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Background: Addition of anti-GD2 antibodies to temozolomide-based chemotherapy has demonstrated increased antitumor activity and progression-free survival in patients with relapsed/progressive high-risk neuroblastoma. However, chemo-immunotherapy is not yet approved for this indication. This study presents the chemo-immunotherapy experience in patients with relapsed/progressive high-risk neuroblastoma treated within the off-label use program of the Neuroblastoma Committee of the French Society of Pediatric Oncology (SFCE)., Methods: Dinutuximab beta (dB) was administered alongside temozolomide-topotecan (TOTEM) or temozolomide-irinotecan (TEMIRI) at first disease relapse/progression or topotecan-cyclophosphamide (TopoCyclo) at further relapse/progression. Real-world data on demographics, treatment, antitumor activity and safety was collected from all patients after inclusion in SACHA-France (NCT04477681), a prospective national registry, which documents safety and efficacy data on innovative anticancer therapies prescribed to patients ≤ 25 years old as compassionate or off-label use., Results: Between February 2021 and July 2023, 39 patients with confirmed relapsed/progressive high-risk neuroblastoma (median age 6 years, range 1-24) were treated with dB+TopoCyclo (n = 24) or dB+TOTEM/TEMIRI (n = 15) across 17 centers. In total, 163 chemo-immunotherapy cycles were administered, main toxicities were mild or moderate, with higher incidence of hematological adverse drug reactions with dB+TopoCyclo than dB+TOTEM/TEMIRI. Objective response rate was 42% for dB+TopoCyclo (CI95% 22-63%) and 40% for dB+TOTEM/TEMIRI (CI95% 16-68%)., Conclusion: Similar objective response rates for dB+TopoCyclo and dB+TOTEM/TEMIRI in patients with relapsed/progressive high-risk neuroblastoma emphasize the importance of chemo-immunotherapy, irrespective of the chemotherapy backbone., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Pablo Berlanga reported an advisory role (institutional funding) for EUSA Pharma and grants and drugs for trials from Bayer outside the submitted work. No other disclosures were reported., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Despite poor survival for patients with relapsed or refractory neuroblastoma, only 10-16% of patients are reported to be included in early phase trials. This study aimed to explore the impact of molecular profiling within the prospective precision cancer medicine trial MAPPYACTS (NCT02613962) on subsequent early phase trial recruitment and treatment by matched targeted therapies in this population., Methods and Materials: Clinical data from all French patients with relapsed/refractory neuroblastoma enrolled in MAPPYACTS were analyzed for subsequent matched/non-matched targeted treatment based on clinical tumor board (CMTB) recommendations., Results: From 93 patients with neuroblastoma included in French centers, 78 (84%) underwent whole exome and RNA sequencing and were discussed in the CMTB. Higher rate of successful sequencing analysis was observed in patients with relapsed disease compared to those with refractory disease (p = 0.0002). Among the 50 patients that presented with a new disease relapse/progression after the CMTB recommendations, 35 patients (70%) had at least one actionable alteration identified on the tumor at the time of relapse. Eighteen patients (36%) were included in an early phase clinical trial, 11 of these with a matched agent, 7 with a non-matched treatment; 13 patients were included in the AcSé ESMART trial. Five patients (10%) received a matched targeted therapy outside a clinical trial., Conclusion: Patients with neuroblastoma in the European MAPPYACTS trial were more likely to be included in early phase trials compared to previous reports. Early deep sequencing at first treatment failure, comprehensive therapeutic discussions in molecular tumor boards and innovative trials like AcSé -ESMART improve access to innovative therapies for patients with relapsed/refractory neuroblastoma., Clinical Trial Registration: NCT02613962., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background and Aims: Extracranial malignant rhabdoid tumours are tumours that mainly affect young children and have a poor prognosis. In 2014, the European Paediatric Soft-tissue sarcoma Study Group developed treatment recommendations consisting in intensive dose chemotherapy every 2 weeks using vincristine-doxorubicin-cyclophosphamide (VDCy) and ifosfamide-etoposide (IE) associated with early surgery and irradiation of tumour sites., Methods: A retrospective study was conducted on children treated in France by these new recommendations up to January 2019., Results: Thirty-five patients were identified. The primary tumour was in miscellaneous soft parts for 18 patients, in the kidney for 11 and in the liver for six. The median age at diagnosis was 17.5 months (range 1.2-198.2). Distant locations (metastatic or synchronous tumours) were present in 37.1% at diagnosis. SMARCB1 germline pathogenic variant was detected in 17.1% of