One of the biggest breakthroughs of 2017 was the approval of two novel chimeric antigen receptor T-cell (CAR T-cell) therapies, tisagenlecleucel and axicabtagene ciloleucel, for the treatment of certain B-cell hematologic malignancies. CAR T cells represent the next generation of immunotherapy and continue to be an area of active research. At the 2017 American Society of Hematology Annual Meeting, results were presented from two studies evaluating CAR T cells in patients with refractory aggressive B-cell lymphoma.
Results from the multicenter, phase II ZUMA1 trial, which evaluated the safety and efficacy of the recently approved CD19-targeting CAR T cell therapy axicabtagene ciloleucel in patients with refractory aggressive B-cell lymphoma, were presented by Sattva Neelapu, MD (MD Anderson Cancer Center, Houston, Texas, United States). In this trial, patients (N = 111) achieved an 82% objective response rate (ORR) when treated with axicabtagene ciloleucel, including a 54% rate of complete response (CR). At 15.4 months follow-up, 42% of responding patients were still in response. The estimated 18-month overall survival rate was 52%. Axicabtagene ciloleucel was associated with a high rate of hematologic adverse events (AEs). The most common grade 3/4 AEs were neutropenia (78%), anemia (43%), and thrombocytopenia (38%). Grade 3/4 cytokine release syndrome occurred in 13% of patients receiving axicabtagene ciloleucel, and 28% experienced neurologic events.
Stephen Schuster, MD (Abramson Cancer Center, Philadelphia, Pennsylvania, United States), presented results from JULIET, a pivotal, phase II study examining the safety and efficacy of a second CD19-targeting CAR T cell therapy, CTL019, in 28 patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) or follicular lymphoma. Treatment with CTL019 resulted in a 64% ORR. The CR rate was 43% in patients with DLBCL and 71% in patients with follicular lymphoma. Responses to CTL019 were durable, with 86% of responding patients with DLBCL and 89% of responding patients with follicular lymphoma maintaining that response at a median 28.6 months follow-up. In patients with DLBCL, CTL019 treatment was associated with a median PFS of 3.2 months and a median OS of 22.2 months. The median OS has not yet been reached for patients with follicular lymphoma. Adverse events of interest occurring in patients treated with CTL019 included cytokine release syndrome (18%) and encephalopathy (11%). One patient died due to unresolved encephalopathy.
Results from both ZUMA1 and JULIET were simultaneously published in the New England Journal of Medicine. In an accompanying editorial, the authors applauded these studies for validating the efficacy of CAR T cells in treatment of B-cell lymphoma, calling these results a “milestone for CAR T cells” After almost a decade of anticipation, the promise of CAR T-cell therapies in hematologic malignancies is beginning to be realized. Despite the promising efficacy of these CAR T-cell therapies, however, the authors noted that this novel therapeutic approach is associated with potentially severe toxicity and high cost, which must be balanced with efficacy on a patient to patient basis.