Lack of survival advantage with autologous stem-cell transplantation in high-risk neuroblastoma consolidated by anti-GD2 immunotherapy and isotretinoin

Abstract

Since 2003, high-risk neuroblastoma (HR-NB) patients at our center received anti-GD2 antibody 3F8/GM-CSF + isotretinoin – but not myeloablative therapy with autologous stem-cell transplantation (ASCT). Post-ASCT patients referred from elsewhere also received 3F8/GM-CSF + isotretinoin. We therefore accrued a study population of two groups treated during the same period and whose consolidative therapy, aside from ASCT, was identical. We analyzed patients enrolled in 1st complete/very good partial remission (CR/VGPR). Their event-free survival (EFS) and overall survival (OS) were calculated from study entry. Large study size allowed robust statistical analyses of key prognosticators including MYCN amplification, minimal residual disease (MRD), FCGR2A polymorphisms, and killer immunoglobulin-like receptor genotypes of natural killer cells. The 170 study patients included 60 enrolled following ASCT and 110 following conventional chemotherapy. The two cohorts had similar clinical and biological features. Five-year rates for ASCT and non-ASCT patients were, respectively: EFS 65% vs. 51% (p = .128), and OS 76% vs. 75% (p = .975). In multivariate analysis, ASCT was not prognostic and only MRD-negativity after two cycles of 3F8/GM-CSF correlated with significantly improved EFS and OS. Although a trend towards better EFS is seen with ASCT, OS is near identical. Cure rates may be similar, as close surveillance detects localized relapse and effective salvage treatments are applied. ASCT may not be needed to improve outcome when anti-GD2 immunotherapy is used for consolidation after dose-intensive conventional chemotherapy.

Hematopoietic Stem Cell Transplantation Activity in Pediatric Cancer between 2008 and 2014 in the United States: A Center for International Blood and Marrow Transplant Research Report

“…A likely reason for this transient decline in tandem transplants for neuroblastoma could be due to the increased use of immune based therapies such as anti-GD2 antibodies. 21 This decline will need to be evaluated in future observations, since the most recent randomized controlled trial conducted by the Children's Oncology Group demonstrated an improved event free survival with tandem transplants for neuroblastoma. 22 Tandem transplants are increasing for CNS tumors, consistent with data that has shown improved survival with this approach.…”

Overview and recent advances in the treatment of neuroblastoma

“…In a retrospective non-randomized study of historical results at a single institution with extended follow-up, patients with high-risk neuroblastoma treated with or without myeloablative therapy had similar survival rates. Therefore, the authors concluded that courses of myeloablative therapy may not be needed to improve outcome when anti-GD2 immunotherapy is used for consolidation after dose-intensive conventional chemotherapy [85]. These mixed results suggest that the optimal consolidation regimen for patients with highrisk neuroblastoma remains to be determined, likely through carefully controlled, large-scale international clinical trials.…”

Survival of high‐risk pediatric neuroblastoma patients in a developing country

“…Our results suggest markedly worse survival in this setting compared with high‐risk pediatric neuroblastoma patients in North America, Europe, and Asia. Specifically, five‐yr overall survival in our setting was 24% (95% CL: 10%, 41), whereas the highest reported five‐yr overall survival in North America was 76% (95% CL: 66%, 88%) in a highly select group of high‐risk pediatric neuroblastoma patients . In addition, our review of prior studies suggests considerable variation in survival even between developed countries.…”

“…Table describes 13 published reports , and the current study, of five‐yr overall survival among high‐risk pediatric neuroblastoma and summarizes survival differences compared with our population. Half of the reports pertained to high‐risk pediatric neuroblastoma cohorts in North America.…”