Severe infections after CD19-directed chimeric antigen receptor T-cell therapy for Relapsed/Refractory large B-cell lymphoma, a retrospective real-life study from the DESCAR-T registry (LYSA)

Abstract Background CD19-directed chimeric antigen receptor (CAR) T-cell therapy has revolutionized the prognosis of relapsed/refractory large B-cell lymphoma (R/R LBCL). Infections are one of the major complications of this therapy. Few real-life studies focus on both short and long-term infections and their risk factors following CAR-T cell infusion, and even fewer were conducted on European cohorts. Methods Using the French DESCAR-T registry (NCT04328298), we analyzed the incidence, types, outcomes and risk factors of severe (grade 3 or higher) infections. We report on 2 187 R/R LBCL patients who received commercial anti-CD19 CAR T-cell (75.3% axicabtagene ciloleucel, 22.7% tisagenlecleucel and 2% lisocabtagene maraleucel) from April 2018 to April 2024 in 32 French centers. Bacterial, viral, fungal and parasitic infections were recorded, along with details of the pathogens involved, up to two years after CAR T-cell infusion. The data was collected at key moments during patient follow-up after infusion (day 10, month 1, 3, 6, 12, 18, 24). The median follow-up period was 13 months (interquartile range 6-24.7 months), 30.7% of the initial population remained at year 2. Results A total of 933 infections occurred during the first two years following infusion, most of which occurred during the first 3 months (76.7%, n=716), with an incidence peak during the first 10 days after infusion. Between days 1 and 10, 350 severe infections were documented in 2 153 patients i.e. 0.163 infections per patient during this period. By comparison, there were 0.125 infections per patient between day 10 and the end of month 1, 0.118 between months 1 and 3, 0.074 between months 3 and 6, 0.082 between months 6 and 12, 0.087 between months 12 and 18 and 0.075 between months 18 and 24. After 2 years, 786 patients had died, and infection was the cause of death in 76 of them (9.6%). Most infections were bacterial (55.9%), with the highest proportion occurring in the first month (64.4%). The majority were due to Enterobacterales, coagulase-negative staphylococci (most frequent between days 1 and 10) and non-fermenting Gram-negative bacilli. The proportion of viral infections was low (4.9%) between day 1 and 10, and gradually increased during the first 6 months (40.5% at month 6), with the majority being respiratory viruses. Fungal infections represented 10% of infections. Parasitic infections were rare (0.2%). Multivariate analysis revealed that patients with an ECOG scale ≥ 2 at infusion, cytokine release syndrome, G-CSF administration, which reflects neutropenia, and gamma globulin administration, which reflects deep hypogammaglobulinemia, were at higher risk for infection. Axicabtagene ciloleucel also appeared to be risk factor for infection though there might be an effect size due to its use as the main treatment in this study, and it was used more widely when the risk of infection was not as well managed. Conclusion This real-life study based on a large French cohort shows that severe infections are a frequent complication of CAR-T cell therapy in R/R LBCL patients, with a significant infection-related mortality. The study provides a detailed overview of the pathogens involved and identifies infection risk factors, which may help physicians to better manage and prevent infections.