Nationwide Multicenter Real-World Survey of CAR-T Cell Toxicity Prophylactic and Treatment Management Strategies
Authors: Gavriilaki Eleni , Tzannou Ifigeneia , Vardi Anna , Tsonis Ioannis , Liga Maria , Gkirkas Kostantinos , Ximeri Maria , Bousiou Zoi , Bouzani Maria , Sagiadinou Eleftheria , Dolgyras Panagiotis , Kotsiou Nikolaos , Bampali Vasiliki , Mallouri Despina , Tzenou Tatiana , Batsis Ioannis , Sotiropoulos Damianos , Gigantes Stavros , Papadaki Helen A , Tsirigotis Panagiotis , Spyridonidis Alexandros , Vassilakopoulos Theodoros P. , Angelopoulou Maria , Baltadakis Ioannis , Sakellari Ioanna 
Published: December 2024

Background: Immunotherapy with Chimeric Antigen Receptor T cells (CAR-Τ) is continuously expanding in numbers of patients, indications, and physicians administering the treatment.Severe cytokine release syndrome (CRS) and neurotoxicity (ICANS) are encountered in CAR-T recipients both in trials and real-world setting, with policies of prophylaxis and treatment mostly utilizing low doses of steroids. Therefore, mapping of management among different centers emerges as an unmet need.

Aim: To this end, we aimed to document prophylactic and treatment strategies associated with severe CRS and ICANS in the real-world setting.

Methods: We collected data from consecutive adult patients from 7 transplant centers in Greece using an online survey. Tisagenlecleucel and axicabtagene ciloleucel (tisa-cel and axi-cel) have been administered since 2020, and brexucabtagene autoleucel (brexu-cel) since 2022. All patients received lymphodepleting therapy before CAR-T cell infusion with combination of cyclophosphamide and fludarabine. Levetiracetam prophylactic treatment was administered by all centers. Data were reported until the end of June 2024, with at least 1 month of follow-up post infusion.

Results: In total, 173 patients received commercial CAR-T cell products (120 axicabtagene ciloleucel, 33 tisagenlecleucel, 20 brexucabtagene autoleucel). Grade 3 CRS was reported in 8/120 (7%) of axi-cel, 1/33 (3%) of tisa-cel, and 2/20 (10%) of brexu-cel recipients. Grade 4 CRS was documented in 3/120 (3%) of axi-cel and 1/20 (5%) of brexu-cel recipients; while grade 5 only in brexu-cel (2/20, 10%). Low dose dexamethasone was administered as prophylactic treatment by 2 centers with a total dose of 30 and 40 mg in 18 and 13 axi-cel recipients, respectively. Among them, only 3 patients developed severe toxicity, only grade 3 CRS. All centers treated patients with tocilizumab at 8 mg/kg for a median of 4 doses (3-6), even from grade 1 CRS lasting for longer than 24 hours. In the absence of improvement or persistence of symptoms, dexamethasone was administered at 10 mg per dose, with a median total dose of 40 mg (10-150). Anakinra was utilized by 2 centers at 100mg every 6 hours, while siltuximab by 1 center. Regarding ICANS, grade 3 was reported in 9/120 (8%) of axi-cel and 2/20 (10%) of brexu-cel recipients, while grade 4 in 3/120 (3%) of axi-cel recipients. Among them, 3 patients had received prophylactic dexamethasone and had not exhibited severe CRS (grade 3 or higher). All patients with severe ICANS received dexamethazone treatment with a median total dose of 30 mg (10-240). Methylprednizolone was administered at a median total dose of 2 gr (1-4) in 2 patients that had already received low dose dexamethasone for CRS. 1 patient with severe CRS and ICANS additionally received anakinra and siltuximab in 1 center. Concerning prognostic markers, 2 centers reported the use of EASIX (The Endothelial Activation and Stress Index) along with bedside EEG (electroencephalogram) in 1 of them, while another center guided management according to the algorithm by the French group DESCAR-T.

Conclusions: Our multi-center real-world experience with CAR-T cell therapy confirms low rates of CRS and ICANS after tisa-cel and axi-cel treatment irrespective of management algorithms. Brexu-cel was administered in a rather small patient population, that does not allow for safe conclusions. Although all centers followed early tocilizumab and steroids administration, different approaches were documented in prophylactic strategies. The steroid-sparing effect of CAR-T cell therapy in selected low-risk patients needs to be further evaluated, especially in the era of bispecific antibody therapy demanding steroid prophylaxis. Further real-world studies are needed to determine the optimal personalized approach in this setting.