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High-Risk Neuroblastoma: New Clinical Insights and Challenges

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (25 February 2024) | Viewed by 6469

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Prof. Dr. Rupert Handgretinger

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Guest Editor

Department I–General Pediatrics, Hematology/Oncology, Children’s Hospital, University Hospital Tübingen, 72076 Tübingen, Germany
Interests: stem cell transplantation; immunotherapy
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Johannes Hubertus Schulte

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Guest Editor

Department of Pediatric Oncology/Hematology, Charité – Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
Interests: pediatric oncology; neuroblastoma

Special Issue Information

Dear Colleagues,

Neuroblastoma is the most common extracranial solid tumor in young children, typically presenting at an average age of 1 to 2 years. Occasionally, newborns can present with metastatic neuroblastoma, but adolescents or younger adults can also be affected. In newborns, even disseminated neuroblastoma can spontaneously regress without any therapy, whereas metastasized neuroblastoma in toddlers and older patients is highly agressive and associated with a poor prognosis. Approximately half of the toddlers and older children present with a local tumor (low risk) with a good prognosis and the other half with a disseminated tumor (high risk) and a poor prognosis. These features make neuroblastoma to a tumor with one of the highest spontaneous regression rates on the one side and one of the most aggressive tumors on the other side, due to its tendency to relapse after initial treatment. The biology behind these features begin slowly to be understood, but there are still major challenges, especially in the treatment for the high-risk patients. Current therapy concepts comprise intensive chemotherapy, radiation, autologous or even allogeneic stem cell transplantation, targeted therapies, tumor vaccination approaches, monoclonal antibodies, chimeric antigen receptor (CAR) T-cells, and their combinations.

In this Special Issue, we welcome authors to submit original papers or reviews on current and future new diagnostic and treatment strategies which will hopefully improve the currently poor prognosis of children with high-risk neuroblastoma.

Prof. Dr. Rupert Handgretinger
Prof. Dr. Johannes Hubertus Schulte
Guest Editors

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Keywords

neuroblastoma
autologous stem cell transplantation
allogeneic stem cell transplantation immunotherapy
anti-GD2 antibody
targeted therapy
CAR T-cells

Published Papers (6 papers)

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Research

15 pages, 3110 KiB

Open AccessArticle

Local MRI before and after Tumor Resection in Neuroblastoma: Impact of Residual Disease on Event Free Survival

by Jürgen F. Schäfer, Sebastian Gassenmaier, Steven Warmann, Cristian Urla, Leonie Frauenfeld, Tim Flaadt, Maryanna Chaika, Michael Esser, Ilias Tsiflikas, Beate Timmermann and Jörg Fuchs

J. Clin. Med. 2023, 12(23), 7297; https://doi.org/10.3390/jcm12237297 - 24 Nov 2023

Viewed by 662

Abstract

(1) Background: The study aimed to investigate the influence of MRI-defined residual disease on local tumor control after resection of neuroblastic tumors in patients without routine adjuvant radiotherapy. (2) Methods: Patients, who underwent tumor resection between 2009 and 2019 and received a pre- and postoperative MRI, were included in this retrospective single-center study. Measurement of residual disease (RD) was performed using standardized criteria. Primary endpoint was the local or combined (local and metastatic) event free survival (EFS). (3) Results: Forty-one patients (20 female) with median age of 39 months were analyzed. Risk group analysis showed eleven low-, eight intermediate-, and twenty-two high-risk patients (LR, IR, HR). RD was found in 16 cases by MRI. A local or combined relapse or progression was found in nine patients of whom eight patients had RD (p = 0.0004). From the six patients with local or combined relapse in the HR group, five had RD (p = 0.005). Only one of 25 patients without RD had a local event. Mean EFS (month) was significantly higher if MRI showed no residual tumor (81 ± 5 vs. 43 ± 9; p = 0.0014) for the total cohort and the HR subgroup (62 ± 7 vs. 31 ± 11; p = 0.016). (4) Conclusions: In our series, evidence of residual tumor, detectable by MRI, was associated with insufficient local control, resulting in relapses or local progression in 50% of patients. Only one of the patients without residual tumor had a local relapse. Full article

(This article belongs to the Special Issue High-Risk Neuroblastoma: New Clinical Insights and Challenges)

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14 pages, 1739 KiB

Open AccessArticle

A Multi-Color Flow Cytometric Assay for Quantifying Dinutuximab Binding to Neuroblastoma Cells in Tumor, Bone Marrow, and Blood

