Outcomes Following GD2-Directed Postconsolidation Therapy for Neuroblastoma After Cessation of Random Assignment on ANBL0032: A Report From the Children's Oncology Group

Abstract

PURPOSE Postconsolidation immunotherapy including dinutuximab, granulocyte-macrophage colony-stimulating factor, and interleukin-2 improved outcomes for patients with high-risk neuroblastoma enrolled on the randomized portion of Children's Oncology Group study ANBL0032. After random assignment ended, all patients were assigned to immunotherapy. Survival and toxicities were assessed. PATIENTS AND METHODS Patients with a pre-autologous stem cell transplant (ASCT) response (excluding bone marrow) of partial response or better were eligible. Demographics, stage, tumor biology, pre-ASCT response, and adverse events were summarized using descriptive statistics. Event-free survival (EFS) and overall survival (OS) from time of enrollment (up to day +200 from last ASCT) were evaluated. RESULTS From 2009 to 2015, 1,183 patients were treated. Five-year EFS and OS for the entire cohort were 61.1 ± 1.9% and 71.9 ± 1.7%, respectively. For patients ≥ 18 months old at diagnosis with International Neuroblastoma Staging System stage 4 disease (n = 662) 5-year EFS and OS were 57.0 ± 2.4% and 70.9 ± 2.2%, respectively. EFS was superior for patients with complete response/very good partial response pre-ASCT compared with those with PR (5-year EFS: 64.2 ± 2.2% v 55.4 ± 3.2%, P = .0133); however, OS was not significantly different. Allergic reactions, capillary leak, fever, and hypotension were more frequent during interleukin-2–containing cycles than granulocyte-macrophage colony-stimulating factor–containing cycles ( P < .0001). EFS was superior in patients with higher peak dinutuximab levels during cycle 1 ( P = .034) and those with a high affinity FCGR3A genotype ( P = .0418). Human antichimeric antibody status did not correlate with survival. CONCLUSION Analysis of a cohort assigned to immunotherapy after cessation of random assignment on ANBL0032 confirmed previously described survival and toxicity outcomes. EFS was highest among patients with end-induction complete response/very good partial response. Among patients with available data, higher dinutuximab levels and FCGR3A genotype were associated with superior EFS. These may be predictive biomarkers for dinutuximab therapy.

Eflornithine as Postimmunotherapy Maintenance in High-Risk Neuroblastoma: Externally Controlled, Propensity Score–Matched Survival Outcome Comparisons

“…ANBL0032 (enrolled 2001-2015) was conducted by COG. [3][4][5] A total of 1,328 patients were randomly or nonrandomly assigned to postconsolidation therapy comprising dinutuximab, RA, sargramostim, and aldesleukin (excluding n 5 112 initially randomly assigned to RA alone). Patients were required to have previously completed high-risk…”

GM‐CSF, G‐CSF or no cytokine therapy with anti‐GD2 immunotherapy for high‐risk neuroblastoma

“…Data from the non-randomized extension of the registration trial demonstrated lower grade 3-4 hematologic adverse events in sargramostim cycles vs IL-2 cycles. 27 Other studies demonstrated the benefit of adding dinutuximab plus sargramostim to chemotherapy for relapsed/ refractory HR-NB, 82,84,85 including patients previously treated with anti-GD2 therapy. 84,85 A more recent study explored earlier use of dinutuximab with GM-CSF as part of induction therapy in HR-NB and showed promising end-of-induction objective response rates of up to 87%.…”

Phase 2 study of anti-disialoganglioside antibody, dinutuximab, in combination with GM-CSF in patients with recurrent osteosarcoma: A report from the Children's Oncology Group

“…Dinutuximab concentrations were measured in plasma on Days 4 and 7 of Cycle 1 dinutuximab infusion and prior to start of Cycle 2 infusion. Samples were analysed using a validated electrochemiluminescence method at BioAgilytix Labs, Durham, NC, as previously published [9].…”

“…This analysis was performed using a validated electro chemiluminescent method (Bioagilytix Labs, Durham, NC). A three-step process of screening assay, confirmatory assay, and titration assay was utilised, as previously published [9].…”

“…The determination of HACA positivity in this study corresponds to that used for a recent COG neuroblastoma trial using dinutuximab [9]. Briefly, patients were considered HACA evaluable if they had at least one sample available for analysis after cycle 1, Day 4 (C1D4).…”