Objective: Immunotherapy with dinutuximab beta (DB) improves the prognosis of patients with high-risk neuroblastoma (HR-NB) but can be associated with severe immune-mediated side effects. A comprehensive side effect management is necessary to improve tolerability and avoid treatment discontinuation. To date, standardized guidelines on co-medication and on the management of acute and chronic side effects are not available in Germany. In a survey, German pediatric oncology departments were therefore asked about their experiences and procedures from which the recommendations described here were developed. Method: A survey was conducted among German pediatric oncology centers to assess their approaches to managing DB-related adverse effects. Centers were asked about their experiences and procedures, and consensus recommendations were subsequently developed by an expert panel based on these findings. Results: Existing international recommendations were expanded by incorporating current clinical practices from German centers, resulting in comprehensive guidelines for adverse event management during DB immunotherapy. Conclusion: These recommendations can contribute to improving tolerability and thereby help prevent treatment discontinuation.

Parvovirus B19 (PVB19) infection is a recognized cause of transient bone marrow suppression and pure red cell aplasia; however, pancytopenia with hypocellular marrow and multilineage dysplasia is uncommon in children and poses a diagnostic challenge. We report the case of a previously healthy 7-year-old girl who presented with pancytopenia during acute PVB19 infection, confirmed by high viral loads in peripheral blood, cerebrospinal fluid, and bone marrow. Initial bone marrow examination demonstrated hypocellularity with multilineage dysplasia but did not meet criteria for myelodysplastic syndrome. Comprehensive evaluation excluded autoimmune disease, primary immunodeficiency, inherited bone marrow failure syndromes, and known pediatric MDS predisposition genes. Serial follow-up revealed persistent hypocellularity and evolving dysplasia, ultimately establishing the diagnosis of childhood MDS with low blasts (cMDS-LB). The patient underwent successful allogeneic hematopoietic stem cell transplantation with stable full donor chimerism and hematologic recovery. Post-transplant, she experienced episodes of febrile pneumonitis accompanied by transient increases in PVB19 DNA levels, followed by a gradual decline with persistent low-level PVB19 DNAemia at last follow-up (day +618). This case highlights that PVB19 infection may temporally coincide with, reveal, or contribute to an evolving pediatric myelodysplastic process rather than directly causing it.

ObjectiveTo assess comparative evidence on the independent contribution of GM-CSF to the efficacy and safety of anti-GD2 immunotherapy in neuroblastoma and to identify evidence gaps.MethodsThis systematic review was conducted in accordance with the PRISMA guidelines in February 2026. MEDLINE (via PubMed), EMBASE, and the Cochrane Library were searched to identify comparative studies evaluating anti-GD2 immunotherapy with and without GM-CSF in patients with neuroblastoma. In addition, the websites of key oncology societies were searched.ResultsNo study directly compared otherwise equivalent anti-GD2 regimens that differed only in the inclusion of GM-CSF. Two studies met the broader comparative eligibility criterion and provided only indirect regimen-level information. Both evaluated older, non-licensed murine anti-GD2 antibodies (m3F8 and 14.G2a), and neither evaluated GM-CSF with currently licensed anti-GD2 antibodies. In the retrospective study by Cheung et al., survival outcomes differed across treatment eras; however, GM-CSF was co-administered with 13-cis-retinoic acid and treatment groups also differed with respect to prior stem cell transplantation, induction therapy, baseline characteristics, follow-up duration and supportive care. Therefore, the observed survival differences cannot be attributed to GM-CSF. Toxicity comparisons in this study were also limited by differences in toxicity ascertainment across treatment eras. The prospective phase I/Ib study by Frost et al. was primarily designed to evaluate dose finding and toxicity, included very small and heterogeneous treatment groups, and did not isolate GM-CSF as an independent treatment variable. No eligible comparative study was identified for dinutuximab, dinutuximab beta or naxitamab.ConclusionAvailable comparative evidence is insufficient to determine the independent contribution of GM-CSF to the efficacy or safety of anti-GD2 immunotherapy in neuroblastoma. These findings should not be used to justify modification of licensed product-specific anti-GD2 regimens. A randomized trial holding the anti-GD2 backbone and relevant co-interventions constant is needed to isolate the effect of GM-CSF.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251116911.

