Clinical Pharmacology of Tisagenlecleucel in B-Cell Acute Lymphoblastic Leukemia

Purpose: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Experimental Design: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across 2 studies in pediatric B-ALL (ELIANA; ENSIGN). Results: Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders (n = 62) had 2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders (n = 7; 73.5% and 104% higher geometric mean Cmax and AUC0-28d, respectively) with persistence measurable beyond 2 years in responding patients. Cmax increased with occurrence and severity of cytokine release syndrome (CRS) and neurological events. Tisagenlecleucel continued to expand and persist following tocilizumab, used to manage CRS. Patients with B cell recovery within 6 months had earlier loss of the transgene compared with patients with sustained clinical response. Clinical responses were seen across the entire dose range evaluated (patients ≤50 kg: 0.2 to 5.0 x 10⁶/kg; patients >50 kg: 0.1 to 2.5 x 10⁸ CAR positive viable T cells) with no relationship between dose and safety. Neither preexisting nor treatment-induced anti-murine CAR19 antibodies impacted the persistence or clinical response. Conclusions: Response to tisagenlecleucel was associated with increased expansion across a wide dose range. These results highlight the importance of cellular kinetics in understanding determinants of response to chimeric antigen receptor T-cell therapy.

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