Risk-Adapted Preemptive Tocilizumab to Prevent Severe Cytokine Release Syndrome After CTL019 for Pediatric B-Cell Acute Lymphoblastic Leukemia: A Prospective Clinical Trial

Abstract

Purpose: To prospectively evaluate the effectiveness of risk-adapted preemptive tocilizumab (PT) administration in preventing severe cytokine release syndrome (CRS) after CTL019, a CD19 chimeric antigen receptor T-cell therapy.

Methods: Children and young adults with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia were assigned to high- (≥ 40%) or low- (< 40%) tumor burden cohorts (HTBC or LTBC) based on a bone marrow aspirate or biopsy before infusion. HTBC patients received a single dose of tocilizumab (8-12 mg/kg) after development of high, persistent fevers. LTBC patients received standard CRS management. The primary end point was the frequency of grade 4 CRS (Penn scale), with an observed rate of ≤ 5 of 15 patients in the HTBC pre-defined as clinically meaningful. In post hoc analyses, the HTBC was compared with a historical cohort of high-tumor burden patients from the initial phase I CTL019 trial.

Results: The primary end point was met. Seventy patients were infused with CTL019, 15 in the HTBC and 55 in the LTBC. All HTBC patients received the PT intervention. The incidence of grade 4 CRS was 27% (95% CI, 8 to 55) in the HTBC and 3.6% (95% CI, 0.4 to 13) in the LTBC. The best overall response rate was 87% in the HTBC and 100% in the LTBC. Initial CTL019 expansion was greater in the HTBC than the LTBC (P < .001), but persistence was not different (P = .73). Event-free and overall survival were worse in the HTBC (P = .004, P < .001, respectively). In the post hoc analysis, grade 4 CRS was observed in 27% versus 50% of patients in the PT and prior phase I cohorts, respectively (P = .18).

Conclusion: Risk-adapted PT administration resulted in a decrease in the expected incidence of grade 4 CRS, meeting the study end point, without adversely impacting the antitumor efficacy or safety of CTL019.

Trial registration: ClinicalTrials.gov NCT02906371.

Figures

FIG 1.

Screening, enrollment, and treatment.

FIG 2.

DOR, event-free survival, overall survival, and B-cell aplasia for the overall study population and broken down by cohort. (A) DOR in the 68 patients who had a response (either complete remission or complete remission with incomplete hematologic recovery), defined as the time from the first response to morphologic relapse (9 patients in the HTBC, 10 in the low-tumor burden cohort [LTBC]) or death (none). Data for 12 patients were censored for DOR, either for allogeneic stem-cell transplant (3 LTBC), or for alternative treatments (2 HTBC, 7 LTBC). (B) Event-free survival, defined as the time from CTL019 infusion to one of the following events: no response (1 HTBC), morphologic relapse (9 HTBC, 10 LTBC), or death (1 HTBC). The same data were censored as for the DOR. (C) Overall survival. By the end of follow-up, 12 patients had died (6 HTBC, 6 LTBC). (D) B-cell aplasia, defined as the time to the emergence of ≥ 1% CD19-positive B cells in a bone marrow aspirate or ≥ 3% B cells by peripheral blood flow cytometry (3 HTBC, 20 LTBC). Data were censored for patients who had relapsed disease (3 HTBC, 2 LTBC). DOR, duration of remission; HTBC, high-tumor burden cohort; LTBC, low-tumor burden cohort.

FIG 3.

CTL019 expansion. (A) and (B) Scatterplots of circulating CAR T-cells measured by flow cytometry (flow) or qPCR over time during the first month after CTL019 infusion. Trends for each cohort were generated by locally estimated scatterplot smoothing (loess) and are shown as solid lines. In the HTBC, CAR-T expansion peaked at 10 days (interquartile range, 10 to 17 by flow and 10 to 18 by qPCR). In the LTBC, CAR-T expansion also peaked at 10 days; however, the interquartile range was narrower (10-12) by both flow and qPCR. Thus, the distribution of time-to-peak CAR-T expansion was wider in the high-tumor burden cohort (P = .027 for qPCR, P = .2 for flow). (C) and (D) Individual CAR T-cell expansion profiles for the six patients who experienced grade 4 cytokine release syndrome (CRS) measured by flow or qPCR. Of note, patient 21, who died on study day 19, had the lowest peak CAR-T expansion in this group. (E) Maximum concentration and (F) Area under the curve of CAR-T transgenes measured by qPCR for the first month after CTL019 infusion, broken down by cohort. P values were derived from Wilcoxon rank-sum tests. CRS, cytokine release syndrome; HTBC, high-tumor burden cohort, LTBC, low-tumor burden cohort; qPCR, quantitative polymerase chain reaction.