Huppler, Anna R

Abstract Background: Infections account for over half of the non-relapse deaths among chimeric antigen receptor (CAR) T-cell recipients. Non-relapse mortality estimates are among the highest in patients with relapsed / refractory multiple myeloma (RRMM) receiving B-cell maturation antigen (BCMA)-directed CAR-T cell therapy. The current Center for International Blood and Marrow Transplantation Research (CIBMTR) study analyzed the burden, types, risk factors, and outcomes of infection and its impact on survival in 807 patients with RRMM receiving commercial idecabtagene vicleucel (ide-cel) CAR-T therapy from March 2021 to December 2023. Methods: The primary endpoint was infection density for overall infections and for organism type (bacterial, viral, or fungal) within 100 days post-CAR-T infusion. Infection density was estimated as the number of infections per 100 person days at risk, stratified into two distinct time intervals following CAR-T cell infusion: days 0-30 and days 31-100.Additional endpoints included the cumulative incidence of infections, infection-related mortality (IRM), and overall survival (OS). Multivariable Cox proportional hazards models were employed to identify factors associated with infectious complications within 100 days post-CAR-T cell infusion. Pre-specified risk factors were considered for the multivariable analysis (MVA) models. We further examined the impact of infections within 100 days of CAR-T on OS at any time beyond 100 days following CAR-T infusion. Results: Infections developed in 114 (14.1%) patients within 30 days and 226 (28%) patients within 100 days post-CAR-T infusion, resulting in an overall infection density of 0.49 per 100 patient-days and a 100-day cumulative incidence of 27.2%. Proportions of bacterial, viral, and fungal infections within 30 days of ide-cel infusion were 82 (10.2%), 50 (6.2%), and 5 (0.6%), respectively. Similarly, proportions of bacterial, viral, and fungal infections within 100 days of CAR T-cell infusion were 126 (15.6%), 125 (15.5%), and 8 (1%), respectively, with corresponding infection densities of 0.23, 0.22, and 0.012 per 100 patient-days. The 100-day cumulative incidence of bacterial, viral, and fungal infections were 14.1% (95% CI, 11.8-16.6%), 14.4% (95% CI, 12-16.9%), and 0.9% (95% CI, 0.3-1.6%) respectively. The 100-day IRM was 1.1% (95% CI, 0.5-2%). With a median follow-up of 11.6 months (1.1-26.7), 222 (27.5%) patients died, and infection was the primary cause of death in 17 cases (7.7%). In MVA, Karnofsky performance score ≤80 (p<0.001), infection prior to CAR-T cell infusion requiring with ongoing treatment after d+0 (p<0.001), cytokine release syndrome grade ³2 (p=0.002), and severe immune effector cell-associated neurotoxicity syndrome [ICANS] (grade ≥3) (p<0.001) were associated with an increased infection risk within 100 days post-infusion. Similarly, infection prior to CAR-T infusion requiring with continuing treatment after d+0 (p<0.001 for bacterial and p=0.003 for viral infections) and grade ≥3 ICANS (p<0.001 for bacterial and p=0.015 for viral infections) significantly conferred a heightened risk for bacterial and viral infections within 100 days of CAR-T infusion. Number of infections within 100 days (hazard ratio [HR], 2.36 for ≥2 vs. 0 infections; 95%CI, 1.48-3.77; p<0.001), extramedullary disease or plasma cell leukemia (HR, 1.8; 95%CI, 1.19-2.74; p=0.006), and prior BCMA-directed therapy (HR, 1.57; 95%CI, 1.06-2.33; p=0.025) were independent risk factors for inferior OS beyond day+100 after CAR-T therapy. Intravenous immunoglobulin (IVIG) replacement post-CAR-T therapy conferred a survival advantage (HR, 0.52; 95%CI, 0.38-0.72; p<0.001). Conclusion: In conclusion, study results demonstrate a significant incidence of infections for a prolonged duration (14.1% in the first 30 days and 28% in the first 100 days) in patients with RRMM undergoing ide-cel therapy. Notably, viral infections increased beyond d+30. Multiple infections (≥2 episodes) were associated with inferior OS. Results identify patients at an increased risk for infection and provide insights into risk-adapted interventions to mitigate infections and improve patient outcomes. Furthermore, continued surveillance for infection pre-emption and prevention beyond 3 months post-CAR T therapy may be necessary to reduce infection burden and IRM. Prophylactic strategies such as IVIG replacement could potentially modify infection risk in patients with RRMM receiving ide-cel.

