Long-Term Durable Responses in Patients with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL), Diffuse Large B-Cell Lymphoma (DLBCL), and Follicular Lymphoma (FL) Treated with Tisagenlecleucel and Its Association with Persistence of Chimeric Antigen Receptor (CAR) T Cells

Introduction Monitoring CAR transgene level in peripheral blood post tisagenlecleucel (tisa-cel) infusion provides information on CAR-T cell expansion and persistence. Objective To analyze the impact of CAR persistence and B-cell aplasia on duration of remission (DOR) in patients (pts) treated with tisa-cel. Methods Blood transgene levels measured by quantitative polymerase chain reaction were available from phase II studies in r/r ALL (ELIANA [N=79], ENSIGN [N=64], NCT03123939 [N=69], NCT01626495 [N=60]), r/r DLBCL (JULIET [N=115]), r/r FL (ELARA [N=97]), and long-term follow-up study (NCT02445222). Time related to loss of persistence of CAR-T cells (Tloss) was defined as time when transgene levels first dropped to <50 transgene copies/µg DNA (lower limit of quantification [LLOQ] of the assay) after maximal expansion. Impact of duration of Tloss and ongoing persistence beyond 1 year on DOR/relapse were measured by Kaplan-Meier analysis. Impact of time to B-cell recovery (ALL: >1% CD19+ B cells/white blood cells or >3% CD19+ B cells/lymphocytes; DLBCL and FL: 80–616 cells/µL) on DOR/relapse was also investigated. Results Long-term CAR persistence in tisa-cel–treated pts was observed for up to 9, 6, and 2.5 years for ALL, DLBCL, and FL, respectively, reflecting differing length of follow-up due to initiation of trials. Pts who lost transgene in ˂6 or 6–12 months had shorter DOR vs pts with persistent transgene (Fig 1, ALL pts). In ALL, median Tloss was 27.4, 18.2, 9.7, and 18 months for ongoing complete response (CR) >12 months, CR pts between 6–12 months, relapsed pts <12 months, and relapsed pts >12 months, respectively. In pts who lost transgene within first ˂6 months, durable responses for ≥12 months were maintained in some pts - ALL: 29%; DLBCL: 15%; FL: 50%. Among ALL-relapsed pts, 17/26 (65%) with Tloss at <6 months showed B-cell recovery; 6 pts had Tloss at <6 months and B-cell recovery but maintained response for ≥12 months. Median time to B-cell recovery was 266 days in relapsed/censored pts within 12 months but was not reached for pts with ongoing response at 12 months.Of ALL pts with CAR persistence, longer DOR observed in pts (with <50% morphologic blasts) prior to tisa-cel infusion vs pts with ≥50% blasts reflect more resistant high-risk ALL at study entry or greater potential for stochastic loss of CD19 in higher disease burden pts. Conclusions Long-term sustained remission/response was observed in tisa-cel–treated pts in pivotal trials. A positive association between CAR persistence and durable clinical responses across indications was demonstrated; however, some pts maintained durable responses despite early loss of transgene and/or early B-cell recovery. In DLBCL and FL, the transgene levels in blood may not represent levels at target sites including lymph nodes, also, persistence or loss of transgene (Tloss) are dependent on the duration of follow-up and LLOQ.