In May 2018, the U.S. Food and Drug Administration expanded the approval of the chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel to the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), based on results from the phase II JULIET trial. At the 23rd Congress of the European Hematology Association, Peter Borchmann, MD, of the University Hospital of Cologne in Germany, presented updated results on behalf of other investigators from the trial, which continued to show high response rates with tisagenlecleucel in this population.
“Tisagenlecleucel was associated with a high rate of durable complete responses,” Dr. Borchmann said. “With longer follow-up, these results confirm findings of an earlier primary analysis.”
The trial enrolled 165 adults with DLBCL who had been treated with at least two prior lines of therapy (including rituximab and an anthracycline) and who were eligible for or previously failed autologous hematopoietic cell transplantation (AHCT).
Patients were infused with a single dose of tisagenlecleucel (median = 3.0×108; range = 0.1- 6.0×108 cells). The CAR T-cell therapy was centrally manufactured via cryopreserved apheresis and a global supply chain.
A total of 111 patients (median age = 56 years; range = 22-76 years) were successfully infused with tisagenlecleucel; these patients comprised the safety analysis. Efficacy was assessed in patients with at least three months of follow-up (n=93) or earlier treatment discontinuation (n=81). Most patients (76%) had stage III/IV disease at study entry, and the median number of prior lines of antineoplastic therapy was three (range = 1-6). Ninety-three percent of patients had received lymphodepleting chemotherapy, and 92 percent received bridging therapy during the study.
After a median follow-up of 13.9 months postinfusion, the overall response rate (ORR) was 52 percent, which included a complete response rate of 40 percent and a partial response rate of 12 percent. Response rates were consistent across patient subgroups, the investigators noted, including patients with double-hit lymphoma and a history of AHCT.
The maximum follow-up for the efficacy population was 17.3 months, and although the median duration of response was not reached, the investigators estimated that the rate of 12-month relapse-free survival was 65 percent. The median overall survival (OS) among all 111 infused patients was 11.7 months (range = 6.6 – not estimable), and the estimated 12-month OS was 49 percent.
No participants proceeded to AHCT while in remission, the investigators noted. Tisagenlecleucel also appeared to be durable and was detected by polymerase chain reaction in the peripheral blood of responders for up to 693 days.
During the first eight weeks after infusion, patients experienced the following grade 3/4 adverse events (AEs):
- cytokine release syndrome (14% [grade 3] and 8% [grade 4])
- neurologic AEs, which were managed with supportive care (12%)
- cytopenias lasting >28 days (32%)
- infections (20%)
- febrile neutropenia (14%)
Three participants died within 30 days of tisagenlecleucel infusion; however, deaths were not considered related to the study drug or cytokine release syndrome. The investigators noted no new deaths for reasons other than disease progression since earlier reports from JULIET.
“This is the first global study of CAR T-cell therapy in DLBCL to show that centralized manufacturing was feasible,” Dr. Borchmann concluded. Future research should focus on better characterizing and predicting “severe cytokine release syndrome and neurologic events,” he added.
The findings from this study are limited by the small number of patients and the lack of a comparator arm.
Borchmann P, Tam CS, Jäger U, et al. An updated analysis of JULIET, a global pivotal phase 2 trial of tisagenlecleucel in adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Abstract #S799. Presented at the 23rd Congress of the European Hematology Association, June 16, 2018; Stockholm, Sweden.