Distinct Safety and Toxicity Profile of CD19-Directed CAR T-Cell Therapy in Systemic Lupus Erythematosus Versus B-Cell Lymphoma - a Single-Center Experience

CD19-directed Chimeric Antigen Receptor (CAR) T-cell therapies have revolutionized the treatment of relapsed/refractory B cell lymphoma. We have recently demonstrated that anti-CD19 CAR T-cell therapy is also feasible and effective in adult and adolescent patients with refractory systemic lupus erythematosus (SLE) (Mackensen et al., 2022; Müller et al., 2024; Krickau et al., 2024). Despite these promising findings, several unresolved questions remain concerning the treatment with CAR T-cells in patients with autoimmune diseases, which were primarily developed for the treatment of cancer patients. Herein, we analyzed the occurrence and severity of toxicities, inflammatory markers, blood counts and the cellular dynamics of SLE patients (N=18; all patients in CR) and lymphoma patients [DLBCL NOS (N=39), MCL (N=3), other types of NHL (N=6); 50% in lasting CR > 6 months] undergoing CAR T-cell therapy. All patients were treated in our center with either commercial CAR T-cell products or with the investigational medicinal product MB-CART19.1 (in-house manufactured 2nd generation anti-CD19 CAR T-cells with a 4.1BB co-stimulatory domain). In both, the SLE and lymphoma cohort, CAR T-cell peak expansion occurred between day 7 to 14 after infusion. In accordance with the simultaneous time of expansion, concentration of CAR T-cells at the peak and within the first 3 months after treatment displayed no difference in SLE and lymphoma patients. In contrast to the comparable CAR T-cell kinetics, SLE patients revealed lower incidence and severity of cytokine-release syndrome (grade 0-1 in 93% SLE versus 55% in lymphoma patients) and immune-effector cell associated neurotoxicity syndrome (0% in SLE versus 44% in lymphoma patients) compared to the lymphoma cohort. Consistent with reduced toxicity, SLE patients received less tocilizumab and glucocorticoid treatment. Bone marrow toxicity with severe and/or prolonged cytopenia is a frequent long-term CAR T-cell related adverse event. Despite comparable lymphodepletion with fludarabine/cyclophosphamide, SLE patients demonstrated on average a deeper nadir of neutrophils compared with lymphoma patients. In contrast, absolute neutrophil counts recovered quicker, and severe neutropenia recovered within a median of 4.5 days in SLE (range: 0-23) vs. 10 days in lymphoma (range: 0-62). Though usually attributed to fludarabine use in lymphodepletion, platelets decreased on average only to CTCAE grade 1 (range: 0-3) in SLE patients compared to grade 3 (range: 0-4) in lymphoma patients. In addition, platelets recovered to normal with a median of 0 days in SLE (range: 0-4) vs. 14.5 days in lymphoma (range: 0-85). Overall, SLE patients showed lower incidence and severity of hematological toxicities, classified as early and late ICAHT (immune effector cell-associated haematotoxicity). In line with HEMATOTOX-Score that associates lasting and higher grade of bone marrow toxicity with baseline inflammation (Rejeski et al., 2021), serum CRP and ferritin were higher in lymphoma patients than in SLE patients prior to and shortly after CAR T-cell treatment. Interestingly, SLE patients showed a shorter duration of CAR T-cell persistence and a faster reconstitution of B-cells than patients with lymphoma in remission (median time of B-cell aplasia: 142 days in SLE vs. 798 days in lymphoma patients). Taken together, while both patient cohorts showed similar CAR T-cell expansion and dynamics, we observed less toxicity and less severe adverse events in SLE patients than in lymphoma patients. This is consistent with a lower base-line inflammation, a shorter CAR T-cell persistence, and a faster B-cell recovery in SLE patients, indicating an overall very good safety profile of CAR T-cell therapy in the treatment of SLE