Die Immuntherapie mit Dinutuximab beta (DB) verbessert die Prognose bei Patienten mit einem Hochrisiko-Neuroblastom, kann aber mit schweren immunvermittelten Nebenwirkungen verbunden sein. Ein umfassendes Nebenwirkungsmanagement ist notwendig, um die Verträglichkeit zu verbessern und Therapieabbrüche zu vermeiden. Bislang fehlen in Deutschland einheitliche Vorgaben zur Co-Medikation und zum Umgang mit akuten und chronischen Nebenwirkungen. In einer Umfrage wurden daher deutsche kinderonkologische Zentren zu ihren Erfahrungen und Verfahren angefragt und hieraus die beschriebenen Empfehlungen erarbeitet. In einer Umfrage wurde das Vorgehen bei DB-Nebenwirkungen an deutschen kinderonkologischen Zentren erhoben; hieraus wurden konsensual Empfehlungen in einem Expertengremium erarbeitet. Existierende internationale Empfehlungen wurden um das Vorgehen aus gängiger Praxis an deutschen Zentren zu einem umfassenden Leitfaden des Nebenwirkungsmanagements bei DB-Immuntherapie erweitert. Diese Empfehlung kann einen Beitrag leisten, die Verträglichkeit zu verbessern, um so Therapieabbrüche zu vermeiden.

OBJECTIVES:The association between exposure to dinutuximab beta (DB) and event-free survival (EFS) or overall survival (OS) of neuroblastoma patients was assessed using data collected during three clinical trials (five cohorts). METHODS:A systematic review (March 2026) was conducted to identify relevant studies (prospective; registered DB indication and posology). Patient-level information on outcomes and their predictors was extracted from study reports. Because of immortal-time and reverse causation biases, survival was examined among patients who were event-free at their end-of-treatment (EOT) date (i.e., last dose + 25 days). To address selection bias, stabilised inverse-probability weights were estimated, and weighted post-EOT survival models were fitted. RESULTS:Of 665 patients, 98 had relapse or progression before EOT. The median duration of follow-up in the post-EOT cohort was 3.78 years. The total number of cycles was independently associated with both EFS (HR = 0.80, 95% CI: 0.70-0.90 per cycle, p < 0.001) and OS (HR = 0.78, 95% CI: 0.68-0.90 per cycle, p < 0.001). With each treatment cycle, post-EOT hazard of an EFS event decreased by 20% (95% CI: 10%-30%) and hazard of death decreased by 22% (95% CI: 10%-32%). The results were consistent across most sensitivity analyses (e.g., excluding IL-2 recipients, restricting to frontline maintenance immunotherapy, alternative specifications and exposure metrics), but not among patients with relapsed or refractory neuroblastoma. In a target-trial emulation (5 cycles vs. <5 cycles), associations were significant for EFS (HR = 0.46, 95% CI: 0.32-0.66, p < 0.001) and OS (HR = 0.44, 95% CI: 0.28-0.67, p < 0.001). CONCLUSIONS:Greater prior exposure to DB, particularly a higher number of treatment cycles, was associated with better post-EOT EFS and OS. The study did not estimate an on-treatment causal effect of DB, and the residual confounding cannot be fully excluded. Prior treatment exposure may help inform post-treatment risk stratification.

10000 Background: Dinutuximab beta (DB) delivered as long-term infusion is associated with a lower frequency and magnitude of side effects compared to short-term infusion (STI). Here, we evaluated the efficacy (event free survival- and cumulative incidence of relapse-rates at 5 years) of LTI compared to STI within the HR-NBL1/SIOPEN trial (EudraCT:2006-001489-17). Methods: High-risk patients as defined by metastatic disease (stage M) or local stage with MYC-N amplification received high intensity induction, surgery, high dose therapy with busulfan/melphalan followed by autologous stem cell transplantation (HDT/SCT) and local radiotherapy. Patients who achieved at least a partial response prior to HDT/SCT within equal or less than 9 months between diagnosis and HDT/SCT without progression were randomized to receive 5 cycles of 100 mg/m 2 DB per cycle either as STI (20 mg/m 2 per day as 8 h infusion; days 1-5) with or without subcutaneous interleukin-2 (scIL2) (6 × 10 6 IU/m 2 per day; days 1-5 and days 8-12) (R2 randomization) or as LTI (10 mg/m 2 per day as 24h infusion; days 1-10) (d8-17) ± 3x10 6 IU/m 2 scIL2 (d1-5; d8, d10, d12, d14, d16) (R4 randomization). All patients received 160 mg/m 2 oral isotretinoin (d19-32). Results: From 2009-2018, 705 patients (pts) from 18 countries were randomized and eligible for this analysis. The median follow-up time is7.7 years. Key patient characteristics were age 1.5-5yrs: 65% (460 pts), disease status before HDCT: CR 56% (396 pts) versus non-CR 38% (268 pts), MYC-N amplification (MNA): 43% (304 pts); > 1 metastatic compartment (MC): 78% (553 pts); time between diagnosis to DB treatment start: > 9 months 48% (302 pts). There were no significantly different patient characteristics between STI and LTI cohorts, except for time to DB start > 9 months: 59% in the LTI cohort vs. 37% in STI.The 5yr EFS was 0.65±0.03 for LTI vs. 0.56±0.03 for STI (p = 0.041). The cumulative incidence of relapse was 0.33±0.03 for LTI vs. 0.42±0.03 for STI (p = 0.034). Multivariable pseudovalue-regression analysis for 5-year EFS found a significantly worse outcome for stage 4 patients with > 1MC (p = 0.025; cHR = 1,97), < CR (p = 0.059; cHR = 1.32) and for STI (p = 0.044; cHR = 0.74). Conclusions: We previously reported that LTI of DB increased the safety profile (less pain and inflammation) (Lancet Oncol 2018;19(12):1617-1629; J Clin Oncol 37, 2019 (suppl; abstr 10013). Here we demonstrate that LTI is also associated with an improved outcome. Clinical trial information: 2006-001489-17 .

