Although 3 commercial CD19-targeted chimeric antigen receptor (CAR) T-cell therapies are available for large B-cell lymphomas (LBCLs), no randomized clinical trials have compared their efficacy and safety. In this retrospective multicenter cohort study, we evaluated real-world clinical outcomes of patients with relapsed/refractory LBCL treated with axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), or lisocabtagene maraleucel (liso-cel). Between April 2016 and July 2024, 624 patients received CD19-targeted CAR T-cell therapies (344 axi-cel, 142 tisa-cel, and 138 liso-cel). At a median follow-up of 20.9 months, the respective estimated 2-year progression-free survival (PFS) and overall survival (OS) rates were 46% and 63% for axi-cel, 30% and 45% for tisa-cel, and 45% and 58% for liso-cel. After adjusting for potential confounders in multivariate analyses, tisa-cel was associated with inferior PFS and OS compared to axi-cel. No significant survival differences were found between liso-cel and axi-cel. Propensity score and subanalyses of patients treated in the second-line vs third-line or later settings yielded similar outcomes. Compared to axi-cel, the objective response rate at 100 days was higher for liso-cel and lower for tisa-cel. Rates of cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, and immune effector cell–associated hematotoxicity, and febrile neutropenia were significantly higher with axi-cel. However, no significant differences in the cumulative incidence of infections or nonrelapse mortality were found. Axi-cel was associated with faster vein-to-vein time (axi-cel, 35 days; tisa-cel, 43 days; liso-cel, 41 days) and fewer out-of-specification products (axi-cel, 2%; tisa-cel, 4%; liso-cel, 11%). These results provide insights into potential differential outcomes depending on product selection.

Chimeric antigen receptor (CAR) T-cell therapy (CART) for central nervous system lymphoma (CNSL) is a promising strategy, yet responses are frequently not durable. Bridging radiotherapy (BRT) is used for extracranial lymphoma in which it can improve CART outcomes through cytoreduction of high-risk lesions. We hypothesized that BRT would achieve similar, significant cytoreduction before CART for CNSL (CNS-BRT). We identified patients with CNSL with non-Hodgkin B-cell lymphoma who received CNS-BRT before commercial CART. Cytoreduction from CNS-BRT was calculated as change in lesion size before CART. Twelve patients received CNS-BRT, and the median follow-up among survivors is 11.8 months (interquartile range, 8.5-21.9). Ten patients had CNSL (9 secondary, 1 primary) and 2 patients had epidural disease (evaluable for toxicity). All 10 patients with CNSL had progressive disease at the time of CNS-BRT. Of 12 patients, 1 experienced grade ≥3 cytokine release syndrome, and 3 of 12 patients experienced grade ≥3 immune effector cell–associated neurotoxicity syndrome. CNS-BRT achieved a 74.0% (95% confidence interval, 62.0-86.0) mean reduction in lesion size from baseline (P = .014) at a median of 12 days from BRT completion and before CART infusion. Best CNS response included 8 complete responses, 1 partial response, and 1 progressive disease. Three patients experienced CNS relapse outside the BRT field. Preliminary data suggest CNS-BRT achieves rapid cytoreduction and is associated with a favorable CNS response and safety profile. These data support further study of BRT as a bridging modality for CNSL CART.

Chimeric antigen receptor (CAR) T cells are an established treatment for B cell non-Hodgkin lymphomas (B-NHL). With the remarkable success in improving survival, understanding the late effects of CAR T cell therapy is becoming more relevant. The aim of this study is to determine the incidence of subsequent malignancies in adult patients with B-NHL. We retrospectively studied 355 patients from 2 different medical centers treated with four different CAR T cell products from 2016 to 2022. The overall cumulative incidence for subsequent malignancies at 36 months was 14% (95% CI: 9.2%, 19%). Subsequent malignancies were grouped into 3 primary categories: solid tumor, hematologic malignancy, and dermatologic malignancy with cumulative incidences at 36 months of 6.1% (95% CI: 3.1%-10%), 4.5% (95% CI: 2.1%-8.1%) and 4.2% (95% CI: 2.1%-7.5%) respectively. Notably, no cases of T cell malignancies were observed. In univariable analysis, increasing age was associated with higher risk for subsequent malignancy. While the overall benefits of CAR T products continue to outweigh their potential risks, more studies and longer follow ups are needed to further demonstrate the risks, patterns, and molecular pathways that lead to the development of subsequent malignancies.

While CD19-directed CAR T-cell therapy represents a transformative immunotherapy for relapsed/refractory large B-cell lymphoma (r/r LBCL), more than 50% of patients ultimately progress or relapse. Recently, the International Metabolic Prognostic Index (IMPI) – incorporating age, stage, and metabolic tumor volume (MTV) – was shown to improve prognostication for LBCL frontline treatment. Here, we examine its utility to predict toxicity and survival in CAR-T recipients. This multicenter observational study spanning six international sites included 504 patients with available ¹⁸FDG-PET/CT imaging at last response assessment prior to lymphodepletion. Optimal CAR-adapted MTV thresholds were identified in a development cohort (n = 256) and incorporated into a CAR-T-specific IMPI (“CAR-IMPI”). The prognostic performance of CAR-IMPI was validated in an independent cohort (n = 248). CAR-IMPI risk categories, defined by the median (1.35) and terciles (1.07, 1.58), demonstrated significant discrimination for progression-free survival (PFS; p < 0.0001) and overall survival (OS; p < 0.0001) in both cohorts. Multivariate Cox regression confirmed CAR-IMPI as an independent predictor of survival, accounting for pre-lymphodepletion LDH and CRP, performance status, treatment center, and CAR-T product. Patients in the CAR-IMPI high-risk category experienced increased severity of CRS and ICANS, and higher rates of intensive care unit (ICU) admissions. In an exploratory analysis, combining CAR-IMPI with established indices of high-risk systemic inflammation (CAR-HEMATOTOX, InflaMix) further enhanced survival stratification. The CAR-IMPI may provide a potent and validated PET-based tool for risk stratification of clinical outcomes in patients with r/r LBCL receiving CD19 CAR-T therapy. Our data highlight the utility of combining clinical and radiological modalities, with implications for patient selection and the anticipated level-of-care for toxicity management.

Patients treated with chimeric antigen receptor T-cell (CAR-T) therapy are subject to profound immunosuppression. Dynamics of immune reconstitution (IR) and impacts of IR on outcomes following infusion across CAR-T products are not well understood. In this study, we profiled IR in 263 patients with relapsed/refractory large B-cell lymphoma receiving CAR-T therapy (axicabtagene ciloleucel 44.9%, lisocabtagene maraleucel 30.4%, and tisagenlecleucel 24.7%). Following infusion, patients remain persistently immunosuppressed, with 48.1% having CD4+ T-cell counts <200/µL and the median CD3-CD19+ B-cell counts remaining zero through 1 year after CAR-T therapy. IR differences exist by product, with the fastest CD4+ T-cell recovery seen for tisagenlecleucel, driven primarily by more rapid recovery of the CD4+CCR7−CD45RA− effector memory subset. NK cell, but not CD4+ T cell, recovery is significantly associated with favorable progression-free (HR, 0.65; 95% confidence interval, 0.48–0.88) and overall survival (HR, 0.64; 95% confidence interval, 0.44–0.92) and inversely correlated with inflammatory markers measured at the time of infusion. Significance: This study reveals differences in IR patterns after CAR-T therapy in patients with large B-cell lymphoma, with early NK cell recovery emerging as a key predictor of survival. These findings provide potential future avenues of research for improving patient outcomes and tailoring post-therapy management strategies to mitigate relapse risk.