Risk-Adapted Preemptive Tocilizumab Decreases Severe Cytokine Release Syndrome (CRS) after CTL019 CD19-Targeted Chimeric Antigen Receptor (CAR) T-Cell Therapy for Pediatric B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Background Patients (pts) receiving CTL019 (tisagenlecleucel) for B-ALL with high tumor burden (HTB) are at high risk for developing severe CRS. Tocilizumab, an IL-6 receptor antibody, is a vital component of severe CRS management; however, its role in preventing severe CRS is not known. We sought to determine the effectiveness of preemptive tocilizumab (PT) administration in decreasing the rate of grade (gr) 4 CRS in HTB pts. Methods We conducted a pilot trial of risk-adapted PT after CTL019 (NCT02906371). HTB pts, defined as ≥40% bone marrow (BM) blasts immediately before infusion, received a single dose of PT for high persistent fever (2 temperatures ≥38.5C in 24hr). The primary endpoint was frequency of gr4 CRS (Penn scale), with an observed rate of ≤5/15 predefined as clinically meaningful. Secondary endpoints included complete remission (CR) rate and ICU length of stay (LOS). A comparator cohort with HTB who received standard CRS management (stdCRS) was identified from the initial CTL019 trial (NCT01626495). Results Characteristics of the PT (n=15) and stdCRS (n=26) HTB cohorts are shown in Table 1. All pts developed gr≥2 CRS; median time to fever was longer in the PT cohort [PT, 3d (IQR 2-9); stdCRS, 2d (IQR 1-7), p=0.03]. Gr4 CRS was observed in 4/15 (27%) pts in the PT cohort vs. 13/26 (50%) in the prior stdCRS cohort [RR 0.53 (95% CI, 0.21-1.34), p=0.18]. In the stdCRS cohort, gr4 CRS was associated with earlier onset of fever (p=0.04). In patients with earlier CRS onset (fever by day +4), gr4 CRS was observed in 4/9 (44%) vs. 13/21 (62%) in the PT and stdCRS cohorts [RR 0.72 (95% CI, 0.32-1.60), p=0.42]. Except for a trend toward fewer vasoactive days in the PT cohort, ICU LOS and resource utilization were not significantly different (Table 2). The CR rate at day 28 was similar in the PT and stdCRS cohorts (87% vs. 85%, p=1.00). Conclusion Risk-adapted PT administration reduced gr4 CRS, meeting the predefined study endpoint, without impacting the CR rate. A secondary comparison to a prior trial showed a clinically meaningful decrease in the rate of gr4 CRS from 50% to 27%; however, the analysis was not powered to detect a statistically significant difference. Ongoing analyses will evaluate CAR T cell expansion, duration of remission, and additional safety endpoints, including rates of neurotoxicity.