Tisagenlecleucel has already received FDA approval and is now available at some treatment centers, thereby imparting significance to results about tocilizumab use in patients at-risk for severe cytokine release syndrome.
Among patients with pediatric B-cell acute lymphoblastic leukemia (ALL), a prospective clinical trial (NCT02906371) found that risk-adapted preemptive tocilizumab (PT; Actemra) administration resulted in a decrease in the anticipated incidence of grade 4 cytokine release syndrome (CRS), meeting the study end point, without adversely impacting the antitumor efficacy or safety of tisagenlecleucel (Kymriah).1
In the time since this trial was initiated, tisagenlecleucel, a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has received FDA approval and is now available at some treatment centers.2 Thus, these study results, published in the Journal of Clinical Oncology, are applicable to a variety of patients who are at risk for severe CRS.
“CRS is the most common severe toxicity associated with CAR T-cells,” wrote the study authors, led by Stephan Kadauke, MD, PhD. “As tisagenlecleucel (originally developed as CTL019) is now commercially available at many centers worldwide, it is crucial to develop strategies to mitigate the risk of severe CRS.”
In this study, children and young adults with CD19-positive relapsed or refractory B-cell ALL were assigned to high- (≥40%) or low- (<40%) tumor burden cohorts (HTBC or LTBC, respectively) based on a bone marrow aspirate or biopsy prior to infusion. Patients in the HTBC received a single dose of tocilizumab (8-12 mg/kg) following the development of high, persistent fevers; those in the LBTC received standard CRS management.
The study’s primary end point was the frequency of grade 4 CRS per the Penn scale, with a pre-defined rate of 5 of 15 patients or fewer in the HTBC determined as clinically meaningful. Of note, the HTBC was also compared with a historical cohort of patients with high-tumor burden from the initial phase 1 CTL019 trial.
A total of 70 patients were infused with tisagenlecleucel, including 15 in the HTBC and 55 in the LTBC. All patients in the HTBC were given the PT intervention.
Ultimately, the primary end point was met. Among those in the HTBC, the incidence of grade 4 CRS was 27% (95% CI, 8%-55%) compared with 3.6% (95% CI, 0.4%-13%) in the LTBC. Grade 4 CRS was also observed in 27% versus 50% of patients in the PT and previous phase I cohorts in the post hoc analysis, respectively (P = .18).
The best overall response rate (ORR) recorded in the HTBC and LTBC was 87% and 100%, respectively. In the HTBC, initial tisagenlecleucel expansion was greater than that observed in the LTBC (P <.001), however persistence was not different (P = .73). Moreover, among the HTBC, event-free and overall survival were worse (P = .004 and P <.001, respectively).
“Importantly, PT did not impact the excellent ORR of CTL019, nor did it affect CTL019 expansion, persistence, or long-term efficacy,” the authors noted. “This intervention was safe with no increase in frequency or severity of neurotoxicity.”
Moving forward, the investigators indicated that further research will be necessary to confirm the current findings across centers and in other patient populations. Further, they added it will be important to establish the optimal timing of tocilizumab administration for each therapy as new CAR T-cell products are developed.
1. Kadauke S, Myers RM, Li Y, et al. Risk-adapted preemptive tocilizumab to prevent severe cytokine release syndrome after CTL019 for pediatric B-cell acute lymphoblastic leukemia: A prospective clinical trial. J Clin Oncol. Published online January 8, 2021. doi: 10.1200/JCO.20.02477
2. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA. August 30, 2017. Accessed February 3, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-b-cell-all-and-tocilizumab-cytokine-release-syndrome