Abstract CT110: Clinical pharmacology of tisagenlecleucel (CTL019) in patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL)
Authors: Awasthi Rakesh , Tam Constantine S. , Jaeger Ulrich , Jaglowski Samantha , Foley Stephen Ronan , Besien Koen van , Wagner-Johnston Nina D. , Kersten Maria José , Schuster Stephen J. , Salles Gilles , Maziarz Richard T. , Anak Özlem , Pacaud Lida Bubuteishvili , Gazi Lucien , Waldron Edward , Hamilton Jason , Pruteanu Iulian , Tai Feng , Mueller Karen Thudium , Waller Edmund K. 
Published: August 2018

Abstract
Background: Tisagenlecleucel is a cellular immunotherapy that uses genetically modified autologous T cells to target CD19+ B cells. Little is known about the effects of dose and cellular kinetics on response and safety of tisagenlecleucel in r/r DLBCL patients (pts).
Methods: Data from a pivotal phase 2 study (JULIET; NCT02445248) were used to characterize exposure, dose, response, and safety in r/r DLBCL pts.
Results: Cellular kinetic parameters were summarized for 81 pts using qPCR measurements from peripheral blood only. The geo-mean AUC0-28d, Cmax, and median Tmax were similar in responding and nonresponding pts, suggesting similar expansion levels (Table 1). The geo-mean Cmax in r/r DLBCL pts was 6-fold lower than in pediatric r/r ALL pts (Mueller EHA 2017), suggesting indication-specific differences. Higher expansion was associated with higher grade CRS. No relationship between dose and exposure (AUC0-28d; Cmax) was observed. Logistic regression analyses showed no impact of dose on month 3 response (2-fold increase; OR, 1.03; 95% CI, 0.624-1.685). Cox regression showed no apparent impact of dose on duration of response. Dose did not impact neurological events (NEs). The probability of CRS increased with increase in dose (2-fold increase in dose; OR, 2.79 for any grade CRS; 95% CI, 1.394-5.567). Anti-mCAR19 antibodies (humoral) and cellular immunity had no impact on cellular kinetics and month 3 response.
Conclusion: Differences in tisagenlecleucel expansion between r/r DLBCL and pediatric r/r ALL suggest mechanistic differences based on location of disease. Tisagenlecleucel was effective across the dose range with no impact of dose on NEs. Increased probability of higher grade CRS with increased dose and an association between expansion and CRS severity were observed. CRS was manageable with appropriately trained staff. These analyses provide insights into the relationships between exposure, response, dose, and safety in r/r DLBCL.
Table 1. Summary of Cellular Kinetic Parameters by Response at Month 3 for DLBCL PatientsParameterStatisticsCR/PR n = 31SD/PD/Unknowna n = 50All Patients N = 81AUC0-28d, copies/μg/dayn293665Geo-mean69,30070,70070,100Geo-CV, %161.3282.0219.3Fold differenceb≈ 1.0Cmax, copies/μgn314576Geo-mean647050505590Geo-CV, %244.4376.5314.4Fold differenceb1.3Tmax, daysn314576Median9.89.09.0(min-max)(5.8-16.8)(3.0-22.7)(3.0-27.7)Tlast, dayscn293665Median18059.990.1(min-max)(56.9-367)(21.9-264)(21.9-367)a Unknown response was assigned to patients (n = 17) who did not qualify as CR, PR, SD, or PD. No notable differences in the Cmax and AUC0-28d estimates were observed between SD/PD patients and patients with unknown response; b Responders over nonresponders; c Tlast is an indicator of persistence of transgene levels in peripheral blood and can be influenced by the data cutoff date, length of assessment, etc. ALL, acute lymphoblastic leukemia; CI, confidence interval; CR, complete response; CRS, cytokine release syndrome; OR, odds ratio; PD, progressive disease; PR, partial response; SD, stable disease.
Citation Format: Rakesh Awasthi, Constantine S. Tam, Ulrich Jaeger, Samantha Jaglowski, Stephen Ronan Foley, Koen van Besien, Nina D. Wagner-Johnston, Maria José Kersten, Stephen J. Schuster, Gilles Salles, Richard T. Maziarz, Özlem Anak, Lida Bubuteishvili Pacaud, Lucien Gazi, Edward Waldron, Jason Hamilton, Iulian Pruteanu, Feng Tai, Karen Thudium Mueller, Edmund K. Waller. Clinical pharmacology of tisagenlecleucel (CTL019) in patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT110.