Tisagenlecleucel shows durable activity in R/R aggressive large B-cell lymphomas

The CD19-directed chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel has demonstrated durable activity and a manageable safety profile in adult patients with relapsed or refractory (R/R) aggressive large B-cell lymphomas (LBCLs) after long-term follow-up of the JULIET trial.

The new data, reported after a median follow-up of 40.3 months, also suggest complete response (CR) at 3 months or 6 months to be a reliable early indicator of long-term survival benefit with tisagenlecleucel. [Lancet Oncol 2021;doi:10.1016/S1470-2045(21)00375-2]

The multicentre, open-label, single-arm phase II trial included 167 adult patients with histologically confirmed R/R LBCLs who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation. The patients received a single intravenous infusion of tisagenlecleucel (target dose, 5 x 10⁸ viable transduced CAR T cells).

The current long-term follow-up analysis included 115 patients. Overall response rate (ORR), the trial’s primary endpoint, was 53 percent (n=61) after a median follow-up of 40.3 months. CR as best overall response was achieved in 39 percent of patients (n=45).

“ORRs at 3 months and best ORRs were largely consistent across major demographic and prognostic subgroups,” the investigators reported. “The median duration of response was not estimable, with 60.4 percent of patients estimated to have a response at 36 months after response onset.”

Median progression-free survival (PFS) was 2.9 months, while median overall survival (OS) was 11.1 months.

“Notably, median PFS and median OS were not reached for patients who achieved a CR at 3 months, 6 months, or both,” they highlighted. “The 3-year event-free survival rate was 78.8 percent in patients who maintained a CR at 3 months and 86.5 percent in those who maintained a CR at 6 months.”

“These results show that patients who achieve a CR with tisagenlecleucel at any time have an overall long-term survival benefit, and suggest that CR at 3 months or 6 months might be a reliable early indicator of this benefit,” they commented.

The safety profile of tisagenlecleucel in this long-term follow-up analysis was largely consistent with previous reports, with no new or unexpected safety signals identified. [N Engl J Med 2017;377:2545-2556]

The most common grade 3/4 adverse events (AEs) were anaemia (39 percent), decreased neutrophil count (34 percent), decreased white blood cell count (32 percent), decreased platelet count (28 percent), cytokine release syndrome (CRS; 23 percent), neutropenia (20 percent), febrile neutropenia (17 percent), hypophosphataemia (13 percent), and thrombocytopenia (12 percent).

The most common treatment-related serious AEs were CRS (27 percent), febrile neutropenia (6 percent), pyrexia (5 percent), pancytopenia (3 percent), and pneumonia (3 percent). No treatment-related deaths were reported.

“In univariable and multivariable analyses, high pre-infusion serum concentrations of lactate dehydrogenase [LDH] were found to be independently associated with nonresponse at 3 months, shorter PFS and OS, and severe CRS,” the investigators noted.

This observation is consistent with previous findings from JULIET and other studies of CAR T-cell therapies, which identified LDH as a surrogate marker of tumour burden as well as a potential predictor of efficacy and safety outcomes. [Haematol Oncol 2019;37(Supl 15):3079(abstract); Blood 2019;133:1876-1887; Blood 2019;133:1652-1663; Blood Adv 2020;4:5607-5615]

“Patients with severe CRS or neurological events and those with pre-infusion grade 3/4 thrombocytopenia also had poorer outcomes [in our analysis],” the investigators added.

“This follow-up study supports the durability of responses and acceptable safety profile of tisagenlecleucel in adult patients with R/R LBCLs,” they concluded. “The final analysis of the JULIET trial is expected when the last patient infused with tisagenlecleucel completes 5 years of follow-up.”

“Future studies are required to identify therapies that are most beneficial for patients who relapse following CAR T-cell therapy failure,” they added.