Axicabtagene Ciloleucel

Chimeric antigen receptor (CAR) T-cell therapies have improved outcomes in patients with relapsed/refractory large B-cell lymphoma (LBCL). However, up to two thirds of these patients do not maintain long-term responses. The phase 1/2 ZUMA-6 study investigated the feasibility of combining the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel) with the PD-L1 inhibitor atezolizumab as a potential approach to increase treatment efficacy while maintaining acceptable safety.

Patients with refractory diffuse LBCL received a single axi-cel infusion (2 × 106 cells/kg), followed by atezolizumab 1,200 mg i.v. every 21 days for four cycles. Primary endpoints were dose-limiting toxicities (phase 1) and complete response rate (phase 2). Other efficacy and safety outcomes and pharmacokinetics/pharmacodynamics were assessed.

Overall, 34 patients received axi-cel plus atezolizumab in ZUMA-6. The median follow-up for the final analysis was 56.9 months. In phase 1, one patient experienced dose-limiting toxicities (grade 4 neutropenia and thrombocytopenia). Thirty patients (88%) experienced grade ≥3 treatment-emergent adverse events. Three (9%) and 11 (32%) patients experienced grade ≥3 cytokine release syndrome and neurologic events, respectively. In the final analysis, 15 patients (54%) had a complete response. The median progression-free survival and overall survival were 9 and 32.2 months, respectively. Peak CAR T-cell and cytokine profiles were comparable with those previously reported for axi-cel monotherapy (ZUMA-1).

Axi-cel plus atezolizumab had a manageable safety profile, with no new safety signals. Safety and efficacy of this combination were consistent with axi-cel monotherapy. Correlative analyses could inform with regard to which patients with LBCL may benefit from axi-cel and immune checkpoint inhibitor combinations.

Chimeric antigen receptor T-cell therapy (CAR-T) and T-cell engager antibody (TCE) revolutionized relapsed refractory multiple myeloma (RRMM), non-Hodgkin lymphoma (NHL), and acute lymphoblastic leukemia (ALL) treatment. Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a potentially fatal rare complication characterized by cytopenia, coagulopathy, transaminasemia, and hyperferritinemia. We aim to analyze the IEC-HS reported cases, patterns, and outcomes in RRMM and NHL patients undergoing CAR-T and TCE therapy utilizing the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. We conducted a retrospective postmarketing pharmacovigilance inquiry using the FAERS database and the Medical Dictionary for Regulatory Activities (MEDRA). The database was accessed on March 20, 2025 to examine the adverse effects of CAR-T: idecabtagene vicleucel (ide-cel), ciltacabtagene autoleucel (cilta-cel), axicabtagene ciloleucel (axi-cel), brexucabtagene autoleucel (brexu-cel), tisagenlecleucel (tisa-cel) and lisocabtagene maraleucel (liso-cel), and TCE (teclistamab, elranatamab, talquetamab, mosunetuzumab, glofitamab, and epcoritamab) since their FDA approval in the United States and non-US populations. Descriptive analysis was used to describe reported proportions and outcomes. Reported mortality per product was calculated for patients with IEC-HS. Cases reported in 2024, were used to calculate reporting odds ratio (ROR) and empirical Bayesian geometric mean (EBGM) to compare the drugs for IECHS events reported. A total of 23,315 unique case safety reports (ICSRs) were analyzed, identifying 378 (1.62%) reports of IEC-HS. Reported mortality was high among these patients (n = 232/378, 61.3%). A formal disproportionality analysis, limited to 2024 reports to ensure a contemporary comparison, was performed. Tisa-cel (ROR 2.20) and cilta-cel (ROR 2.24) both demonstrated statistically significant disproportionate reporting signals for IEC-HS. In contrast, axi-cel, which accounted for the highest absolute number of reports (n = 114/378), did not show a significant signal in this analysis (ROR 1.02), suggesting its high case volume is proportional to its high overall reporting frequency. Teclistamab showed a significantly reduced likelihood of HLH reporting (ROR 0.43). IEC-HS is a rare but potentially fatal complication. Our disproportionality analysis identifies significant reporting signals for tisa-cel and cilta-cel. The high absolute number of cases observed for products like axi-cel appears to reflect high utilization rather than a disproportionate risk, underscoring the necessity of using statistical signal detection methods when interpreting spontaneous reports.