Cardiovascular Toxicity of Tisagenlecleucel in Children and Adolescents: Analysis of Spontaneous Reports Submitted to FAERS

Overview

Journal Front Immunol

Date 2025 Feb 6

PMID 39911387

Authors

Ganggang Wang

Lin Su

Yanjun Liu

Xiaohan Yang

Yi Li

Qi Mei

Wen Gao

Affiliations

Soon will be listed here.

Abstract

Background: The advent of tisagenlecleucel has been a major advance in the pharmacological treatment of relapsed/refractory B-cell acute lymphoblastic leukemia in children and adolescents. However, further research is required to better define its safety profile.

Objectives: To determine the cardiovascular toxicity of tisagenlecleucel in children and adolescents.

Methods: The US Food and Drug Administration's Adverse Event Reporting System was searched to identify cardiovascular adverse events (CVAEs) related to tisagenlecleucel in pediatric patients up to the age of 18 years.

Results: The median time to onset of tisagenlecleucel-associated CVAEs was shorter than that of tisagenlecleucel-associated non-CVAEs (3 days [interquartile range (IQR) 1, 6] vs. 7 days [IQR 2, 54]). The median time to onset was longer in patients with fatal CVAEs than in those with non-fatal CVAEs (4 days [IQR 1, 12.5] vs. 2 days [IQR 1, 4]). The most frequently reported CVAEs were mitral valve disease, hypotension, and capillary leak syndrome. Patients who developed shock had the highest mortality rate (66.67%). Concomitant use of medication for a neurological disorder was an independent risk factor for CVAEs, and concomitant use of medication for a respiratory disease was an independent risk factor for fatal CVAEs. Most CVAEs were associated with cytokine release syndrome, and older patients had a more favorable prognosis.

Conclusions: Children and adolescents who receive tisagenlecleucel should be closely monitored for CVAEs, particularly during the first week of treatment.

References

Gattinoni L, Finkelstein S, Klebanoff C, Antony P, Palmer D, Spiess P . Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005; 202(7):907-12. PMC: 1397916. DOI: 10.1084/jem.20050732. View

Burstein D, Maude S, Grupp S, Griffis H, Rossano J, Lin K . Cardiac Profile of Chimeric Antigen Receptor T Cell Therapy in Children: A Single-Institution Experience. Biol Blood Marrow Transplant. 2018; 24(8):1590-1595. DOI: 10.1016/j.bbmt.2018.05.014. View

Goldman A, Maor E, Bomze D, Liu J, Herrmann J, Fein J . Adverse Cardiovascular and Pulmonary Events Associated With Chimeric Antigen Receptor T-Cell Therapy. J Am Coll Cardiol. 2021; 78(18):1800-1813. PMC: 8562317. DOI: 10.1016/j.jacc.2021.08.044. View

Frey C, Cherniawsky H, Etminan M . Ocular adverse events following CAR-T cell therapy: A pharmacovigilance study and systematic review. Eur J Haematol. 2024; 113(1):66-71. DOI: 10.1111/ejh.14208. View

Awasthi R, Maier H, Zhang J, Lim S . Kymriah® (tisagenlecleucel) - An overview of the clinical development journey of the first approved CAR-T therapy. Hum Vaccin Immunother. 2023; 19(1):2210046. PMC: 10294746. DOI: 10.1080/21645515.2023.2210046. View

Yang Y, Zhang Y, Xing X, Xu G, Lin X, Wang Y . IL-6 translation is a therapeutic target of human cytokine release syndrome. J Exp Med. 2023; 220(11). PMC: 10432851. DOI: 10.1084/jem.20230577. View

Awasthi R, Pacaud L, Waldron E, Tam C, Jager U, Borchmann P . Tisagenlecleucel cellular kinetics, dose, and immunogenicity in relation to clinical factors in relapsed/refractory DLBCL. Blood Adv. 2020; 4(3):560-572. PMC: 7013261. DOI: 10.1182/bloodadvances.2019000525. View

