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Cited by 308CAR-T cell therapy researchMultiple Myeloma Research and TreatmentsImmunotherapy and Immune Responses

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Incidence and management of CAR-T neurotoxicity in patients with multiple myeloma treated with ciltacabtagene autoleucel in CARTITUDE studies

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Cohen, Adam D., Parekh, Samir, Santomasso, Bianca D., Gállego Pérez-Larraya, Jaime, van de Donk, Niels W. C. J., Arnulf, Bertrand, Mateos, Maria-Victoria, Lendvai, Nikoletta, Jackson, Carolyn C., De Braganca, Kevin C., Schecter, Jordan M., Marquez, Loreta, Lee, Erin, Cornax, Ingrid, Zudaire, Enrique, Li, Claire, Olyslager, Yunsi, Madduri, Deepu, Varsos, Helen, Pacaud, Lida, Akram, Muhammad, Geng, Dong, Jakubowiak, Andrzej, Einsele, Hermann, Jagannath, Sundar·2022·Blood Cancer Journal
DOI 10.1038/s41408-022-00629-1PMC PMC8873238
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Abstract

Chimeric antigen receptor (CAR) T-cell therapies are highly effective for multiple myeloma (MM) but their impressive efficacy is associated with treatment-related neurotoxicities in some patients. In CARTITUDE-1, 5% of patients with MM reported movement and neurocognitive treatment-emergent adverse events (MNTs) with ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-targeted CAR T-cell therapy. We assessed the associated factors for MNTs in CARTITUDE-1. Based on common features, patients who experienced MNTs were characterized by the presence of a combination of at least two variables: high tumor burden, grade ≥2 cytokine release syndrome (CRS) or any grade immune effector cell-associated neurotoxicity syndrome (ICANS) after cilta-cel infusion, and high CAR T-cell expansion/persistence. Strategies were implemented across the cilta-cel development program to monitor and manage patients with MNTs, including enhanced bridging therapy to reduce baseline tumor burden, early aggressive treatment of CRS and ICANS, handwriting assessments for early symptom detection, and extended monitoring/reporting time for neurotoxicity beyond 100 days post-infusion. After successful implementation of these strategies, the incidence of MNTs was reduced from 5% to <1% across the cilta-cel program, supporting its favorable benefit–risk profile for treatment of MM.

