3% (95% CI, 38.1-44.1) and the 2-year OS rate was 9.6% (95% CI, 7.8-11.3). At 5 years, the median OS rate was 2.2% (95% CI, 1.4-3.4).

Ten percent (n = 101) of patients were long-term survivors (LTSs), defined as a survival time of ≥24 months. The median OS in this group was 33 months (range, 24-156). Very long-term survivors (1.6%; n = 16) were patients who had a median OS of at least 60 months.

The median OS in this group was 78 months (range, 60-156) for a small cohort of very long-term survivors. Short term survivors (STSs; n = 907) were patients with survival times <24 months.

According to univariate analysis, LTSs were more likely to be aged <3 years (28% vs 3% of STSs) or >10 years (33% vs 23% of STSs) at presentation.

Longer symptom duration at diagnosis was also associated with longer OS in univariate analysis. The odds ratio (OR) for 6 to 12 weeks of symptom duration was 1.49 (95% CI, 0.76-2.92), compared with 2.43 (95% CI, 1.04-5.75) for 12 to 24 weeks, and 5.7 (95% CI, 2.77-14.54) for >24 weeks.

On multivariate analysis, age at presentation and symptom duration remained predictors for long-term survival.

Corresponding author Maryam Fouladi, MD, Cincinnati Children’s Hospital Medical Center, and colleagues wrote that, according to their research, these data represent “the most accurate rates of long- and very long-term survival for this rare tumor.”

“Identification of robust survival-associated factors in this study is vital for development of prognostic subgroups and emphasizes patient subsets from whom the most could be learned from analyzing pretreatment biopsy tissue,” they wrote.

“Understanding biologic differences that confer survival advantage in DIPG paves the road toward development of subgroup-specific therapies that, when implemented in the context of clinical trials, may improve outcomes for this devastating disease,” Fouladi et al added.

Most patients presented with ≥1 cranial nerve (CN) palsy (82%), pyramidal tract sign (51%), or cerebellar sign (62%).

Molecular characterization on 181 tumors showed that LTSs were more likely to harbor an HIST1H3B mutation (OR, 1.28; 95% CI, 1.1-1.5; P = .002).

Compared with the H3.3 K27M mutation, the H3.1 K27M mutation was associated with long-term survival and longer median OS (10.4 vs 15 months). H3.3 K27M was associated with short-term survival (OR, 0.88; 95% CI, 0.78-0.99; P = .04).

Median OS was 10.5 months for patients with H3 wild-type tumors (n = 26).

Although age >10 years was associated with long-term survival, 38 (78% of 50 patients in this subgroup displayed the H3.3 K27M mutation. Nine (18%) patients were H3 wild-type, and 3 (6%) had H3.1 K27M mutation.

STSs were more likely to have cranial nerve palsy compared with LTSs (83% vs 72%; P = .008), extrapontine extension (92% vs 85%; P = .04), ring enhancement (38% vs 23%; P = .007), and tumor necrosis (45% v 26%; P = .009). However, CN palsy was not associated with short-term survival on multivariate analysis.

Ring enhancement and tumor necrosis were associated with short-term survival on univariate analysis. Investigators did not perform multivariate analysis because >15% of data was missing for each variable, so the findings could not be validated.

Eighteen (2%) STSs had metastatic disease at diagnosis compared with zero among LTSs.

Data on radiation therapy and systemic therapy was available for 968 patients; 24% received radiation alone, 2% received systemic therapy alone, and 74% received both. Among patients for whom data on type of systemic therapy were available (n = 702), 50% received cytotoxic therapy alone, 27% received targeted therapy alone, and 23% received both.

On multivariate analysis, LTSs received systemic therapy at diagnosis more often than STSs (88% vs 75%; OR, 3; 95% CI, 1.46-7.3; P = .01). After adjusting for age and symptom duration, multivariable logistic regression showed that treatment with bevacizumab (Avastin; OR, 2.67; 95% CI, 1.09-6.55; P = .03) or an EGFR inhibitor (OR, 2.32; 95% CI, 1.1-4.82; P = .03) was associated with long-term survival.

Hoffman LM, Veldhuijzen van Zanten SEM, Colditz N, et al. Clinical, radiologic, pathologic, and molecular characteristics of long-term survivors of diffuse intrinsic pontine glioma (DIPG): a collaborative report from the International and European Society for Pediatric Oncology DIPG Registries [published online May 10, 2018]. J Clin Oncol. doi: 10.1200/JCO.2017.75.9308.