The differential effects of tumor burdens on predicting the net benefits of ssCART-19 cell treatment on r/r B-ALL patients

Minghao Li,Miao Miao,Nan Xu,Yang Xu,Huiying Qiu,Zhou Yu,Suning Chen,Liqing Kang,Zhiqiang Yan,Xiaowen Tang,Sheng-Li Xue,Xiaoyan Lou,Jia Chen,Yue Han,Jingwen Tan,Depei Wu,Weixing Feng,Lei Yu,Jiayu Xu

doi:10.1038/s41598-021-04296-3

Abstract

The tumor burden (TB) is significantly related to the severity of cytokine release syndrome (CRS) caused by CAR-T cells, but its correlation with therapeutic efficacy has not been systematically studied. This study focused on the effects of the TB level on both the safety and efficacy of ssCART-19 as a treatment for r/r B-ALL. Taking the 5% tumor burden as the boundary, the study participants were divided into 2 groups, high and low tumor burden groups. Under this grouping strategy, the impacts of differential r/r B-ALL TBs on the clinical therapeutic efficacy (CR rate and long-term survival) and safety profiles after ssCART-19 cell treatment were analysed. 78 patients were reported in this study. The differential B-ALL TBs significantly affected the complete remission (CR) rates of patients treated with ssCART-19, with rates of 93.94% and 75.56% in the low and high TB groups, respectively (P = 0.0358). The effects of TBs on long-term therapeutic efficacy were further studied based on event-free survival (EFS) and overall survival (OS) profiles; both the OS and EFS of the low TB group were better than those of the high TB group, but the differences were not statistically significant. Importantly, the time points of TB measurement did not significantly affect the OS and EFS profiles regardless of whether the TBs were measured before or after fludarabine-cyclophosphamide (FC) preconditional chemotherapy. On the other hand, the severity of CRS was significantly correlated with the TB level (P = 0.0080), and the incidence of sCRS was significantly related to the TB level (the sCRS incidence increased as the TB level increased, P = 0.0224). Unexpectedly, the ssCART-19 cell expansion peaks were not significantly different (P = 0.2951) between the study groups. Patients with a low r/r B-ALL TB yield more net benefits from CAR-T treatment than those with a high TB in terms of safety and CR rate. These findings are critical and valuable for determining the optimal CAR-T cell treatment window for r/r B-ALL patients and will further the development of comprehensive and reasonable CAR-T cell treatment plans for r/r B-ALL patients with differential TBs.Trial registration: ClinicalTrials.gov identifier, NCT03919240.

Highlights

The tumor burden (TB) is significantly related to the severity of cytokine release syndrome (CRS) caused by chimeric antigen receptor T (CAR-T) cells, but its correlation with therapeutic efficacy has not been systematically studied
Studies have shown that the complete remission (CR)/CR with incomplete haematologic recovery (CRi) rate of CAR-T cell therapy can be as high as 90%1,2
Thirty-three patients were included in the low tumor burden group and had minimal residual disease (MRD) with bone marrow blast percentages ranging from 0.01 to less than 5; the remaining 45 patients were in the high tumor burden group, with bone marrow blasts percentages equalling or exceeding 5

Summary

Introduction

The tumor burden (TB) is significantly related to the severity of cytokine release syndrome (CRS) caused by CAR-T cells, but its correlation with therapeutic efficacy has not been systematically studied. Taking the 5% tumor burden as the boundary, the study participants were divided into 2 groups, high and low tumor burden groups Under this grouping strategy, the impacts of differential r/r B-ALL TBs on the clinical therapeutic efficacy (CR rate and long-term survival) and safety profiles after ssCART-19 cell treatment were analysed. Some studies have reported that tumor burden factors are correlated with CR after CAR-T cell therapy and with the survival rate, their inconsistent patient treatment methods and CAR-T cell infusion doses potentially affect the accuracy of statistical a nalyses[17]. T found high levels of 24 cytokines, including IFNγ, IL6, sgp[130], and sIL6R, within the first month after CAR-T cell infusion, which implied an intricate and high correlation with C RS7

Objectives

Methods

Results

Discussion

Conclusion