Improved outcome for patients with alternative lengthening of telomeres (ALT) neuroblastoma randomized to tandem myeloablative therapy on COG ANBL0532
Introduction
High-risk neuroblastoma (HRNB) patients with alternative lengthening of telomeres (ALT) tumors (~23% of patients) have lower overall survival (OS) compared to other HRNB patients. HRNB patients enrolled in COG ANBL0532 randomized to tandem autologous stem cell transplant (ASCT) had a superior event-free survival (EFS) compared to those randomized to single ASCT. We sought to determine if ALT HRNB patients on ANBL0532 benefited from tandem ASCT.
Methods
We determined the presence of telomere maintenance mechanisms (TMM) in 204 primary tumors from ANBL0532 patients. Telomere maintenance mechanism was defined as per Cancer Res 80:2663, 2020; patients designated as TERT+ had high TERT mRNA expressing tumors and as ALT if tumors were positive for the telomeric DNA C-circle assay (CCA) or ultrabright telomere foci (UTF). Due to non-proportional hazards, survival comparisons were performed using the Improved Two-Stage Procedure (J Stat Comput Simul. 2017; 87:1877).
Results
TMM status was: ALT n=48 (23.5%), TERT+ n=140 (68.6%), TMM negative n=16 (7.8%). Patients with TERT+ tumors more frequently progressed early, but 8-year OS was superior for TERT+ compared to ALT (58.1±4.6% vs 41.6±8.2%; p=0.0007), while 8-year OS for TMM negative was 67.7±12.2%. The 8-year OS for TERT+ patients randomized to single (n=67) vs tandem (n=59) ASCT was 56.9±6.7% vs 71.8±6.5% (p=0.32) and for ALT patients randomized to single (n=20) vs tandem (n=19) ASCT was 26.9±11.5% vs 61.1±13.5% (p=0.011). For patients on ANBL0532 who received dinutuximab post-consolidation therapy, the 8-year OS for TERT+ patients who underwent single (n=52) vs tandem (n=43) ASCT was 53.5±7.6% vs 75.8±7.8% (p=0.10) while for ALT patients who underwent single (n=13) vs tandem (n=10) ASCT it was 23.1±14.3% vs 77.8±16.4% (p=0.022).
Conclusion
This is the first study of TMM for neuroblastoma patients treated on a single prospective clinical trial. As previously reported, patients with ALT HRNB have inferior OS relative to TERT+ HRNB. As expected, TMM negative HRNB patients had apparently higher OS than ALT or TERT+ but small numbers preclude formal analyses. OS was significantly improved in ALT HRNB by tandem ASCT. These data support use of tandem myeloablative therapy for patients with ALT neuroblastoma until effective targeted therapies become available.