High-risk neuroblastoma (HR-NB) is associated with a poor prognosis. Standard first-line maintenance therapy with anti-disialoganglioside 2 (GD2) monoclonal antibodies, such as dinutuximab beta, has improved survival rates; however, approximately 50

High-risk neuroblastoma is a poor prognosis cancer of the sympathetic nervous system that accounts for a disproportionate number of childhood cancer deaths. Many viable biological targets have been identified, and the number of potential combinations is even larger. Several products have attained marketing authorization for treatment of patients with neuroblastoma. Patient outcomes remain poor, with approximately 50% of children with newly diagnosed high-risk neuroblastoma cured of their disease. International, multistakeholder Neuroblastoma Drug Development Strategy (NDDS) meetings were established more than a decade ago. This third NDDS meeting included academia, industry, regulatory, and patient advocacy representatives to prioritize agents and to address key challenges in drug development in this disease. Given the central role that anti-GD2 therapy plays, novel GD2-directed combinations were a key focus, including epigenetic enzymes such as EZH2 and immunologic targets such as IL15 and TIGIT as potential combination partners. GD2-directed chimeric antigen receptor (CAR)-T cells were a top priority, along with emerging CAR-T targets such as B7-H3 and GPC2. Recognizing that combination therapies are likely to be most impactful for patients and for advancing therapies to frontline, another key focus was on high priority combinations of targeted therapies, including Aurora A kinase plus BCL2 or ATR inhibitors. Additional targets and agents were prioritized or deprioritized based upon current data. Access to drugs for clinical trials was viewed as a major barrier to progress. Strategies to overcome this challenge focused on united efforts by the international scientific and advocacy community and early engagement by industry with regulatory authorities.

The clinical course of neuroblastoma is more heterogeneous than any other malignant disease. Many low-risk patients experience regression after limited or even no chemotherapy. However, more than half of high-risk patients die from disease despite intensive multimodal treatment. Precise disease characterization for each patient at diagnosis is key for risk-adapted treatment. The guidelines presented here incorporate results from national and international clinical trials to produce recommendations for diagnosing and treating neuroblastoma patients in German hospitals outside of clinical trials.

Objective: Dinutuximab beta (DB) and naxitamab (NAXI) with GM-CSF are used for maintenance treatment of relapsed/refractory neuroblastoma. The objective of this study was to systematically assess comparative efficacy of the two therapies within their designated indications in accordance with established clinical guidelines. Methods: Relevant evidence was identified in systematic literature review. Individual patient data (IPD) from prospective clinical trials of DB were assessed and data on patients with disease in bone or bone marrow, as assessed in MRI, CT, mIBG or biopsy, with incomplete response to previous therapy were included. Patients with complete response, progressive disease and/or soft tissue disease were excluded. DB population was adjusted for sex, MYCN amplification, disease type (relapsed, refractory), and disease site (bone marrow and/or bone) to balance aggregated characteristics of NAXI population. More characteristics were included in sensitivity analyses, including DB treatment without interleukin-2, as currently recommended. Overall response rate (ORR) was assessed as best response. Results: Aggregated data for NAXI from Study 201 (n = 52) and Study 230 (n = 38) and IPD from DB studies (APN311-202, APN311-304, c = 77) met the inclusion criteria. Compared to NAXI, DB significantly extended progression-free survival (PFS): hazard ratio, DB vs. NAXI of 0.47 (95% CI: 0.26 to 0.87, p = 0.015). ORR was 60.1% (95% CI: 48.5% to 71.6%) for DB vs. 43.3% (33.1% to 53.6%) for NAXI (ORR odds ratio, DB vs. NAXI was 1.97, 95% CI: 1.02 to 3.80, p = 0.044). Sensitivity analyses and unadjusted comparisons supported the results. Conclusion: In the indirect comparison, dinutuximab beta significantly extended PFS and increased ORR compared to naxitamab.