by Michelle E. Keyel, Kathryn L. Furr, Min H. Kang and C. Patrick Reynolds

J. Clin. Med. 2023, 12(19), 6223; https://doi.org/10.3390/jcm12196223 - 27 Sep 2023

Cited by 1 | Viewed by 1322

Abstract

GD2, a disialoganglioside, is present on the surface of most neuroblastomas, as well as on some other cancers, such as melanoma and osteogenic sarcoma. The anti-GD2 antibody ch14.18 (dinutuximab) has an FDA-registered indication for use as maintenance therapy for high-risk neuroblastoma with cytokines and 13-cis-retinoic acid after myeloablative therapy. Recent studies using immunohistochemistry of tumor or tumor cells in marrow have shown that some neuroblastomas are negative for GD2. Dinutuximab and other anti-GD2 antibodies are increasingly used in combination with cytotoxic chemotherapy for treating relapsed neuroblastoma, so it is important to be able to identify patients with tumor cells with low GD2 expression, as such patients may experience toxicity but not benefit from the antibody therapy. As the most common clinical samples available for relapsed neuroblastoma are bone marrow aspirates, we developed a method to quantify dinutuximab binding density and the frequency of neuroblastoma cells positive for the antibody in bone marrow aspirates. Here, we describe a multi-color flow cytometry assay that employs non-GD2 antibodies to identify neuroblastoma cells in a mixed population (tumor, bone marrow, or blood) and an anti-GD2 antibody to quantify both the frequency and density of GD2 expression on neuroblastoma cells. Full article

(This article belongs to the Special Issue High-Risk Neuroblastoma: New Clinical Insights and Challenges)

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19 pages, 843 KiB

Open AccessArticle

Multimodal Therapy with Consolidating Haploidentical Stem Cell Transplantation and Dinutuximab Beta for Patients with High-Risk Neuroblastoma and Central Nervous System Relapse

by Tim Flaadt, Martin Ebinger, Malin Schreiber, Ruth L. Ladenstein, Thorsten Simon, Holger N. Lode, Barbara Hero, Martin U. Schuhmann, Jürgen Schäfer, Frank Paulsen, Beate Timmermann, Angelika Eggert and Peter Lang

J. Clin. Med. 2023, 12(19), 6196; https://doi.org/10.3390/jcm12196196 - 25 Sep 2023

Cited by 1 | Viewed by 1014

Abstract

Despite highly intensive multimodality treatment regimens, the prognosis of patients with high-risk neuroblastoma (HRNB) and central nervous system (CNS) relapse remains poor. We retrospectively reviewed data from 13 patients with HRNB and CNS relapse who received multimodal therapy with consolidating haploidentical stem cell transplantation (haplo-SCT) followed by dinutuximab beta ± subcutaneous interleukin-2 (scIL-2). Following individual relapse treatment, patients aged 1−21 years underwent haplo-SCT with T/B-cell-depleted grafts followed by dinutuximab beta 20 mg/m²/day × 5 days for 5–6 cycles. If a response was demonstrated after cycle 5 or 6, patients received up to nine treatment cycles. After haplo-SCT, eight patients had a complete response, four had a partial response, and one had a stable disease. All 13 patients received ≥3 cycles of immunotherapy. At the end of the follow-up, 9/13 patients (66.7%) demonstrated complete response. As of July 2023, all nine patients remain disease-free, with a median follow-up time of 5.1 years since relapse. Estimated 5-year event-free and overall survival rates were 55.5% and 65.27%, respectively. Dinutuximab beta ± scIL-2 following haplo-SCT is a promising treatment option with a generally well-tolerated safety profile for patients with HRNB and CNS relapse. Full article

(This article belongs to the Special Issue High-Risk Neuroblastoma: New Clinical Insights and Challenges)

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12 pages, 7032 KiB

Open AccessArticle

Combined Metabolic and Functional Tumor Volumes on [¹⁸F]FDG-PET/MRI in Neuroblastoma Using Voxel-Wise Analysis

by Maryanna Chaika, Simon Männlin, Sebastian Gassenmaier, Ilias Tsiflikas, Helmut Dittmann, Tim Flaadt, Steven Warmann, Brigitte Gückel and Jürgen Frank Schäfer

J. Clin. Med. 2023, 12(18), 5976; https://doi.org/10.3390/jcm12185976 - 15 Sep 2023

Viewed by 613

Abstract

Purpose: The purpose of our study was to evaluate the association between the [¹⁸F]FDG standard uptake value (SUV) and the apparent diffusion coefficient (ADC) in neuroblastoma (NB) by voxel-wise analysis. Methods: From our prospective observational PET/MRI study, a subcohort of patients diagnosed with NB with both baseline imaging and post-chemotherapy imaging was further investigated. After registration and tumor segmentation, metabolic and functional tumor volumes were calculated from the ADC and SUV values using dedicated software allowing for voxel-wise analysis. Under the mean of thresholds, each voxel was assigned to one of three virtual tissue groups: highly vital (v) (low ADC and high SUV), possibly low vital (lv) (high ADC and low SUV), and equivocal (e) with high ADC and high SUV or low ADC and low SUV. Moreover, three clusters were generated from the total tumor volumes using the method of multiple Gaussian distributions. The Pearson’s correlation coefficient between the ADC and the SUV was calculated for each group. Results: Out of 43 PET/MRIs in 21 patients with NB, 16 MRIs in 8 patients met the inclusion criteria (PET/MRIs before and after chemotherapy). The proportion of tumor volumes were 26%, 36%, and 38% (v, lv, e) at baseline, 0.03%, 66%, and 34% after treatment in patients with response, and 42%, 25%, and 33% with progressive disease, respectively. In all clusters, the ADC and the SUV correlated negatively. In the cluster that corresponded to highly vital tissue, the ADC and the SUV showed a moderate negative correlation before treatment (R = −0.18; p < 0.0001) and the strongest negative correlation after treatment (R = −0.45; p < 0.0001). Interestingly, only patients with progression (n = 2) under therapy had a relevant part in this cluster post-treatment. Conclusion: Our results indicate that voxel-wise analysis of the ADC and the SUV is feasible and can quantify the different quality of tissue in neuroblastic tumors. Monitoring ADCs as well as SUV levels can quantify tumor dynamics during therapy. Full article

