Siltuximab Prophylaxis Prior to Standard of Care CD19 Directed Chimeric Antigen Receptor T-Cell Therapy for B-Cell Lymphomas: Interim Results from a Phase I Clinical Trial

Introduction Chimeric antigen receptor T-cell therapy is highly effective for B-cell lymphomas; however, toxicities including cytokine release syndrome (CRS) and immune effector cell associated neurologic toxicity (ICANS) remain a clinical challenge. Methods We designed a phase I investigator-initiated, single center trial to evaluate the safety of siltuximab administered prior to standard of care (SOC) CD19 directed CAR-T (CAR19) for patients (pts) with B-cell lymphomas. Eligible pts were ≥ 18 years of age, were diagnosed with non-Hodgkin lymphoma, and were considered eligible for axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), brexucabtagene autoleucel, or lisocabtagene maraleucel (liso-cel). Pts received a single dose of siltuximab (11mg/kg) 1-hour prior to SOC CAR19 infusion. Prophylactic corticosteroids were not permitted. Per protocol, additional doses of siltuximab could be administered for management of CRS or ICANS. The primary objective was to determine safety of siltuximab prior to CAR19. Secondary objectives included incidence of grade ≥ 3 CRS and ICANS and objective response rate of CAR19. Results From 1/2023 to 9/2023, 11 pts signed consent, 1 pt was deemed ineligible prior to treatment. The median age was 71 years (range 53 – 79). Disease characteristics are described in Table 1. Diagnoses included diffuse large B-cell lymphoma (n=6), high grade B-cell lymphoma (n=3), and grade 3B follicular lymphoma (n=1). Median prior lines of therapy was 3 (range 1 – 4). CAR19 product was axi-cel (4 pts), tisa-cel (4 pts), and liso-cel (2 pts). No dose limiting toxicities were observed. CRS was observed in 6/10 pts, Table 2. Median time to CRS was 2.5 days (range 2-5). Max CRS grade was 1-2 in all 6 pts (grade 1, n=1; grade 2, n=5). No pt developed grade ≥ 3 CRS. CRS was managed with additional doses of siltuximab (n=5), tocilizumab (n=4), and corticosteroids (n=2). Median time to CRS resolution was 2 days (range 1 – 5). ICANS was observed in 3/10 pts (2 axi-cel, 1 tisa-cel), Table 2. All 3 pts who developed ICANS experienced preceding/concurrent CRS. Max ICANS grade was 2 in 2 pts and 4 in 1 pt. ICANS was managed with corticosteroids. Median time to ICANS resolution was 2 days (range 1 – 5). Nine pts were eligible for disease response assessment (1 pt withdrew consent at day 14 visit due to frequency of lab draws). CAR19 objective response rate at day 30 was 78% (7/9 pts), 6 complete responses and 1 partial response. Conclusion There were no dose limiting toxicities associated with siltuximab prophylaxis prior to CAR19. In this cohort, no grade ≥ 3 CRS was observed and only 1 pt developed grade ≥ 3 ICANS which fully resolved. Siltuximab prophylaxis prior to CAR19 should be investigated further in a larger cohort.