patients. Overall tolerance was good, with 87-97% of theoretical chemotherapy cumulative doses actually delivered. The median interval between two courses was 18 days. Surgical resection was performed in 83% (19 R0, 7 R1 and 3 R2) and local radiotherapy in 49% of patients. After a median follow-up of 50.4 months (range 16.5-134.1), the 2-year overall and event-free survivals were 47.6% (95% confidence interval [CI] 30.2-63.1) and 42.9% (95% [CI] 26.5-58.3), respectively. On univariate analyses, localised disease and gross total resection were significantly associated with favourable outcomes., Conclusions: Intensive dose chemotherapy with VDCy/IE can be administrated with no remarkable short-term toxicity, including in infants. However, the outcome remains poor for patients without gross total resection and with metastatic or multifocal disease. These patients could be stratified into a high-risk group that requires a new immediate therapeutic approach such as targeted agents combined with multimodal therapy., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: AcSé-ESMART is a European multicentre, proof-of-concept multiarm phase I/II platform trial in paediatric patients with relapsed/refractory cancer. Arm G assessed the activity and safety of nivolumab in combination with metronomic cyclophosphamide +/- irradiation., Experimental Design: Following a Phase II Simon two-stage design, nivolumab was administered intravenously at 3 mg/kg every 2 weeks of a 28-day cycle, oral cyclophosphamide at 25 mg/m 2 twice a day, 1 week on/1 week off. The primary endpoint was objective response rate. Irradiation/radioablation of primary tumour or metastasis could be administered as per physician's choice. Biomarker evaluation was performed by tumour immunohistochemistry, whole exome and RNA sequencing, and immunophenotyping of peripheral blood by flow cytometry., Results: Thirteen patients were treated with a median age of 15 years (range: 5.5-19.4). The main histologies were high-grade glioma, neuroblastoma, and desmoplastic small round cell tumour (DSRCT). The safety profile was similar to those of single-agent nivolumab, albeit haematologic toxicity, mainly lymphocytopenia, was commonly reported with the addition of cyclophosphamide +/- irradiation. Two patients with DSRCT and ependymoma presented unconfirmed partial response and prolonged disease stabilisation. Low mutational load with modest intratumour CD3+ T-cell infiltration and immunosuppressive tumour microenvironment were observed in the tumour samples. Under combined treatment, no positive modulation of circulating T cells was displayed, while derived neutrophil-to-lymphocyte ratio increased., Conclusions: Nivolumab in combination with cyclophosphamide was well tolerated but had limited activity in this paediatric setting. Metronomic cyclophosphamide did not modulate systemic immune response that could compensate limited T-cell infiltration and the immunosuppressive tumour microenvironment. CLINICALTRIALS., Gov Identifier: NCT2813135., Competing Interests: Conflict of interest statement N.A., V.M.C., G.V., and B.G. declared consultancy or advisory role to BMS. All other authors declared no potential conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Due to the extensive initial distant tumour spread in metastatic rhabdomyosarcoma, the importance of local treatment is sometimes underestimated. A retrospective study was conducted to identify the prognostic value of aggressive local treatment in paediatric metastatic rhabdomyosarcoma., Patients: Patients with metastatic rhabdomyosarcoma aged 1-21 years treated in France from 1998 to 2011 according to European protocols MMT-4-89, 4-91, 98 and recent national guidelines were selected. Survival comparison were performed between patients with 'aggressive local treatment' (surgery and radiotherapy) and exclusive surgery or radiotherapy, after exclusion of patients with early progression. End-points were event-free and overall survival (OS)., Results: A total of 101 children, median age 9 years, with majority of primaries in unfavourable sites (73 patients, pts), T2 tumours (66 pts), alveolar subtypes (65 pts) and large tumours (>5 cm, 83 pts) received various chemotherapy regimens. On univariate and multivariate analyses, OS was better after 'aggressive local treatment' (49 pts; 44.3 ± 8%), than after exclusive surgery (10 pts; 18.8% ± 15.5%) or exclusive radiotherapy (29 pts; 16.1 ± 7.2%, P < 0.006). Moreover, OS was better in the case of surgery with complete resection (41.1 ± 10.2%) or microscopic residue (56.4 ± 14.9%) than macroscopic residue (20.0 ± 12.6%; P < 0.03)., Conclusions: In this large retrospective analysis, OS appeared to be better for patients receiving 'aggressive local treatment' even after adjustment for the initial patient and tumour characteristics. Isolated debulking surgery is associated with a very poor outcome and should be avoided. Aggressive local treatment in patients with rhabdomyosarcoma, even with metastasis, should be seriously considered., (Copyright © 2014 Elsevier Ltd. All rights reserved.)