Tisagenlecleucel for the Management of Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma: An Interim Report of the European Post-Authorisation Safety Study Conducted By EBMT
Authors: Montoto Silvia , Kuball Jurgen , Mooyaart Jarl E , Ghandilyan Artak , Georgieva Dilyana , Sánchez-Ortega Isabel , Bonini Chiara , Novak Urban , Schneidawind Dominik , Yakoub-Agha Ibrahim , Passweg Jakob , Kröger Nicolaus , Schultze-Florey Christian R , Dreta Barbara , Lopez Corral Lucia , Stepensky Polina , Corradini Paolo , Kuhnl Andrea , Bramanti Stefania , Solano Carlos , Gabellier Ludovic , van Biezen Anja , Ruggeri Annalisa , Glass Bertram , Chabannon Christian 
Published: December 2024

Introduction:
CAR-T therapy has become an indispensable strategy in the management of patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) since its first approval in Europe in 2018, with an exponential increase in the number of patients undergoing CAR-T therapy over years. Tisagenlecleucel was the 1st product approved by EMA for patients with r/r DBCL after &gt; 2 lines of systemic therapy. We report here the preliminary results of a post-authorisation safety (PAS) study reported to the EBMT registry.
Patients and Methods:
From August 2018 to May 2023, 484 patients (pts) received Tisagenlecleucel for r/r DLBCL and were reported to the EBMT registry and included in the PAS study as mandated by EMA. The median age at the time of CAR-T was 63 years (range: 18-89) and 37% were female. Race and ethnicity data were not available. Thirty-seven percent of pts with available data had double hit/triple hit disease and almost one fifth had transformed lymphoma. Most of the pts (86%) had a good performance status (PS: 0-1) at the time of treatment, despite the fact that the majority had advanced disease. Sixty-four percent had relapse/refractory disease at the time of CAR-T, 27% had received a prior hematopoietic stem cell transplant (autologous transplant in most of the cases) and 66% of the patients had received &gt; 3 lines of therapy prior to CAR-T.
Endpoints in this study were overall survival (OS), progression-free survival (PFS), duration of response (DOR) and incidence of cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). PFS was defined as time from infusion to death or progression of disease, whichever came first, and DOR as the time from first complete response (CR) or partial response (PR) until death/disease progression. For both cumulative incidence (CI) of CRS and ICANS after infusion, death was considered as a competing event.
Results:
The median time from apheresis to infusion was 51 days (range: 11-280) and in 97% of the cases lymphodepletion was with cyclophosphamide/fludarabine. With a median follow-up of 10 months (range: 0-46), the best overall response rate (ORR) was 62% with a CR rate of 42%. The median duration of response (DOR) was 15 months. Two-year PFS and OS were 26% and 46%, respectively. Two-hundred and thirty (47.5%) pts died, 83% of them due to disease progression. Twenty-six patients died within 30 days of infusion (11% of all deaths), due to disease progression (64%), sepsis (17%), CRS (9%), bacterial infection (4%) and hemophagocytic syndrome (4%). The CI of CRS was 67% at 30 days, with grade &gt;3 CRS in 9% of the study population (grade &gt; 3 in 13% of the pts experiencing CRS). At 30 days the CI of ICANS was 18%, with a total of 6% grade &gt; 3 ICANS in the study population (grade &gt; 3 in 38% of pts experiencing ICANS). Other frequent reported toxicities were hypogammaglobulinemia and infections, in 211 and 213 pts, respectively. Fifteen secondary malignancies were reported, including myelodysplastic syndromes/myeloproliferative neoplasms in 7 cases. No T-cell lymphomas were reported.
Conclusion:
This study reports the results of Tisagenlecleucel for r/r DLBCL in the real world, and confirms its efficacy with a manageable toxicity (including a low incidence of ICANS), serving as benchmarking for future studies.