CAR-T (Doubllebio)

Anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy is an innovative and effective treatment for patients with B‐cell hematological malignancies. Despite its high efficacy, it has been associated with the development of acute toxicities that can be severe or even fatal. Indeed, cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS) can induce significant morbidity and require close monitoring. Identification of clinical and laboratory markers able to predict the occurrence of ICANS may allow prompt recognition and more effective management strategies.

Here, we report a retrospective study on a cohort of 81 Italian adult patients treated in our hospital between September 2019 and April 2024. We reviewed all clinical, demographic, laboratory, and neurophysiological data in order to identify potential predictors.

The results of the multivariate analysis confirmed that ICANS typically occurred less frequently in younger patients, especially when treated with 41BB co‐stimulated CAR‐T. Baseline EEG abnormalities are confirmed to be a fundamental predictor of neurotoxicity. Interestingly, we identified GammaGT as a new, statistically significant marker of ICANS. This represents a novel finding, probably related to the important role of GammaGT also in neuroinflammation.

Our results need to be confirmed in a larger cohort of patients in order to eventually be integrated into current clinical practice and management of patients undergoing CAR‐T.

Treatment options for relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL) patients ineligible for autologous stem cell transplant (ASCT) or chimeric antigen receptor (CAR)‐T‐cell therapy remain limited. The PI3K inhibitor copanlisib has shown activity as a single agent in DLBCL. This phase II, single‐arm, multicentre trial evaluated copanlisib with rituximab and bendamustine (copa‐BR) in ASCT‐ and CAR‐T‐ineligible R/R DLBCL. Patients received six cycles of copa‐BR, followed by up to 12 cycles of copanlisib maintenance. The primary end‐point was 12‐month progression‐free survival (PFS). Thirty‐seven patients (aged 68–87 years, R/R after 1–2 prior lines) were enrolled. The overall response rate was 24.3%, with complete responses in 13.5%. After a median follow‐up of 20 months, the 12‐month PFS and overall survival rates were 25.1% and 44.5% respectively. Grade ≥3 toxicities included neutropenia (56.8%), infections (27.0%, including 6 death due to COVID‐19 infection with 25% fatality) and thrombocytopenia (16.2%). Due to limited efficacy, poor tolerability and emerging alternative treatments, the trial was terminated prematurely. Copa‐BR showed limited activity and an unfavourable safety profile, discouraging further investigation of this combination in ASCT‐ and CAR‐T‐ineligible R/R DLBCL.