High risk neuroblastoma (HR-NB) with MNA and age <18 months: Results from the HR-NBL1/SIOPEN trial.

person Ruth Lydia Ladenstein St. Anna Children's Hospital and St. Anna Kinderkrebsforschung, Department of Paediatrics, Medical University Vienna, Vienna, Austria info_outline Ruth Lydia Ladenstein, Ulrike Poetschger, Dominique Valteau Couanet, Shifra Ash, Maja Beck Popovic, Walentyna Balwierz, Tom Boterberg, Godfrey Chi-Fung Chan, Martin Elliott, Per Kogner, Holger N. Lode, Genevieve Laureys, Roberto Luksch, Josef Malis, Cormac Owens, Vassilios Papadakis, Sabine Sarnacki, Sabine Taschner-Mandl, Gudrun Schleiermacher, Adela Canete

Authors person Ruth Lydia Ladenstein St. Anna Children's Hospital and St. Anna Kinderkrebsforschung, Department of Paediatrics, Medical University Vienna, Vienna, Austria info_outline Ruth Lydia Ladenstein, Ulrike Poetschger, Dominique Valteau Couanet, Shifra Ash, Maja Beck Popovic, Walentyna Balwierz, Tom Boterberg, Godfrey Chi-Fung Chan, Martin Elliott, Per Kogner, Holger N. Lode, Genevieve Laureys, Roberto Luksch, Josef Malis, Cormac Owens, Vassilios Papadakis, Sabine Sarnacki, Sabine Taschner-Mandl, Gudrun Schleiermacher, Adela Canete Organizations St. Anna Children's Hospital and St. Anna Kinderkrebsforschung, Department of Paediatrics, Medical University Vienna, Vienna, Austria, Children’s Cancer Research Institute (CCRI), St. Anna Kinderkrebsforschung GmbH, Department for Studies and Statistics and Integrated Research and Projects, Vienna, Austria, Children and Adolescent Oncology Department, Gustave Roussy, Villejuif, France, Schneider Children‘s Medical Center of Israel, Sackler Faculty of Medicine Tel Aviv University, Petach Tikvah, Israel, University Hospital Lausanne, Pediatric Hematology Oncology Unit, Department Women-Mother-Child, Lausanne, Switzerland, Paediatric Haematology Oncology, Jagiellonian University Medical College, Kraków, Poland, Ghent University Hospital, Department of Radiation Oncology, Ghent, Belgium, Department of Pediatrics & Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong, Leeds Children's Hospital, Leeds General Infirmary, Leeds, United Kingdom, Karolinska Institutet, Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Stockholm, Sweden, University Medicine Greifswald, Pediatric Hematology and Oncology, Greifswald, Germany, Ghent University Hospital, Department of Pediatric Hematology, Oncology and Stem Cell Transplant, Ghent, Belgium, Fondazione IRCCS Istituto Nazionale dei Tumori, S.C. Pediatria Oncologia, Milan, Italy, Dept. of Paediatric Oncology, University Hospital Motol, Prague, Czech Republic, Children’s Health Ireland, Department of Paediatric Haematology Oncology, Dublin, Ireland, Agia Sofia Children's Hospital, Department of Pediatric Hematology-Oncology, Athens, Greece, Department of Pediatric Surgery, Necker Enfants – Malades Hospital, Paris Descartes University, Paris, France, Children’s Cancer Research Institute (CCRI), St. Anna Kinderkrebsforschung GmbH, Department for Tumour Biology, Vienna, Austria, Institut Curie, SIREDO Pediatric Oncology Center, Paris, France, Paediatric Haematology Oncology, Hospital Universitario y Politecnico La Fe, Valencia, Spain Abstract Disclosures Research Funding Other EC 5th Frame Work Grant SIOPEN-R-NET EC grant no. QLRI-CT-2002-01768, St. Anna Kinderkrebsforschung, Pierre Fabre Médicament, Apeiron Biologics Background: The INES 99.4 trial (JCO 2009,27(7):1014-9) for MYCN amplified (MNA) infants using 6 courses of CBDCA-Vp16/CADO showed early progressions or non-response in 30%. Two-year overall survival (OS) was 30% (SE, 0.08) with median survival of 12 months. Aims are to report risk factors and outcomes for patients < 18 months with MNA neuroblastoma treated on HR-NBL1/SIOPEN. Methods: From 2006-2022, patients < 18 months with MNA INSS stages > 1 were eligible. All infants received Rapid Cojec induction, eventually 2 TVDs, Busulfan-Melphalan as high-dose treatment and could receive Dinutuximab- beta immunotherapy. Toddlers (12-18 months) followed the HR-NBL1/SIOPEN respective eligibility criteria. Results: Median age at diagnosis was 1.2 years in 414 patients (median follow up 7 years): 56% were male; 18.6% had localised tumours, 6.8% stage 4S and 75% stage 4. The predominant primary tumour site was abdominal (85%). Rapid Cojec was used in 85%, BUMEL in 89% and 26% received Dinutuximab-beta. Multiple metastatic compartments were reported in 82% of stage 4. Five-year event-free (5y-EFS) and overall survival (5y-OS) was 0.46±0.03 and 0.51±0.03. Stage 2,3&4S patients had a better 5y-EFS of 0.64±0.03 (p < 0.005) (5y-OS:0.66±0.06), compared to stage 4 with 0.41±0.03 (OS:0.46±0.03). Infants’ 5y-EFS was superior with 0.53±0.04 (5y-OS:0.57±0.04) (p = 0.015) over the toddlers with 5y-EFS 0.42±0.03 (5y-OS:0.46±0.03). Patients with bone marrow (BM) and skeletal metastases ± other sites (MS) did worse (p < 0.005) with a 5y-EFS of 0.31±0.04 (5y-OS:0.36±0.04) whilst other metastatic combinations revealed outcomes above 0.50 ±0.03. LDH (2x > normal) predicted a worse 5y-EFS of 0.43±0.03 (5y-OS:0.46±0.03) (p < 0.001) versus normal LDH (5y-EFS 0.71±0.07; 5y-OS:0.80±0.06). EFS multivariable analysis at diagnosis (MVA) showed independent significance for stage 4 (p-value 0.0139; HR: 1.608) and LDH (p-value 0.0042; HR: 2,237), but not for age. In stage 4 patients MVA on EFS found LDH (p-value 0.0098; HR: 2,567) and BM/skeleton involvement (p-value 0.0024; HR: 1,693) as independent risk predictors. In maintenance Dinutuximab-beta had a major impact on 5y-EFS in stage 4 patients with 0.69±0.05(5y-OS:0.71±0.05) vs. 0.41±0-07 (0.46±0.07) for those treated with 13-cis retinoic acid (p = 0.002 & p = 0.001), but not on others. Conclusions: In HR-NBL1/SIOPEN outcomes improved with almost half of patients alive at 5 years and only few late events. Clinical trial information: NCT01704716.