Cytokine Release Syndrome (CRS) after Chimeric Antigen Receptor (CAR) T Cell Therapy for Relapsed/Refractory (R/R) CLL

CTL019 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) consisting of an external anti-CD19 domain with the CD3z and 4-1BB signaling domains, and mediate potent anti-tumor effects in patients (pts) with advanced, R/R CLL, ALL and NHL. CRS is the most serious toxicity of CTL019 therapy; symptoms can include fevers, nausea, myalgias, capillary leak, hypoxia, and hypotension.

Standard CRS grading criteria are not applicable to CAR T cell therapies. To better capture clinical manifestations of CRS and guide intervention after CTL019, we devised a novel CRS grading scale. that was applied to 40 pts treated with CTL019 for R/R CLL; 14 pts on an initial pilot and 26 pts on an ongoing dose-optimization trial (reported separately).

Our new CRS grading system is shown below. Pts were 80% male, a median age of 65 (range 51-78) and received a median of 4 prior therapies (range 1-10). 41% had known mutation at p53. 83% of 24 pts tested had unmutated IgVH. Response rate to CTL019 (CR+PR) was 42%. CRS was the major toxicity and occurred in 57% (23/40) of pts. CRS was gr 1 in 10%, gr 2 in 17%, gr 3 in 15% and gr 4 in 15%. Development of CRS correlated with response; 13/23 (57%) pts with CRS responded versus 4/17 (24%) pts without CRS responded (p=0.05). CRS was associated with elevations in IL-6, IFN-g, and other cytokines; details for 33 pts will be presented. Peak fold-increase over baseline for IL-6 was a median of 10.6x (range 0.28–649) and for IFN- g a median of 32.9x (1–7243x). For pts with CRS, this increase in IL-6 was a median of 23.5x compared to 1.86x in pts without CRS (p=0.001); and in IFN- g was a median of 97.2xin pts with CRS compared to 24.2x without (p=0.018). Increasing CRS severity was associated with peak fold change in IL-6 (p< 0.0001) and IFN- g (p=0.015). Notably, unlike cytokine changes associated with sepsis, TNF-a did not markedly increase during CRS.

CRS occurred with a consistent and often dramatic increase in ferritin, C reactive protein (CRP), and hemophagocytosis, suggesting concurrent macrophage activation syndrome (MAS). Increasing CRS severity was associated with an increasing trend for peak ferritin (log scale, p<0.001) and peak CRP (p<0.001). The median peak ferritin was 13,463 ng/ml in pts with CRS compared to 378 in pts without (p<0.001). Median peak CRP was 16 mg/dl in pts with CRS compared to 3.86 in pts without (p=0.002). CRS required intervention in 8 pts. 1 pt was successfully treated with corticosteroids. Given marked increases in IL-6, 7 patients received the IL6-receptor antagonist tocilizumab with or without corticosteroids with resolution of CRS. Tocilizumab was given to 1/7 pts with gr 2 CRS, 1/6 pts with gr 3 and 5/6 pts with gr 4. Several pts also received corticosteroids and/or etanercept. All pts had resolution of CRS signs with no TRM from CRS.

CRS is the most significant complication of CTL019 and can be life threatening. A novel CRS grading system was needed to identify CRS severity more accurately guide intervention timing. CTL019-related CRS is associated with a unique cytokine profile and has been manageable with anti-cytokine therapy in pts with R/R CLL. CRS appears to correlate with response of CLL to CTL019. Further study is needed to develop reliable methods to predict severity and minimize CRS toxicity without inhibiting anti-leukemia activity of CTL019.

New CRS Grading System for CTL019