The rarity of recurrent somatic mutations poses a challenge for the targeted treatment of neuroblastoma (NB). Differentiation therapy is an encouraging prospect, with cyclin-dependent kinase inhibitors (CDKis) representing a promising avenue for promoting NB differentiation. This study investigated three CDKis (abemaciclib, fadraciclib, and dinaciclib) alone or combined with retinoic acid (RA) to assess the effects on morphology, growth, gene expression, and the induction of immunogenic cell death in NB cell lines with (LAN-1 and CHLA-90) and without (CHLA-172) MYCN amplification. All cell lines demonstrated sensitivity to CDK inhibition. Notably, low-dose abemaciclib promoted cellular differentiation, as evidenced by the emergence of stromal-like morphological features and upregulation of the differentiation markers STMN4 and ROBO2. Treatment with abemaciclib or fadraciclib led to the upregulation of calnexin and holocytochrome C, which are part of the global stress response, along with the protein p27, which arrests the cell cycle. Molecularly, CDKis sensitivity correlated with an increased CDK4-specific copy number, along with a partial deletion of CDKN2a in two cases (LAN-1, CHLA-172). The addition of RA augmented the effects of the monotherapy, particularly in LAN-1 cells, in both 2D and 3D culture, and both treatments triggered immunogenic cell death, evidenced by calreticulin translocation. Transcriptomic analysis of LAN-1 and CHLA-90 cells revealed that genes deregulated by monotherapy (fadraciclib or RA) were re-regulated in the presence of the second drug. Combination therapy significantly downregulated CRABP2 and CYP26B1, both of which are involved in RA metabolism and its degradation. Furthermore, CCNE2, MYBL2, and MCM4 were strongly suppressed in the fadraciclib/RA combination, confirming the induction of cell cycle arrest. CDKi treatments promote NB differentiation via ER stress, with cytotoxicity enhanced by RA co-treatment. This may increase NB immunogenicity and support immunotherapy eligibility.

Surface expression of the disialoganglioside subtype GD2 has been observed on Ewing sarcoma (ES) cells, making it a suitable target for immunotherapy with the anti-GD2 antibody dinutuximab beta (DB). Here we report our experience of using DB in a cohort of 13 patients with GD2-positive, metastatic ES, in both the frontline (n=9) and relapsed/refractory (n=4) settings, when added to standard chemotherapeutic regimens. Outcomes were compared with 24 patients, primarily with localized ES, who were also treated at our center with standard therapy alone (without DB). Patients treated with DB had a median overall survival (OS) of 1877 days in the frontline setting and 810 days in the relapsed/refractory setting. Median time to progression was 1811 days and 782 days, respectively. In contrast, those treated with standard therapy alone in our center demonstrated a median OS of 1547 days and 210 days in the frontline and relapsed/refractory setting, respectively, with median times of progression of 1261 days and 113 days. DB treatment was well tolerated, with no new or unexpected adverse events reported. Anti-GD2 immunotherapy with DB represents a promising therapeutic option to improve outcomes in patients with metastatic ES, in both the frontline and relapsed/refractory settings.

Background/Objectives: High-risk neuroblastoma patients are treated with approved anti-ganglioside GD2 antibodies of moderate (dinutuximab beta; DB) and higher binding affinity (naxitamab; NAXI). We evaluated the functional potency of DB compared to NAXI and investigated the target-mediated drug disposition (TMDD). Methods: Tumor spheroids were generated from neuroblastoma cells with varying GD2 expression, stably expressing iRFP680 as a viability marker. Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) were assessed in a long-term life-cell viability assay using serial dilutions of the GD2 antibodies. Binding activity was determined by flow cytometry. Processes involved in TMDD were analyzed, including antibody binding to dead tumor cells and to soluble GD2 (sGD2), antibody internalization into tumor and immune cells and the impact of sGD2 on DB and NAXI-mediated ADCC. Results: DB and NAXI mediated a concentration-dependent ADCC response against GD2-positive spheroids and no response against GD2-negative spheroids. DB showed a significantly higher ADCC potency than NAXI in all GD2-positive spheroid models. Binding activity of DB and NAXI was not significantly different. However, the decrease of anti-GD2 antibody binding to viable GD2-positive tumor cells following co-incubation with dead GD2-positive tumor cells or sGD2 was significantly higher for NAXI than DB. Additionally, we found an increased internalization of NAXI compared to DB by tumor cells and particularly CD64+ monocytes. Finally, sGD2 impaired NAXI-mediated ADCC to a significantly greater extent than DB-mediated ADCC. Conclusions: DB has a higher ADCC potency over NAXI at clinically relevant concentrations, attributed to stronger TMDD effects of NAXI compared to DB.

