Early administration of tocilizumab (Toci) for the prevention of grade 4 cytokine release syndrome (CRS) after CD19-directed CAR T-cell therapy (CTL019)

Abstract

Background & Aim The most common side effect of CD19-directed CAR-T cell therapy is CRS. IL-6 blockade by toci typically results in rapid resolution of severe CRS in CTL019 treated pts; however, the ideal timing of toci remains unclear. Pts with high tumor burden (TB; defined as ≥40% marrow blasts) are at high risk for severe CRS. We hypothesized that preemptive toci administration early in the course of CRS in pts with high TB might decrease acute CRS severity without compromising efficacy. Methods, Results & Conclusion MTD We conducted a two-cohort, open-label study of the timing of toci on CTL019-associated CRS. Pts were 1-24 yo with CD19-expressing relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). CTL019 was manufactured at the UPenn Cell and Vaccine Production Facility. Enrolled pts were assigned to high (≥ 40%) or low ( 38.5 C measured twice in 24 hours (“early toci”) and subsequently treated per standard CRS algorithm. Primary endpoint: frequency of gr4 CRS (Penn scale) in ≤5/15 pts. Secondary endpoints: D28 tumor response, remission duration, additional toxicities. RES 78 pts were screened, all were enrolled. 65 pts were evaluable for analysis at data cutoff. 15 pts were assigned to HTBC, 50 pts to LTBC and all were infused with CTL019 (median dose 5.0 × 106 [range 5.6 × 105-3.9 × 107] CAR+ T cells/kg). The overall rate of gr4 CRS was 9% (27% in the HTBC, 4% in the LTBC, Table 1). The overall rate of gr1-4 CRS was 72% (100% in the HTBC, 64% in the LTBC). One pt in the HTBC died from CNS hemorrhage after gr4 CRS. All patients in the HTBC received the early toci intervention. The overall rate of gr3 and 4 CRS was lower than in two prior studies of CTL019 therapy in pediatric r/r B-ALL (18% vs 42% in CHP959 and 48% in ELIANA). The ORR at day 28 follow-up was 97% (87% HTBC, 100% LTBC, with 71% CR and 26% CRi, Table 2). CONC We defined clincially meaningful reduction in severe CRS if ≤5/15 subjects had gr4 CRS in the HTBC; this a priori defined primary end-point was met. Early administration of toci targeted to pts with high TB may reduce the incidence of severe CRS while maintaining excellent efficacy of CTL019 therapy. TB remains a major predictor of toxicity. Longer follow-up is ongoing to assess impact on duration of remission.