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Clinical Trial
. 2012 Sep 10;30(26):3264-70.
doi: 10.1200/JCO.2011.41.3807. Epub 2012 Aug 6.

Murine anti-GD2 monoclonal antibody 3F8 combined with granulocyte-macrophage colony-stimulating factor and 13-cis-retinoic acid in high-risk patients with stage 4 neuroblastoma in first remission

Nai-Kong V Cheung  1 , Irene Y Cheung, Brian H Kushner, Irina Ostrovnaya, Elizabeth Chamberlain, Kim Kramer, Shakeel Modak
Affiliations
Clinical Trial

Murine anti-GD2 monoclonal antibody 3F8 combined with granulocyte-macrophage colony-stimulating factor and 13-cis-retinoic acid in high-risk patients with stage 4 neuroblastoma in first remission

Nai-Kong V Cheung et al. J Clin Oncol. .

Abstract

Purpose: Anti-GD2 monoclonal antibody (MoAb) combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown efficacy against neuroblastoma (NB). Prognostic variables that could influence clinical outcome were explored.

Patients and methods: One hundred sixty-nine children diagnosed with stage 4 NB (1988 to 2008) were enrolled onto consecutive anti-GD2 murine MoAb 3F8 ± GM-CSF ± 13-cis-retinoic acid (CRA) protocols after achieving first remission (complete remission/very good partial remission). Patients enrolled in regimen A (n = 43 high-risk [HR] patients) received 3F8 alone; regimen B (n = 41 HR patients), 3F8 + intravenous GM-CSF + CRA, after stem-cell transplantation (SCT); and regimen C (n = 85), 3F8 + subcutaneous GM-CSF + CRA, 46 of 85 after SCT, whereas 28 of 85 required additional induction therapy and were deemed ultra high risk (UHR). Marrow minimal residual disease (MRD) was measured by quantitative reverse transcription polymerase chain reaction. Survival probability was calculated by the Kaplan-Meier method, and prognostic variables were analyzed by multivariate Cox regression model.

Results: At 5 years from the start of immunotherapy, progression-free survival (PFS) improved from 44% for HR patients receiving regimen A to 56% and 62% for those receiving regimens B and C, respectively. Overall survival (OS) was 49%, 61%, and 81%, respectively. PFS and OS of UHR patients were 36% and 75%, respectively. Relapse was mostly at isolated sites. Independent adverse prognostic factors included UHR (PFS) and post-cycle two MRD (PFS and OS), whereas the prognostic factors for improved outcome were missing killer immunoglobulin-like receptor ligand (PFS and OS), human antimouse antibody response (OS), and regimen C (OS).

Conclusion: Retrospective analysis of consecutive trials from a single center demonstrated that MoAb 3F8 + GM-CSF + CRA is effective against chemotherapy-resistant marrow MRD. Its positive impact on long-term survival can only be confirmed definitively by randomized studies.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
(A) Progression-free survival (PFS) for 169 patients with stage 4 neuroblastoma in first remission after consecutive immunotherapy regimens: 3F8 alone (regimen A–high risk [HR]; n = 43), 3F8 + intravenous granulocyte-macrophage colony-stimulating factor (GM-CSF) + 13-cis-retinoic acid (CRA; regimen B-HR; n = 41), and 3F8 + subcutaneous GM-CSF + CRA (regimen C-HR; n = 57 and regimen C–ultra HR [UHR]; n = 28); P = .018 (derived from log-rank test to compare PFS among these four groups). (B) Overall survival (OS) among same cohort of patients; P = .003 (derived from log-rank test to compare OS among these four groups).
Fig 2.
Fig 2.
Strong association between minimal residual disease status after two cycles of 3F8 therapy (post-MRD) and progression-free survival for 169 high-risk patients with stage 4 neuroblastoma; P < .001.
Fig A1.
Fig A1.
Overall survival among patients treated with regimen C, stratified according high-risk (HR; with or without stem-cell transplantation [SCT]) and ultra-HR (UHR; with or without SCT) status; P = .64.
Fig A2.
Fig A2.
Absence of association between minimal residual disease status before therapy (pre-MRD) and progression-free survival among 169 high-risk patients with stage 4 neuroblastoma.
Fig A3.
Fig A3.
Prognostic importance of missing killer immunoglobulin-like receptor (KIR) ligand among (A) all patients, (B) those with positive minimal residual disease status after two cycles of 3F8 therapy (post-MRD; P = .16), and (C) those with negative post-MRD (P = .1).
See this image and copyright information in PMC

Comment in

  • About the benefits of immunotherapy for high-risk neuroblastoma.
    Moreno L, Barone G, Park JR, Pearson AD. Moreno L, et al. J Clin Oncol. 2013 Feb 10;31(5):649-50. doi: 10.1200/JCO.2012.47.4080. Epub 2013 Jan 7. J Clin Oncol. 2013. PMID: 23295791 No abstract available.
  • Reply to L. Moreno et al.
    Cheung NK, Cheung IY, Ostrovnaya I, Kushner BH. Cheung NK, et al. J Clin Oncol. 2013 Feb 10;31(5):650-1. doi: 10.1200/JCO.2012.47.4593. J Clin Oncol. 2013. PMID: 23520645 No abstract available.

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