GLA/DRST real-world outcome analysis of CAR-T cell therapies for large B-cell lymphoma in Germany

Abstract

CD19-directed chimeric antigen receptor (CAR) T cells have evolved as new standard-of-care (SOC) treatment in patients with relapsed/refractory large B-cell lymphoma (LBCL). Here, we report the first German real-world data on SOC CAR-T cell therapies with the aim to explore risk factors associated with outcome. Patients who received SOC axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for LBCL and were registered with the German Registry for Stem Cell Transplantation (DRST) were eligible. Main outcomes analyzed were toxicities, response, overall survival (OS), and progression-free survival (PFS). We report 356 patients who received axi-cel (n=173) or tisa-cel (n=183) between November 2018 and April 2021 at 21 German centers. Whereas the axi-cel and tisa-cel cohorts were comparable for age, sex, LDH, IPI, and pretreatment, the tisa-cel group comprised significantly more patients with poor performance status, ineligibility for ZUMA-1, and need for bridging, respectively. With a median follow-up alive of 11 months, Kaplan-Meier estimates of OS, PFS, and non-relapse mortality (NRM) 12 months after dosing were 52%, 30%, and 6%, respectively. While NRM was largely driven by infections subsequent to prolonged neutropenia and/or severe neurotoxicity and significantly higher with axi-cel, significant risk factors for PFS on multivariate analysis included bridging failure, elevated LDH, age, and tisa-cel use. In conclusion, this study suggests that important outcome determinants of CD19-directed CAR-T cell treatment of LBCL in the real-world setting are bridging success, CAR-T product selection, LDH, and the absence of prolonged neutropenia and/or severe neurotoxicity. These findings may have implications for designing risk-adapted CAR-T cell therapy strategies.

A national service for delivering CD19 CAR‐Tin large B‐cell lymphoma – The UK real‐world experience

“…For axi-cel, no difference in high-grade ICANS between ZUMA-1 and the two large US RW cohorts was seen, but there was a lower rate in European datasets including ours. 5,6,15,18 Similar to the German RW cohort, 9 we observed ongoing NRM events beyond month 1, with a 12-month rate of 7%, mainly caused by complications from long-term cytopenia and infections (6/21 were COVID19-related deaths).…”

“…The incidence of high-grade CAR-T toxicities was favourable for both products compared to the pivotal trials and other RW datasets. For tisa-cel, a consistently low rate of severe CRS and ICANS was observed across different RW datasets, 8,11,9 in line with the more permissive use of tocilizumab and corticosteroids in daily practice. For axi-cel, no difference in high-grade ICANS between ZUMA-1 and the two large US RW cohorts was seen, but there was a lower rate in European datasets including ours.…”

“…5,6 Preliminary results from European RW cohorts appear more heterogeneous, likely reflecting differences in patient selection, bridging approaches and manufacturing times. [7][8][9] Collection of larger registry datasets of axi-cel and tisa-cel treated patients are underway. 10,11 Most datasets are restricted to the "intentionto-manufacture" or infused patient cohorts, not providing results of the intention-to-treat (ITT) population, which should be the benchmark for comparing CAR-T to emerging therapies such as bispecific antibodies.…”

“…Two retrospective US axi‐cel real‐world (RW) datasets have been published showing outcomes similar to ZUMA‐1 5,6 . Preliminary results from European RW cohorts appear more heterogeneous, likely reflecting differences in patient selection, bridging approaches and manufacturing times 7–9 . Collection of larger registry datasets of axi‐cel and tisa‐cel treated patients are underway 10,11 .…”

Axicabtagene ciloleucel compared to tisagenlecleucel for the treatment of aggressive B-cell lymphoma

“…We report herein one of the largest European cohort of patients with R/R aggressive B-cell lymphoma treated with commercial CAR T-cells, including a detailed comparison between axi-cel and tisa-cel, which has been very little addressed in previous real-world studies. 23,24,25,26 In our study, patient and disease characteristics at apheresis were similar between both cohorts, suggesting that CAR-T selection was likely driven by other factors including logistical aspects, manufacturing slot availability and expected turnaround time. More patients in the axi-cel group received the CAR-T infusion, probably influenced by the shorter turnaround time.…”