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Fig. 1 Overview of CAR T-cell neurotoxicities in CARTITUDE-1. aICANS per ASTCT consensus criteria. bNeurotoxicity as assessed by the investigator to be related to cilta-cel occurring after a period of recovery from CRS and/or ICANS. ICANS and other neurotoxicity events are not mutually exclusive; eight (8.2%) patients experienced both ICANS and other neurotoxicity events of any grade. Patients in the other-neurotoxicity group (n = 12) include the subset with MNTs (n = 5). ASTCT American Society for Transplantation and Cellular Therapy, CAR chimeric antigen receptor, CRS cytokine release syndrome, ICANS immune effector cell-associated neurotoxicity syndrome, MNTs movement and neurocognitive treatment-emergent adverse events.
Fig. 1 Overview of CAR T-cell neurotoxicities in CARTITUDE-1. aICANS per ASTCT consensus criteria. bNeurotoxicity as assessed by the investigator to be related to cilta-cel occurring after a period of recovery from CRS and/or ICANS. ICANS and other neurotoxicity events are not mutually exclusive; eight (8.2%) patients experienced both ICANS and other neurotoxicity events of any grade. Patients in the other-neurotoxicity group (n = 12) include the subset with MNTs (n = 5). ASTCT American Society for Transplantation and Cellular Therapy, CAR chimeric antigen receptor, CRS cytokine release syndrome, ICANS immune effector cell-associated neurotoxicity syndrome, MNTs movement and neurocognitive treatment-emergent adverse events.CC BY · PubMed Central
Fig. 2 Analysis of lymphocytes, T cells, and cytokines over time following cilta-cel infusion in patients with and without MNTs in CARTITUDE-1. Values are shown for A lymphocyte counts; B absolute CD4+ T-cell counts; C absolute CAR+ T cells; D frequency of CAR+ T cells; E IL-6; and F IFN-γ. CAR chimeric antigen receptor, EOI end of infusion, IFN interferon, IL interleukin, MNT(s) movement and neurocognitive treatment-emergent adverse event(s), NTX neurotoxicity, SE standard error.
Fig. 2 Analysis of lymphocytes, T cells, and cytokines over time following cilta-cel infusion in patients with and without MNTs in CARTITUDE-1. Values are shown for A lymphocyte counts; B absolute CD4+ T-cell counts; C absolute CAR+ T cells; D frequency of CAR+ T cells; E IL-6; and F IFN-γ. CAR chimeric antigen receptor, EOI end of infusion, IFN interferon, IL interleukin, MNT(s) movement and neurocognitive treatment-emergent adverse event(s), NTX neurotoxicity, SE standard error.CC BY · PubMed Central
Fig. 3 Analysis of CAR transgene levels in patients with and without MNTs in CARTITUDE-1. Predicted values are shown for A Cmax, B AUC0–28d, and C Tmax. AUC0–28d area under the CAR transgene systemic level-time curve from the first dose to Day 28, CAR chimeric antigen receptor, Cmax maximum CAR transgene systemic level, gDNA genomic DNA, MNTs movement and neurocognitive treatment-emergent adverse events, Tmax time of maximum cilta-cel transgene expansion.
Fig. 3 Analysis of CAR transgene levels in patients with and without MNTs in CARTITUDE-1. Predicted values are shown for A Cmax, B AUC0–28d, and C Tmax. AUC0–28d area under the CAR transgene systemic level-time curve from the first dose to Day 28, CAR chimeric antigen receptor, Cmax maximum CAR transgene systemic level, gDNA genomic DNA, MNTs movement and neurocognitive treatment-emergent adverse events, Tmax time of maximum cilta-cel transgene expansion.CC BY · PubMed Central
Fig. 4 Forest plot of potential factors associated with MNTs in CARTITUDE-1. ALC absolute lymphocyte count, CBC complete blood count, CRS cytokine release syndrome, ICANS immune effector cell-associated neurotoxicity syndrome, IL interleukin, MNTs movement and neurocognitive treatment-emergent adverse events.
Fig. 4 Forest plot of potential factors associated with MNTs in CARTITUDE-1. ALC absolute lymphocyte count, CBC complete blood count, CRS cytokine release syndrome, ICANS immune effector cell-associated neurotoxicity syndrome, IL interleukin, MNTs movement and neurocognitive treatment-emergent adverse events.CC BY · PubMed Central
Fig. 5 Patient-management strategies for neurologic adverse events following treatment with cilta-cel. aFewer restrictions (per protocol) on the investigator’s choice of bridging therapy, including its duration, to reduce baseline tumor burden before cilta-cel infusion. ASTCT American Society for Transplantation and Cellular Therapy, CAR chimeric antigen receptor, CRS cytokine release syndrome, ICANS immune effector cell-associated neurotoxicity syndrome, IL interleukin.
Fig. 5 Patient-management strategies for neurologic adverse events following treatment with cilta-cel. aFewer restrictions (per protocol) on the investigator’s choice of bridging therapy, including its duration, to reduce baseline tumor burden before cilta-cel infusion. ASTCT American Society for Transplantation and Cellular Therapy, CAR chimeric antigen receptor, CRS cytokine release syndrome, ICANS immune effector cell-associated neurotoxicity syndrome, IL interleukin.CC BY · PubMed Central

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Metadata

Authors
Cohen, A. D., Parekh, S., Santomasso, B. D., Gállego Pérez-Larraya, J., van de Donk, N. W. C. J., Arnulf, B., Mateos, M.-V., Lendvai, N., Jackson, C. C., De Braganca, K. C., Schecter, J. M., Marquez, L., Lee, E., Cornax, I., Zudaire, E., Li, C., Olyslager, Y., Madduri, D., Varsos, H., Pacaud, L., Akram, M., Geng, D., Jakubowiak, A., Einsele, H., & Jagannath, S.
Affiliations
  • Abramson Cancer Center (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • Amsterdam University Medical Centers (NL)
  • Hôpital Saint-Louis (FR)
  • Janssen Research & Development (United States) (US)
  • Janssen (Belgium) (BE)
  • Legend Biotech (United States) (US)
  • University of Chicago (US)
  • Universitätsklinikum Würzburg (DE)
Corresponding author
Jagannath, Sundar
ORCID
Venue
Blood Cancer Journal
Publisher
Springer Science and Business Media LLC
Published
2022-02-24
Volume
12
Issue
2
Pages
32-32
ISSN
2044-5385 (ISSN-L)
DOI
10.1038/s41408-022-00629-1
PMC
PMC8873238
OpenAlex
W4213437837
Cited by
308
References
20
Citations by year
2026: 81 · 2025: 85 · 2024: 70 · 2023: 51 · 2022: 21
FWCI
23.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Blood Cancer Journal (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
This study was funded by Janssen Research & Development, LLC and and Legend Biotech, Inc.
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
multiple myeloma, ciltacabtagene autoleucel, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, BCMA, CAR-T cell expansion, tumor burden, neurotoxicity management, bridging therapy, handwriting assessment, benefit-risk profile
MeSH terms
Receptors, Chimeric Antigen, Humans, Multiple Myeloma, Incidence, Immunotherapy, Adoptive, Neurotoxicity Syndromes

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