乌鸦传媒

ORLANDO -- The frequency of severe cytokine release syndrome (CRS) with CAR T-cell therapy declined by almost 50% when patients received risk-adapted preemptive treatment with tocilizumab (Actemra), a prospective cohort study showed.

Grade 4 CRS occurred in four of 15 pediatric patients with leukemia and high tumor burden who received the interleukin (IL)-6 inhibitor prior to CAR T-cell infusion. In contrast, 13 of 26 historical patients with high tumor burden developed grade 4 CRS with conventional CRS management. Duration of CRS, regardless of grade, was briefer in patients who received preemptive tocilizumab, according to Regina M. Myers, MD, of Children's Hospital of Philadelphia.

Preemptive tocilizumab did not adversely affect the safety or clinical efficacy of CAR T-cell therapy, she reported at the Transplantation and Cellular Therapy Meetings.

"In comparison to a prior trial, risk-adapted preemptive tocilizumab administration resulted in a clinically meaningful decrease in the incidence of grade 4 cytokine release syndrome, although the study was now powered to detect a statistically significant difference," Myers explained. "Preemptive tocilizumab did not substantially decrease ICU length of stay or resource utilization. Patients who developed grade 4 cytokine release syndrome with preemptive tocilizumab were as sick as those who did not receive preemptive treatment."

The anti-CD19 CAR T-cell therapy tisagenlecleucel (Kymriah) has demonstrated potent antitumor activity in pediatric B-cell acute lymphoblastic leukemia but is associated with several unique toxicities. Among the toxicities, CRS is the most common and severe and can be life threatening, Myers noted.

CRS arises as a result of T-cell engagement and proliferation leading to elevated levels of cytokines, including IL-1, IL-10, and interferon-γ, and subsequently to systemic inflammation. Tocilizumab has for treatment of severe CRS. Whether the drug has a role in preventing severe CRS is unknown, Myers continued.

Previous studies showed that patients with a high tumor burden prior to CAR T-cell infusion have a high risk of developing severe CRS. That observation provided a rationale to evaluate the effectiveness of preemptive tocilizumab to decrease the incidence of grade 4 CRS in children, adolescents, and young adults treated with tisagenlecleucel.

Investigators conducted a two-cohort pilot trial of risk-adapted preemptive tocilizumab following tisagenlecleucel infusion. Preemptive treatment was limited to patients who had ≥40% bone marrow blasts (high tumor burden) prior to CAR T-cell infusion. They received a single preemptive dose of the IL-6 inhibitor, whereas patients with low tumor burden received standard CRS management.

To compare the preemptive strategy, investigators used data from patients enrolled in a of tisagenlecleucel. The phase I trial included 26 patients who had high tumor burden prior to treatment with tisagenlecleucel and received standard CRS management.

The patients who received preemptive tocilizumab and the historical cohort did not differ significantly with respect to age (7 vs 10), sex distribution (53% female vs 58%), proportion that had prior allogeneic stem cell transplantation (47% vs 39%), or percent bone marrow blasts prior to CAR T-cell infusion (86% vs 90%).

The primary endpoint was the proportion of patients who developed severe (grade 4) CRS. The data showed that 26.7% of the tocilizumab group developed grade 4 CRS as compared with 50% of the historical cohort. The incidence of grade 3/4 CRS was similar between the groups (60% vs 76.9%). All patients in both cohorts developed grade ≥2 CRS, which had a median duration of 8 days in the tocilizumab group versus 10 in the historical cohort (P=0.092).

Preemptive tocilizumab did not affect resource utilization during the first 30 days after CAR T-cell infusion. The tocilizumab and historical comparison group had similar rates of ICU admission, use of mechanical ventilation, use of vasoactive medications, and need for renal replacement therapy. The two groups also had similar mortality risk by two different assessment scales.

About a third of patients in both groups received corticosteroids. One patient in the tocilizumab group and two in the comparator group received additional medication for CRS. Half the patients in both groups developed grade ≥2 neurotoxicity, including one case each of grade 4 neurotoxicity.

The proportion of patients who achieved a complete response at day 28 was virtually identical: 87% in the tocilizumab group and 85% in the comparator group. Preemptive tocilizumab also did not significantly affect duration of CAR T-cell persistence, as compared with the low-tumor-burden group that received standard CRS management.

In the discussion that followed the presentation, Daniel W. "Trey" Lee, MD, of the University of Virginia in Charlottesville, wondered whether the preemptive tocilizumab merely delayed the onset of severe CRS rather than prevent it. Myers said the time to onset did not differ between the two groups and that the duration of grade 4 CRS was briefer in the tocilizumab group.

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