In a single-institution study reported in the Journal of Clinical Oncology, Kadauke et al found that risk-adapted tocilizumab reduced the expected incidence of grade 4 cytokine-release syndrome in pediatric patients receiving CD19-directed chimeric antigen receptor (CAR) T-cell therapy—specifically, tisagenlecleucel—for B-cell acute lymphoblastic leukemia (ALL).
Study Details
In the open-label trial, 70 children or young adults with relapsed or refractory disease were assigned to high-tumor-burden (≥ 40% marrow blasts, n = 15) or low-tumor-burden cohorts (< 40% blasts, n = 55) based on bone marrow aspirate or biopsy prior to tisagenlecleucel infusion. High-tumor-burden patients received a single dose of tocilizumab at 8–12 mg/kg after development of high, persistent fevers. Low-tumor-burden patients received standard cytokine-release syndrome management.
The primary endpoint was incidence of grade 4 cytokine-release syndrome, with an observed rate of 5 or less of 15 patients in the high-tumor-burden cohort defined as clinically meaningful.
“Risk-adapted preemptive tocilizumab administration resulted in a decrease in the expected incidence of grade 4 cytokine-release syndrome, meeting the study endpoint, without adversely impacting the antitumor efficacy or safety of tisagenlecleucel.”— Kadauke et al
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Key Findings
Median tisagenlecleucel doses were 5.0 x 106 (range = 1.1–15 x 106) CAR-T/kg in the high-tumor-burden cohort and 5.0 x 106 (range = 0.56–19 x 106) CAR-T/kg in the low-tumor-burden cohort (P = .5).
All 15 high-tumor-burden patients developed grade ≥ 2 cytokine-release syndrome and received preemptive tocilizumab. Grade 4 cytokine-release syndrome occurred in four patients (27%, 95% confidence interval [CI] = 8%–55%), with the primary endpoint thus being met. Any-grade cytokine-release syndrome occurred in 37 (67%) of 55 low-tumor-burden patients, with grade 4 cytokine-release syndrome observed in 2 (3.6%, 95% CI = 0.4%–13%).
Complete remission with or without complete blood count recovery (complete response) was observed in 87% of the high-tumor-burden cohort and 100% of the low-tumor-burden cohort (P = .043). Median duration of response was not reached among responders in either cohort. The minimal residual disease–negative complete response rate was 80% in the high-tumor-burden cohort and 100% in the low-tumor-burden cohort.
Initial tisagenlecleucel expansion was greater in the high-tumor-burden vs low-tumor-burden cohorts (P < .001). No difference in persistence was observed (P = .73).
In the high-tumor-burden cohort, event-free survival at 12 and 24 months was 42% and 34%; overall survival at 12 and 24 months was 67% and 60%. In the low-tumor-burden cohort, event-free survival at 12 and 24 months was 86% and 78% (P = .004 vs high-tumor-burden cohort); overall survival at these timepoints was 96% and 92% (P < .001 vs high-tumor-burden cohort).
In a post hoc analysis, the incidence of grade 4 cytokine-release syndrome in the high-tumor-burden cohort was numerically lower—but not significantly different—vs that in the cohort of high-tumor burden patients from the initial phase I tisagenlecleucel trial (27% vs 50%, P = .18).
Treatment-related neurologic adverse events occurred in 60% of patients in the high-tumor-burden cohort and 18% of the low-tumor-burden cohort. Grade 3 or 4 adverse events occurred in 20% and 4% of patients.
The investigators concluded, “Risk-adapted preemptive tocilizumab administration resulted in a decrease in the expected incidence of grade 4 cytokine-release syndrome, meeting the study endpoint, without adversely impacting the antitumor efficacy or safety of tisagenlecleucel.”
Stephan Grupp, MD, PhD, of the Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the National Cancer Institute, Frontier Program at Children’s Hospital of Philadelphia, a St. Baldrick’s/Stand Up To Cancer Pediatric Dream Team Translational Research grant, Novartis Pharmaceuticals Corporation, and others. For full disclosures of the study authors, visit ascopubs.org.
