As reported by Noelle V. Frey, MD, and colleagues in the Journal of Clinical Oncology, single-center experience with the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel has shown that high-dose fractionated infusion with the ability to modify dosing in case of early signs of cytokine-release syndrome is associated with improved safety—without reduced efficacy—in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.

Noelle V. Frey, MD

Study Details

The analysis included 35 patients receiving tisagenlecleucel in two trials at the University of Pennsylvania. Patients received lymphodepletion followed by tisagenlecleucel in one of three dose cohorts: a high-dose single-infusion cohort with a maximum dose of 5 × 10⁸ CAR T cells (n = 6), a fractionated high-dose cohort with a maximum dose of 5 × 10⁸ CAR T cells (n = 20), and a low-dose cohort with a maximum dose of 5 × 10⁷ CAR T cells via single or fractionated infusion (n = 9). Fractionated infusions were given over 3 days, with 10% of the dose given on day 1, 30% on day 2, and 60% on day 3, with the intent of allowing dosing on days 2 and 3 to be held if patients experienced fever or other early signs of cytokine-release syndrome.

Toxicity and Survival

In the low-dose cohort, toxicities were manageable and complete response was observed in three patients (33%). In the high-dose single-infusion cohort, three patients (50%) died from refractory cytokine-release syndrome with culture-positive sepsis; complete response was observed in three patients (50%). In the high-dose fractionated cohort, cytokine-release syndrome was manageable and complete response was observed in 18 patients (90%). Overall, cytokine-release syndrome of grade ≥ 4 occurred in two patients (22%) in the low-dose cohort, three (50%) in the high-dose single-infusion cohort, and one (5%) in the high-dose fractionated cohort.

Two-year rates for overall survival and event-free survival were 73% and 50% in the high-dose fractionated cohort, 17% and 17% in the high-dose single-infusion cohort, and 22% and 0% in the low-dose cohort, respectively.

The investigators concluded: “Fractionated dosing of [tisagenlecleucel] with intrapatient dose modification optimizes safety without compromising efficacy in adults with [relapsed/refractory] acute lymphoblastic leukemia.”

Dr. Frey, of the Hospital of the University of Pennsylvania, Philadelphia, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Novartis. For full disclosures of the study authors, visit ascopubs.org.