(This article belongs to the Special Issue High-Risk Neuroblastoma: New Clinical Insights and Challenges)

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16 pages, 878 KiB

Open AccessArticle

Dinutuximab Beta Maintenance Therapy in Patients with High-Risk Neuroblastoma in First-Line and Refractory/Relapsed Settings—Real-World Data

by Aleksandra Wieczorek, Urszula Żebrowska, Marek Ussowicz, Agnieszka Sokół, Marzena Stypińska, Bożenna Dembowska-Bagińska, Katarzyna Pawińska-Wąsikowska and Walentyna Balwierz

J. Clin. Med. 2023, 12(16), 5252; https://doi.org/10.3390/jcm12165252 - 11 Aug 2023

Cited by 2 | Viewed by 1307

Abstract

Dinutuximab beta is approved for the maintenance treatment of patients with high-risk neuroblastoma (HR-NB), including patients with relapsed/refractory (R/R) disease. However, the data on its use in real-world clinical practice is limited. We retrospectively reviewed the clinical records of 54 patients with HR-NB who received maintenance therapy with dinutuximab beta in first-line (37 patients) or R/R settings (17 patients) at three centers in Poland. Of the 37 patients who received first-line treatment, twenty-eight had a complete response, two had a partial response, three had progressive disease, and four relapsed at the end of treatment. The median overall survival (OS) was 24.37 months, and the three-year progression-free survival (PFS) and OS were 0.63 and 0.80, respectively. Of the 17 patients in the R/R group, 11 had a complete response, two had a partial response, one had stable disease, and three had progressive disease or relapsed at the end of treatment. The median OS was 33.1 months and the three-year PFS and OS were 0.75 and 0.86, respectively. Treatment was generally well tolerated, including in patients with co-morbidities and those who had experienced toxicities with previous therapies. These findings demonstrate that the use of dinutuximab beta is feasible and beneficial as a first-line or R/R treatment in routine clinical practice in Poland. Full article

(This article belongs to the Special Issue High-Risk Neuroblastoma: New Clinical Insights and Challenges)

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18 pages, 2993 KiB

Open AccessArticle

Hybrid Molecules of Benzylguanidine and the Alkylating Group of Melphalan: Synthesis and Effects on Neuroblastoma Cells

by Gernot Bruchelt, Chihab Klose, Matthias Lischka, Marietta Brandes, Rupert Handgretinger and Reinhard Brueckner

J. Clin. Med. 2023, 12(13), 4469; https://doi.org/10.3390/jcm12134469 - 03 Jul 2023

Viewed by 1013

Abstract

The therapy of neuroblastoma relies, amongst other things, on administering chemotherapeutics and radioactive compounds, e.g., the (meta-iodobenzyl)guanidine [¹³¹I]mIBG. For special applications (conditioning before stem cell transplantation), busulfan and melphalan (M) proved to be effective. However, both drugs are not used for normal chemotherapy in neuroblastoma because of their side effects. The alkylating drug melphalan contains a (Cl-CH₂-CH₂-)₂N- group in the para-position of the phenyl moiety of the essential amino acid phenylalanine (Phe) and can, therefore, be taken up by virtually all kinds of cells by amino acid transporters. In contrast, mIBG isotopologs are taken up more selectively by neuroblastoma cells via the noradrenaline transporter (NAT). The present study aimed at synthesising and studying hybrid molecules of benzylguanidine (BG) and the alkylating motif of M. Such hybrids should combine the preferential uptake of BGs into neuroblastoma cells with the cytotoxicity of M. Besides the hybrid of BG with the dialkylating group (Cl-CH₂-CH₂-)₂N- bound in the para-position as in M (pMBG), we also synthesised mMBG, which is BG meta-substituted by a (Cl-CH₂-CH₂-)₂N- group. Furthermore, two monoalkylating hybrid molecules were synthesised: the BG para-substituted by a (Cl-CH₂-CH₂-)NH- group (pM*BG) and the BG meta-substituted by a (Cl-CH₂-CH₂-)NH- group (mM*BG). The effects of the four new compounds were studied with human neuroblastoma cell lines (SK-N-SH, Kelly, and LS) with regard to uptake, viability, and proliferation by standard test systems. The dialkylating hybrid molecules pMBG and mMBG were at least as effective as M, whereas the monoalkylating hybrid molecules pM*BG and mM*BG were more effective than M. Considering the preferred uptake via the noradrenaline transporter by neuroblastoma cells, we conclude that they might be well suited for therapy. Full article

(This article belongs to the Special Issue High-Risk Neuroblastoma: New Clinical Insights and Challenges)

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