麻豆传媒

Risk-adapted prophylactic tocilizumab (Actemra) proved feasible for reducing the incidence of severe cytokine release syndrome (CRS) in pediatric acute leukemia treated with CAR T-cell therapy, without making the latter less effective, a prospective study showed.

Incidence of grade 4 CRS was 27% in patients with baseline high tumor burden (≥40% tumor blasts in bone marrow) with prophylactic tocilizumab, versus 50% in a prior phase I trial of tisagenlecleucel (CTL019, Kymriah). Grade 4 CRS incidence was 3.6% in patients with low tumor burden, who received the CAR T-cell treatment without tocilizumab.

The best overall response rate was 87% in the high tumor-burden cohort and 100% in the patients with low baseline tumor burden, Stephan A. Grupp, MD, PhD, of the University of Pennsylvania and Children's Hospital of Philadelphia, and coauthors reported in the .

"In the time since this clinical trial was initiated, CTL019 received FDA approval and is now available at a large number of centers," the authors said in conclusion. "Thus these results are applicable to broad groups of patients at risk for severe CRS, the critical tisagenlecleucel toxicity. Further research is needed to confirm our findings across centers and in other patient populations."

"In addition, as new CAR constructs are developed, it will be important to determine optimal tocilizumab timing for each product."

CD19-targeted CAR T-cell therapy has helped transform therapy for relapsed/refractory B-cell malignancies, improving survival for many patients. However, the therapy carries a risk of potentially life-threatening toxicities, the most common being CRS. In a phase II , three-fourths of patients developed CRS (all grades) and almost half required ICU admission for CRS management.

Baseline high tumor burden is the principal risk factor for severe CRS. In the initial phase I trial of tisagenlecleucel, half of patients with ≥40% bone marrow blasts developed grade 4 CRS. A primary driver of CRS is interleukin (IL)-6, and the anti-IL-6 receptor antibody tocilizumab can induce rapid reversal of CRS, the authors noted.

Early last year, Grupp and colleagues reported initial findings from a prospective evaluation of risk-adapted administration of tocilizumab to prevent severe CRS in pediatric relapsed/refractory acute lymphoblastic leukemia (ALL). Their publication represented an update of that report, including data on conventionally managed patients with low tumor burden.

The study included a total of 70 children and young adults with relapsed/refractory B-cell ALL, treated with tisagenlecleucel. Patients with baseline high tumor burden received a single infusion of tocilizumab at the onset of high persistent fever (≥38.5 °C on two measurements at least 4 hours apart). Patients with low tumor burden received standard CRS management at the onset of clinical CRS.

The primary endpoint was the incidence of grade 4 CRS, as determined by the . Data analysis included 70 patients, 15 with high tumor burden and 55 with low tumor burden. Median follow-up was 24 months.

If grade 4 CRS occurred in no more than five of the high tumor-burden patients, the trial outcome was considered clinically meaningful. Investigators also compared the results with those from high tumor-burden patients in the initial phase I evaluation of tisagenlecleucel (50% incidence of grade 4 CRS). All the patients in the phase I trial received standard treatment for CRS.

All 15 patients in the high tumor-burden cohort developed CRS (median time to onset of 2 days) and received tocilizumab. In four patients, CRS evolved to grade 4 severity. One patient died from cerebral hemorrhage within the context of coagulopathy and resolving grade 4 CRS, the authors reported.

In the low tumor-burden group, 37 (67%) patients developed CRS, which evolved to grade 4 severity in two patients. Three patients subsequently received tocilizumab a median of 2.2 days after CRS onset. Whether patients achieved minimal residual disease status was unrelated to development of CRS or progression to severe CRS.

Treatment with tisagenlecleucel led to complete response (CR) or to CR with incomplete blood count recovery in 68 of the 70 patients, including 13 of 15 patients with high tumor burden and all 55 with low tumor burden. For the high tumor-burden group, the probability of sustained response at 12 months was 49%, decreasing to 39% at 24 months. Two patients received additional anticancer therapy. Morphologic relapse occurred in nine of the 13 responding patients.

The low tumor-burden group had an 86% probability of sustained remission at 12 months and 78% at 24 months. Ten had morphologic relapse, seven others received additional cancer therapy, and six patients underwent allogeneic stem-cell transplantation.

Event-free survival (EFS) in the high tumor-burden group was 42% at 12 months and 34% at 24 months, and overall survival was 67% and 60% at the same landmarks. In the low tumor-burden cohort, EFS was 86% at 12 months and 78% at 24 months, and OS at the same time points was 96% and 92%.

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