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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
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
2072-6694
Wieczorek, Aleksandra
5890e74a-d232-458e-889e-3fc4ebae6b04
Manzitti, Carla
b5818ea2-1504-4f27-b2bb-0c583a01083c
Garaventa, Alberto
0b09830c-a9cf-464a-b0b1-575c26766c66
Gray, Juliet
12d5e17c-97bb-4d6d-8fc4-3914b730ed42
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
20e08ca0-b2d9-4bc0-b7d5-f1e5f4e265c6
Fiedler, Stefan
4e5455a5-acff-4c2c-b953-b65e9827c740
Ladenstein, Ruth
646da3c0-c69d-4dde-9f9d-e3cd41bd0ec9
Lode, Holger
c6482d76-8235-40b9-adbd-1d3cae4ac2c3
Wieczorek, Aleksandra
5890e74a-d232-458e-889e-3fc4ebae6b04
Manzitti, Carla
b5818ea2-1504-4f27-b2bb-0c583a01083c
Garaventa, Alberto
0b09830c-a9cf-464a-b0b1-575c26766c66
Gray, Juliet
12d5e17c-97bb-4d6d-8fc4-3914b730ed42
Papadakis, Vassilios
f204152b-86f5-40b1-84cd-57d0eb46d019
Valteau-Couanet, Dominique
a5e438b6-51a9-4b39-a4d1-9c99ca35cc8b
Zachwieja, Katarzyna
3d8d0242-994f-4459-9a0e-86bc2a8c9b7e
Poetschger, Ulrike
b1c62fd6-0381-4660-8cf7-c50208add611
Pribill, Ingrid
20e08ca0-b2d9-4bc0-b7d5-f1e5f4e265c6
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).

Record type: Article

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.

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Accepted/In Press date: 8 April 2022
Published date: 10 April 2022
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
ORCID for Juliet Gray: ORCID iD orcid.org/0000-0002-5652-4722

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Date deposited: 11 May 2022 16:51
Last modified: 14 May 2022 01:38

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Contributors

Author: Aleksandra Wieczorek
Author: Carla Manzitti
Author: Alberto Garaventa
Author: Juliet Gray ORCID iD
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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