Abstract
Tisagenlecleucel has revolutionized the pharmacological approach of relapsed or refractory B-cell acute lymphoblastic leukaemialeukaemia in paediatrics. The safety profile of tisagenlecleucel still needs to be better defined. The aim of this study was a post-marketing evaluation of the safety of tisagenlecleucel through the analysis of the Eudravigilance database with focus on the paediatric population. From 2017 to 2020, one third of Individual Case Safety Reports referring to tisagenlecleucel (117/364) have been collected in paediatrics, on average nine year-old boys. Overall, 92% of the638 adverse events were serious and caused or prolonged hospitalisation. A total of 55 adverse events presented a fatal outcome, mainly due to progression of malignant neoplasm (N = 10; 18.2%), recurrence of acute lymphocytic leukaemia (N = 6; 10.9%) or occurrence of acute lymphocytic leukaemia (N = 5; 9.1%). Cytokine release syndrome was commonly reported after tisagenlecleucel infusion (54/638), followed by pyrexia (45/638) and hypotension (27/638). Only 18/638 events referred to neurotoxicity, none of them resulted in death. More than one third of cases (41/117) were suggestive of therapeutic failure. This first post-marketing analysis confirms pre-approval evidence of the safety profile of tisagenlecleucel in paediatrics. Since only a few years of marketing is available, further followed-up studies need to be performed to investigate longer-term safety of tisagenlecleucel.
Highlights
The development of second-generation CAR-T and the choice of CD19 as a tumour antigen significantly increased CAR-T activity in preclinical studies that were translated into unprecedented clinical results in B-cell acute lymphoblastic leukaemia (B-ALL) and non-Hodgkin lymphoma (NHL) [1,2,3,4,5,6,7,8,9]
The feasibility and the efficacy of anti-CD19 CAR-T cells was demonstrated through the study ENSIGN, a phase II multicenter trial (NCT02228096) enrolling paediatric and young adults with r/r B-ALL, showing a high overall remission rate (ORR) with durable remissions [16]
A total of 364 individual case safety reports (ICSRs) collected from 2017 to 2020 in the EV database were associated to tisagenlecleucel, 117 out of them (32.7%) referred to paediatric patients
Summary
The development of second-generation CAR-T and the choice of CD19 as a tumour antigen significantly increased CAR-T activity in preclinical studies that were translated into unprecedented clinical results in B-cell acute lymphoblastic leukaemia (B-ALL) and non-Hodgkin lymphoma (NHL) [1,2,3,4,5,6,7,8,9]. The first-in-human study of tisagenlecleucel, hereafter referred to as anti-CD19 CAR-T cell, was performed in 2010 only in adults with r/r CD19+ B-cell leukaemia and lymphomas (CART19 phase I trial (NCT01029366)), while the first results of its use in two children were published in 2013, showing a complete remission of the B-ALL [8,14]. A pilot clinical trial on 30 children and adults with r/r ALL treated with anti-CD19 CAR-T cells showed a complete response in 90% of the study population, a 6-month event-free survival of 67% and Overall Survival of 78% [15]. The feasibility and the efficacy of anti-CD19 CAR-T cells was demonstrated through the study ENSIGN, a phase II multicenter trial (NCT02228096) enrolling paediatric and young adults with r/r B-ALL, showing a high overall remission rate (ORR) with durable remissions [16]. There is a need to further characterise identified complications which include prolonged cytopaenias, hypogammaglobulinaemia, risk of secondary malignancies and both neurological and autoimmune disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
