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Investigation of the Role of Dinutuximab Beta-Based Immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1)
Ladenstein, R., Potschger, U., Valteau-Couanet, D., Luksch, R., Castel, V., Ash, S., Laureys, G., Brock, P., Michon, J. M., Owens, C., et al
Cancers. 2020;12(2)
Abstract
To explore the effects of immunotherapy in the International Society of Paediatric Oncology Europe Neuroblastoma Group SIOPEN high-risk neuroblastoma 1 trial (HR-NBL1 trial), two cohorts were studied: one prior to and one after the introduction of dinutuximab beta. All patients received standard induction and high-dose therapy (HDT) with autologous stem cell rescue (ASCR); the local control comprised surgery and radiotherapy to the primary tumour site, followed by isotretinoin. A landmark timepoint of 109 days, resulting from the median time between ASCR and initiation of immunotherapy, was used to define patients' eligibility in the pre-immunotherapy analysis cohort. Median follow-up was 5.8 years (inter-quartile range (IQR): 4.2-8.2 years) for 844 eligible patients balanced for risk factors, such as age, sex, stage 4, MYCN amplification and response prior to HDT. The five-year event-free and overall survival (95% confidence interval (CI) of 466 patients not receiving immunotherapy was 42% (38-47%) and 50% (46-55%) but was 57% (51-62%) and 64% (59-69%) for 378 patients receiving immunotherapy (p < 0.001). A multivariate analysis identified absence of immunotherapy (p = 0.0002, hazard ratio (HR) 1.573); type of HDT (p = 0.0029, HR 1.431); less than complete response prior to maintenance therapy (p = 0.0043, HR 1.494) and >1 metastatic compartment at diagnosis (p < 0.001, HR 2.665) as risk factors for relapse or progression. Results suggest an important role for dinutuximab beta-based immunotherapy within the treatment concepts applied in HR-NBL1/SIOPEN.
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Anti-GD2 antibody-containing immunotherapy postconsolidation therapy for people with high-risk neuroblastoma treated with autologous haematopoietic stem cell transplantation
Peinemann, F., van Dalen, E. C., Enk, H., Tytgat, G. A.
The Cochrane database of systematic reviews. 2019;4:Cd012442
Abstract
BACKGROUND Neuroblastoma is a rare malignant disease that primarily affects children. The tumours mainly develop in the adrenal medullary tissue, and an abdominal mass is the most common presentation. High-risk disease is characterised by metastasis and other primary tumour characteristics resulting in increased risk for an adverse outcome. The GD2 carbohydrate antigen is expressed on the cell surface of neuroblastoma tumour cells and is thus a promising target for anti-GD2 antibody-containing immunotherapy. OBJECTIVES To assess the efficacy of anti-GD2 antibody-containing postconsolidation immunotherapy after high-dose chemotherapy (HDCT) and autologous haematopoietic stem cell transplantation (HSCT) compared to standard therapy after HDCT and autologous HSCT in people with high-risk neuroblastoma. Our primary outcomes were overall survival and treatment-related mortality. Our secondary outcomes were progression-free survival, event-free survival, early toxicity, late non-haematological toxicity, and health-related quality of life. SEARCH METHODS We searched the electronic databases CENTRAL (2018, Issue 9), MEDLINE (PubMed), and Embase (Ovid) on 20 September 2018. We searched trial registries and conference proceedings on 28 October 2018. Further searches included reference lists of recent reviews and relevant articles as well as contacting experts in the field. There were no limits on publication year or language. SELECTION CRITERIA Randomised controlled trials evaluating anti-GD2 antibody-containing immunotherapy after HDCT and autologous HSCT in people with high-risk neuroblastoma. DATA COLLECTION AND ANALYSIS Two review authors independently performed study selection, abstracted data on study and participant characteristics, and assessed risk of bias and GRADE. Any differences were resolved by discussion, with third-party arbitration unnecessary. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We used the five GRADE considerations, that is study limitations, consistency of effect, imprecision, indirectness, and publication bias, to judge the quality of the evidence. MAIN RESULTS We identified one randomised controlled trial that included 226 people with high-risk neuroblastoma who were pre-treated with autologous HSCT. The study randomised 113 participants to receive immunotherapy including isotretinoin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and ch14.18, a type of anti-GD2 antibody also known as dinutuximab. The study randomised another 113 participants to receive standard therapy including isotretinoin.The results on overall survival favoured the dinutuximab-containing immunotherapy group (hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31 to 0.80; P = 0.004). The results on event-free survival also favoured the dinutuximab-containing immunotherapy group (HR 0.61, 95% CI 0.41 to 0.92; P = 0.020). Randomised data on adverse events were not reported separately. The study did not report progression-free survival, late non-haematological toxicity, and health-related quality of life as separate endpoints. We graded the quality of the evidence as moderate. AUTHORS' CONCLUSIONS The evidence base favours dinutuximab-containing immunotherapy compared to standard therapy concerning overall survival and event-free survival in people with high-risk neuroblastoma pre-treated with autologous HSCT. Randomised data on adverse events are lacking, therefore more research is needed before definitive conclusions can be made regarding this outcome.
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Immune Reconstitution Following Autologous Stem Cell Transplantation in Patients with High-Risk Neuroblastoma at the Time of Immunotherapy
Nassin, M. L., Nicolaou, E., Gurbuxani, S., Cohn, S. L., Cunningham, J. M., LaBelle, J. L.
Biology of Blood & Marrow Transplantation. 2017
Abstract
Outcomes for patients with high-risk neuroblastoma (HR-NBL) are significantly improved with the addition of immunotherapy (dinutuximab + cytokines) following autologous hematopoietic stem cell transplantation (autoHSCT). We hypothesized that the immune system is not fully reconstituted at the initiation of immunotherapy. To test this hypothesis, we evaluated hematologic and immune subsets in thirty-four patients with HR-NBL before and following autoHSCT(s). We found that absolute T-, B-, and NK cell counts at the time of immunotherapy were below normal in 80% of patients. Patients with residual disease at the time of transplant had significantly lower absolute lymphocyte counts (ALC; P = 0.008), CD16+ cells (P = 0.009), and abnormal ratio of cytokine releasing to cytotoxic NK cells at the time of dinutuximab treatment. Additionally, the preparative regimen used during autoHSCT predicted immune recovery. Lastly, higher total white blood cell (WBC; P = 0.013) and ALC (P = 0.013) three months following completion of therapy was measured in patients who remained in remission compared to those who relapsed. Our results indicate that most patients with HR-NBL have not fully immune reconstituted at the time of dinutuximab treatment post autoHSCT and that immune recovery may correlate with disease-related outcomes in patients with highest risk disease.
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Lack of survival advantage with autologous stem-cell transplantation in high-risk neuroblastoma consolidated by anti-GD2 immunotherapy and isotretinoin
Kushner, B. H., Ostrovnaya, I., Cheung, I. Y., Kuk, D., Modak, S., Kramer, K., Roberts, S. S., Basu, E. M., Yataghene, K., Cheung, N. K.
Oncotarget. 2016;7(4):4155-66
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.