Wudhikarn, Kitsada

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 Little is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse–enriched training set. Using a complete case analysis (n = 182), including 91 with CNS relapse, we applied a least absolute shrinkage and selection operator Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (n = 566). CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (25%). Median time to CNS relapse and median overall survival after CNS relapse were 8.0 and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (n = 158) and high-risk (n = 188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio, 5.24; 95% confidence interval, 1.50-18.26; P = .018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at the highest risk of developing CNS relapse.