Background: The incorporation of anti-GD2 antibodies such as ch14.18/SP2/0 into the multimodal treatment of high-risk neuroblastoma (HR-NB) patients has improved their outcomes. As studies assessing the long-term outcomes, long-term sequelae, and health-related quality of life (HRQoL) of this treatment are limited, this retrospective analysis aimed to explore these. Patients and Methods: Between 1991 and 2002, 65 children received a multimodal treatment, including ch14.18/SP2/0, for primary HR-NB. All received chemotherapy according to the NB90/NB97 trial, 51 received high-dose chemotherapy, and all received ch14.18/SP2/0 treatment. We analyzed the long-term sequelae and HRQoL (EORTC QLQ-C30), and evaluated overall and event-free survival (OS/EFS). Results: Twenty-five survivors were evaluated for HRQoL and long-term effects. All reported long-term sequelae, including ototoxicity in 16/25 (64%), cardiac toxicity in 6/25 (24%), and endocrine toxicity in 19/25 (76%) patients. Chronic diarrhea was reported in 20% of female patients. Seven patients developed autoimmune diseases. HRQoL scores were better across multiple scales than those of the matched German general population. Twenty-five-year OS and EFS were 50.8% (95% confidence interval: 31–55) and 43% (30.1–55.3), with 33 (50.8%) long-term survivors. Thirty-two patients died: 28 (43.1%) because of progression/relapse and 4 (6.2%) because of secondary neoplasms. Conclusions: Multimodal treatment, including ch14.18/SP2/0, can achieve long-term survival in HR-NB patients, with a substantial proportion of survivors reporting better HRQoL compared to the general population. All patients reported long-term side effects mostly attributable to chemotherapy and radiotherapy. The relatively high prevalence of autoimmune diseases and persistent diarrhea warrants additional longitudinal research on individuals treated with anti-GD2 antibodies.

PURPOSE:To identify a tolerable dinutuximab beta long-term infusion (LTI) schedule with immunomodulatory activity for relapsed/refractory high-risk neuroblastoma (HRNBL). PATIENTS AND METHODS:In this phase I/II trial, dinutuximab beta LTI (five 35-day cycles) with subcutaneous interleukin-2 (IL-2) was evaluated in HRNBL cohorts (1× exploratory and 2× confirmatory). The composite primary endpoint was >80% patients free of intravenous morphine by day 5/cycle 1 plus ≥100 natural killer (NK) cells/μL and ≥1 μg/mL dinutuximab beta concentration by day 15/cycle 1. Secondary endpoints included objective response rate, event-free survival (EFS), overall survival (OS), Fcγ receptor (FCYR) polymorphisms, and NK cells. RESULTS:Overall, 122 patients were treated. At 10 mg/m2/day dinutuximab beta LTI, 95% patients (22/24 exploratory cohort and 20/20 confirmatory cohort 1) achieved the composite primary endpoint, with ≥80% patients intravenous morphine-free by day 5/cycle 1. The end-of-treatment objective response rate was 45% in 78 evaluable patients. Two-year EFS and OS were 56% (±4%) and 73% (±4%) overall and 45% (±5%) and 65% (±5%) in relapsed/refractory disease, respectively. Two-year survival rates were greater in patients with high-affinity FCYR polymorphisms and high-level NK cells versus patients with low-affinity FCYR polymorphisms and low-level NK cells [EFS, 79% (±9%) vs. 35% (±11%), P = 0.009; OS, 84% (±8%) vs. 70% (±10%); P = 0.083]. Multivariate analysis identified age >5 years, low-affinity FCYR polymorphisms, and relapse/refractory disease as independent risk factors. CONCLUSIONS:Dinutuximab beta LTI was well tolerated and clinically active in patients with relapsed/refractory HRNBL, with FCYR polymorphisms and NK cells identified as prognostic biomarkers.