Levine J, Grupp S, Pulsipher M, Dietz A, Rives S, Myers G . Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia. J Immunother Cancer. 2021; 9(8). PMC: 8344270. DOI: 10.1136/jitc-2020-002287. View

Ganatra S, Redd R, Hayek S, Parikh R, Azam T, Yanik G . Chimeric Antigen Receptor T-Cell Therapy-Associated Cardiomyopathy in Patients With Refractory or Relapsed Non-Hodgkin Lymphoma. Circulation. 2020; 142(17):1687-1690. DOI: 10.1161/CIRCULATIONAHA.120.048100. View

10.

Badar T, Shah N . Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia. Curr Treat Options Oncol. 2020; 21(2):16. DOI: 10.1007/s11864-020-0706-6. View

11.

Maude S, Laetsch T, Buechner J, Rives S, Boyer M, Bittencourt H . Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018; 378(5):439-448. PMC: 5996391. DOI: 10.1056/NEJMoa1709866. View

12.

Camilli M, Lombardo A, Crea F, Minotti G . Temporal patterns of left ventricular systolic and diastolic metrics changes in adult patients with haematological malignancies treated with chimeric antigen receptor (CAR)-T cells: results from the CARdio-Tox prospective study. Eur Heart J Cardiovasc Imaging. 2023; 25(3):e101-e103. DOI: 10.1093/ehjci/jead317. View

13.

Ganatra S, Dani S, Yang E, Zaha V, Nohria A . Cardiotoxicity of T-Cell Antineoplastic Therapies: Primer. JACC CardioOncol. 2023; 4(5):616-623. PMC: 9830211. DOI: 10.1016/j.jaccao.2022.07.014. View

14.

Sheth V, Gauthier J . Taming the beast: CRS and ICANS after CAR T-cell therapy for ALL. Bone Marrow Transplant. 2020; 56(3):552-566. PMC: 8592274. DOI: 10.1038/s41409-020-01134-4. View

15.

Page C, Mostafa A, Saiao A, Grice J, Roberts M, Isbister G . Cardiovascular toxicity with levetiracetam overdose. Clin Toxicol (Phila). 2016; 54(2):152-4. DOI: 10.3109/15563650.2015.1115054. View

16.

Hendren N, Drazner M, Bozkurt B, Cooper Jr L . Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome. Circulation. 2020; 141(23):1903-1914. PMC: 7314493. DOI: 10.1161/CIRCULATIONAHA.120.047349. View

17.

Lefebvre B, Kang Y, Smith A, Frey N, Carver J, Scherrer-Crosbie M . Cardiovascular Effects of CAR T Cell Therapy: A Retrospective Study. JACC CardioOncol. 2020; 2(2):193-203. PMC: 7413146. DOI: 10.1016/j.jaccao.2020.04.012. View

18.

Camilli M, Maggio L, Tinti L, Lamendola P, Lanza G, Crea F . Chimeric antigen receptor-T cell therapy-related cardiotoxicity in adults and children cancer patients: A clinical appraisal. Front Cardiovasc Med. 2023; 10:1090103. PMC: 9988907. DOI: 10.3389/fcvm.2023.1090103. View

19.

Alvi R, Frigault M, Fradley M, Jain M, Mahmood S, Awadalla M . Cardiovascular Events Among Adults Treated With Chimeric Antigen Receptor T-Cells (CAR-T). J Am Coll Cardiol. 2019; 74(25):3099-3108. PMC: 6938409. DOI: 10.1016/j.jacc.2019.10.038. View

20.

Fusaroli M, Isgro V, Cutroneo P, Ferrajolo C, Cirillo V, Del Bufalo F . Post-Marketing Surveillance of CAR-T-Cell Therapies: Analysis of the FDA Adverse Event Reporting System (FAERS) Database. Drug Saf. 2022; 45(8):891-908. PMC: 9360149. DOI: 10.1007/s40264-022-01194-z. View