Clinical phenotype and management of severe neurotoxicity observed in patients with neuroblastoma treated with dinutuximab beta in clinical trials
Clinical phenotype and management of severe neurotoxicity observed in patients with neuroblastoma treated with dinutuximab beta in clinical trials
Neurotoxicity is an off-tumour, on-target side effect of GD2-directed immunotherapy with monoclonal antibodies. Here, we report the frequency, management and outcome of patients enrolled in two prospective clinical trials who experienced severe neurotoxicity during immunotherapy with the anti-GD2 antibody dinutuximab beta (DB) administered as short-term infusion (HR-NBL1/SIOPEN study, randomisation R2, EudraCT 2006-001489-17) or as long-term infusion (HR-NBL1/SIOPEN study, randomisation R4, EudraCT 2006-001489-17 and LTI/SIOPEN study, EudraCT 2009-018077-31), either alone or with subcutaneous interleukin-2 (scIL-2). The total number of patients included in this analysis was 1102. Overall, 44/1102 patients (4.0%) experienced Grade 3/4 neurotoxicities (HR-NBL1 R2, 21/406; HR-NBL1 R4, 8/408; LTI study, 15/288), including 27 patients with severe neurotoxicities (2.5%). Events occurred predominantly in patients receiving combined treatment with DB and scIL-2. Neurotoxicity was treated using dexamethasone, prednisolone, intravenous immunoglobulins and, in two patients, plasmapheresis, which was highly effective. While neurological recovery was observed in 16 of 21 patients with severe neurotoxicities, 5/1102 (0.45%) patients experienced persistent and severe neurological deficits. In conclusion, severe neurotoxicity is most commonly observed in patients receiving DB with scIL-2. Considering the lack of clinical benefit for IL-2 in clinical trials so far, the administration of IL-2 alongside DB is not recommended.
anti-GD2 antibody, dinutuximab beta, neuroblastoma, neurotoxicity
Wieczorek, Aleksandra
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Manzitti, Carla
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Garaventa, Alberto
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Gray, Juliet
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Papadakis, Vassilios
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Valteau-Couanet, Dominique
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Zachwieja, Katarzyna
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Poetschger, Ulrike
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Pribill, Ingrid
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Fiedler, Stefan
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Ladenstein, Ruth
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Lode, Holger
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10 April 2022
Wieczorek, Aleksandra
5890e74a-d232-458e-889e-3fc4ebae6b04
Manzitti, Carla
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Garaventa, Alberto
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Gray, Juliet
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Papadakis, Vassilios
f204152b-86f5-40b1-84cd-57d0eb46d019
Valteau-Couanet, Dominique
a5e438b6-51a9-4b39-a4d1-9c99ca35cc8b
Zachwieja, Katarzyna
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Poetschger, Ulrike
b1c62fd6-0381-4660-8cf7-c50208add611
Pribill, Ingrid
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Fiedler, Stefan
4e5455a5-acff-4c2c-b953-b65e9827c740
Ladenstein, Ruth
646da3c0-c69d-4dde-9f9d-e3cd41bd0ec9
Lode, Holger
c6482d76-8235-40b9-adbd-1d3cae4ac2c3
Wieczorek, Aleksandra, Manzitti, Carla, Garaventa, Alberto, Gray, Juliet, Papadakis, Vassilios, Valteau-Couanet, Dominique, Zachwieja, Katarzyna, Poetschger, Ulrike, Pribill, Ingrid, Fiedler, Stefan, Ladenstein, Ruth and Lode, Holger
(2022)
Clinical phenotype and management of severe neurotoxicity observed in patients with neuroblastoma treated with dinutuximab beta in clinical trials.
Cancers, 14 (8), [1919].
(doi:10.3390/cancers14081919).
Abstract
Neurotoxicity is an off-tumour, on-target side effect of GD2-directed immunotherapy with monoclonal antibodies. Here, we report the frequency, management and outcome of patients enrolled in two prospective clinical trials who experienced severe neurotoxicity during immunotherapy with the anti-GD2 antibody dinutuximab beta (DB) administered as short-term infusion (HR-NBL1/SIOPEN study, randomisation R2, EudraCT 2006-001489-17) or as long-term infusion (HR-NBL1/SIOPEN study, randomisation R4, EudraCT 2006-001489-17 and LTI/SIOPEN study, EudraCT 2009-018077-31), either alone or with subcutaneous interleukin-2 (scIL-2). The total number of patients included in this analysis was 1102. Overall, 44/1102 patients (4.0%) experienced Grade 3/4 neurotoxicities (HR-NBL1 R2, 21/406; HR-NBL1 R4, 8/408; LTI study, 15/288), including 27 patients with severe neurotoxicities (2.5%). Events occurred predominantly in patients receiving combined treatment with DB and scIL-2. Neurotoxicity was treated using dexamethasone, prednisolone, intravenous immunoglobulins and, in two patients, plasmapheresis, which was highly effective. While neurological recovery was observed in 16 of 21 patients with severe neurotoxicities, 5/1102 (0.45%) patients experienced persistent and severe neurological deficits. In conclusion, severe neurotoxicity is most commonly observed in patients receiving DB with scIL-2. Considering the lack of clinical benefit for IL-2 in clinical trials so far, the administration of IL-2 alongside DB is not recommended.
Text
Neurotoxicity manuscript_revision_060422
- Accepted Manuscript
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cancers-14-01919-v2
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Accepted/In Press date: 8 April 2022
Published date: 10 April 2022
Additional Information:
Funding Information: The St. Anna Kinderkrebsforschung e.V (Vienna, Austria) acted as academic sponsor of both studies. The HR-NBL study received funding from the European Commission 5th Framework Grant (SIOPEN-R-NET EC grant number QLRI-CT-2002-01768). The investigational medical product (IMP) dinutuximab beta (ch14.18/CHO) was first recloned and produced by Polymun Scientific (Vienna, Austria), commissioned by the St. Anna Kinderkrebsforschung e.V on behalf of respective European charities and institutions after a Europe-wide fund-raising campaign. During the course of studies, industry partners Apeiron Biologics (Vienna, Austria) and EUSA Pharma Ltd. (Hemel Hemp-stead, United Kingdom) took over the antibody production and provided IMP free of charge to both studies. The project was in part carried out within TEMICARE (German-Polish pediatric oncology center integrated by telemedicine in the Euroregion Pomerania (INT113)) funded by the European Union. Editorial assistance was provided by Katrin Male from mXm Medical Communications and the article-processing charge and editorial support were funded by EUSA Pharma. The content of the article represents the views of the authors and has not been influenced by third-party sponsorship
Keywords:
anti-GD2 antibody, dinutuximab beta, neuroblastoma, neurotoxicity
Identifiers
Local EPrints ID: 456808
URI: http://eprints.soton.ac.uk/id/eprint/456808
ISSN: 2072-6694
PURE UUID: e9815e0d-db75-4694-af47-6a59f4b351de
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Date deposited: 11 May 2022 16:51
Last modified: 27 Sep 2022 01:38
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Contributors
Author:
Aleksandra Wieczorek
Author:
Carla Manzitti
Author:
Alberto Garaventa
Author:
Vassilios Papadakis
Author:
Dominique Valteau-Couanet
Author:
Katarzyna Zachwieja
Author:
Ulrike Poetschger
Author:
Ingrid Pribill
Author:
Stefan Fiedler
Author:
Ruth Ladenstein
Author:
Holger Lode
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