Background: Outcome for high-risk neuroblastoma (HRNBL) patients (pts) with refractory disease at end of induction (EOI) is poor. The impact of therapies such as I-131-MIBG or irinotecan/temozolomide/dinutuximab (I/T/DIN) prior to autologous stem cell transplant (ASCT) on outcome is unknown. Methods: A multi-center, retrospective study of HRNBL pts diagnosed between 2008-2018 with refractory disease at EOI was conducted. Demographics, tumor biology, treatment response, and outcomes were abstracted. 3-year (yr) EFS and OS from time of diagnosis were estimated by the Kaplan-Meier method. Results: 3-yr EFS and OS were 54% and 79% for the 136 pts analyzed. 91 pts received no additional therapy prior to ASCT (Cohort 1); 32 pts received post-induction therapy prior to ASCT (Cohort 2); and 13 pts did not undergo ASCT (Cohort 3). The prevalence of metastatic disease in Cohort 1, 2, and 3 was 65%, 97%, and 85%. 3-yr EFS and OS were not statistically different between Cohort 1 (3-yr EFS and OS; 62% and 81%) and Cohort 2 [3-yr EFS and OS; 49% (p = 0.48) and 82% (p = 0.19)]. Outcome for Cohort 3 pts was significantly worse than Cohort 1 [3-yr EFS: 15% vs. 62% (p < .001); and 3-yr OS: 48% vs. 81% (p = 0.003)] and Cohort 2 [3-yr EFS: 15% vs. 49% (p < .001); and 3-yr OS 48% vs. 82% (p = 0.035)]. For Cohort 2 pts with metastatic disease, post-induction therapy included I/T/DIN (n = 12), MIBG (n = 16), MIBG plus I/T/DIN (n = 1), and other (n = 2). Metastatic disease response was observed in 10/12 (83%) pts who received I/T/DIN and 9/16 (56%) who received MIBG. MIBG plus I/T/DIN (n = 1) or MIBG with chemotherapy (n = 1) also induced response. Among the 21 pts with metastatic disease response, 3-yr EFS and OS were 69% and 94%; significantly better than Cohort 2 patients who did not respond to post-induction therapy [3-yr EFS and OS: 11% (p = 0.016) and 66% (p = 0.2)]. 6 Cohort 2 pts achieved a complete response (CR) in metastatic sites following I/T/DIN (n = 5) or MIBG (n = 1), and all are alive without relapse with median follow-up of 3.4 years (range 2.7-8.1). The single Cohort 3 patient who achieved a metastatic CR with I/T/DIN and did not undergo ASCT remains disease-free 2.4 years from diagnosis. Conclusions: Patient characteristics differed in the 3 Cohorts, reflecting the influence of refractory disease on treatment decisions. For Cohort 2 pts, outcome was better for those with metastatic disease at EOI who responded to post-induction therapy compared to those who did not. Pts who achieved a metastatic CR of refractory disease had excellent survival. Prospective studies testing the efficacy of I/T/DIN in pts with refractory metastatic disease at EOI are warranted.

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