Fractionated CAR-T Therapy Dosing Improves Safety in Relapsed/Refractory ALL

In adult patients with acute lymphoblastic leukemia (ALL), fractionated dosing of tisagenlecleucel, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, with intrapatient dose modification improves safety without compromising efficacy (J Clin Oncol. 2019 Dec 9. Epub ahead of print).

“Tisagenlecleucel has an 81% response rate in children with relapsed or chemotherapy refractory…B-cell…[ALL],” explained Noelle V. Frey, MD, Division of Hematology Oncology, Abramson Cancer Center, Cell Therapy and Transplant, University of Pennsylvania Perelman School of Medicine, Philadelphia, and colleagues.

“Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults,” they continued.

Dr Frey and colleagues analyzed outcomes of patients with relapsed or refractory ALL treated in 1 of 2 trials. Lymphodepletion followed by tisagenlecleucel was given as either a 1-time infusion or fractionated infusions over 3 days (day 1, 10%; day 2, 30%; day 3, 60%).

The 3-day split allowed for day 2 and 3 doses to be held for early CRS. The total tisagenlecleucel dose varied with adaptive protocol modifications in response to efficacy and toxicity.

A total of 35 adult patients with relapsed or refractory ALL received tisagenlecleucel in 1 of 3 dosing cohorts: low-dose, high-dose single infusion, and high-dose fractionated.

Patients in the low-dose cohort (n=9) received single or fractionated dosing and had manageable toxicity with a complete remission (CR) rate of 33%. Three of 6 patients with refractory CRS concurrent with culture-positive sepsis in the high-dose single infusion cohort died. The other 3 patients achieved CR.

Patients in the high-dose fractionated (HDF) cohort (n=20) had a 90% CR rate and manageable CRS. The highest survival was shown in the HDF cohort, with a 2-year overall survival of 73% (95% CI, 46%-88%) and event-free survival of 49.5% (95% CI, 21%-73%).

“Fractionated dosing of CTL019 [tisagenlecleucel] with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL,” Dr Frey and colleagues concluded.—Janelle Bradley