Abstract Tisagenlecleucel (tisa-cel) is a CD19-directed chimeric antigen receptor T-cell therapy for relapsed/refractory precursor B-cell acute lymphoblastic leukemia (R/R B-ALL). We report infectious complications for 100 days (D100) following tisa-cel therapy in 471 pediatric and young adults (median age 13.8 years) with R/R B-ALL reported from September 2017 to June 2022. By D100, 137 (29%) patients had an infectious event, with an infection density of 0.542 per 100 person-days at risk. D100 cumulative incidences of bacterial, viral, and fungal infections were 14.1%, 11.6%, and 1.3%, corresponding to infection density scores of 0.296, 0.213, and 0.033 per 100 person-days at risk, respectively. In a multivariable analysis, receipt of ≥3 lines of therapy before tisa-cel (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.13-3.08; P = .015), any-grade cytokine release syndrome (HR, 1.78; 95% CI, 1.17-2.71; P = .007), and lack of neutrophil recovery (HR, 2.63; 95% CI, 1.47-4.69; P = .001) were associated with an increased risk for any infection. Similar associations were observed for bacterial infections, with the addition of younger age as an adverse risk (<6 vs 6-15 years; HR, 2.38; 95% CI, 1.23-4.61; P = .01). Risk factors for viral infections included increasing age (1-year increase; HR, 1.05; 95% CI, 1.01-1.09; P = .016), prior history of any infection (HR, 2.76, 95% CI, 1.40-5.46; P = .004), and prior hematopoietic cell transplant (HR, 2.10; 95% CI, 1.18-3.71; P = .011). D100 infection-related mortality (IRM) rate was low at 0.2% (95% CI, 0.0-0.8). In this multicenter real-world study, we observed a high incidence of infectious complications but a low IRM following tisa-cel for R/R B-ALL.

Abstract Infection is increasingly recognized as a significant cause of morbidity and mortality in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving CD19 chimeric antigen receptor (CAR) T-cell therapy. The current study analyzed the natural history, risk factors, and outcomes of infection in 3350 patients with R/R LBCL receiving commercial CD19 CAR T-cell therapy (n = 2804 axicabtagene ciloleucel [axi-cel], n = 546 tisagenlecleucel) from December 2017 to June 2022. Infection developed in 834 patients (24.9%) within 100 days after infusion, resulting in an infection density of 0.43 per 100 patient days and a 100-day cumulative incidence of 22%. Bacterial, viral, and fungal infections were recorded in 527 (15.7%), 374 (11.2%), and 108 patients (3.2%), respectively, with corresponding infection densities of 0.23, 0.15, and 0.04 per 100 patient days. After a 24-month median follow-up, 1482 patients (44%) had died, with infection as the primary cause in 173 cases (12%). The 100-day infection-related mortality (IRM) was 1.6% (95% confidence interval, 1.2-2.0). Patients with a Karnofsky performance score of ≤80, infection history before CAR T-cell therapy, axi-cel therapy, severe cytokine release syndrome (grade ≥3), and severe immune effector cell–associated neurotoxicity syndrome (grade ≥3) had increased infection risk. Infections within 100 days were an independent risk factor for inferior overall survival beyond day 100 after CD19 CAR T-cell therapy. In conclusion, study results show a significant incidence of infection and IRM in patients with R/R LBCL treated with CD19 CAR T-cell therapy. Furthermore, results identify patients at a heightened risk of infection, offering insights to guide potential interventions aimed at mitigating infection and improving patient outcomes after CAR T-cell therapy.