The results of 5-year follow-up in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma who were treated with CD19-directed, 4-1BB costimulated chimeric antigen receptor (CAR) T cells (tisagenlecleucel) were reported on 18 February 2021 in The New England Journal of Medicine. The researchers from the University of Pennsylvania in Philadelphia, PA, US reported that most responses observed at 1 year were sustained at 5 years. No unexpected late safety concerns emerged in their single centre study.
The authors wrote that data on outcomes beyond 2 years after CAR T cell infusion are limited. They previously reported 28-month outcomes from the NCT02030834 study and in the latest article they report the results of the 5-year outcomes. Patients were followed for a median of 60.7 months.
Complete or partial responses were observed in 14 of 24 patients with DLBCL with best overall response 58%, and 11 of 24 patients (46%) having a complete response. At 5 years, progression-free survival was 31% (95% confidence interval [CI] 14 to 51). The median duration of response was 61.4 months with 60% of patients having a sustained response at 5 years.
Among patients with follicular lymphoma, complete or partial responses were observed in 11 of 14 patients with best overall response 79%, and 10 of 14 (71%) having a complete response. At 5 years, 43% of patients (95% CI 18 to 66) were progression-free. The median duration of response has not been reached and 60% had a sustained response at 5 years.
Lymphodepletion regimens varied, but did not affect clinical outcomes.
In patients who had complete remissions beyond 1 year, the CAR19 transgene was continuously detectable throughout the follow-up period in 6 of 12 patients by quantitative polymerase-chain-reaction assay; transgene could not be detected in 4 patients between 32.7 and 47.8 months, and the remaining patients had CAR19 transgene levels that alternated between detectable and undetectable levels. Among 18 patients who had a relapse of lymphoma within 1 year, only 1 had loss of transgene persistence. Among 5 patients who had a relapse beyond 1 year, 3 had undetectable transgene levels.
Among all patients who had relapse or progression of lymphoma, only 1 of 12 had loss of CD19 expression on tumour cells, assessed by flow cytometry, despite persistence of CAR19 transgene. No patient who had a relapse of lymphoma after 1 year had loss of CD19 expression on tumour cells by flow cytometry.
The median time from the start of infusion to resolution of all cytopenias was 56 days.
Within 2 years, 11 of 16 patients who were in complete remission beyond 1 year had recovery of B cells, and 9 of 11 had detectable CAR19 transgene at the time of B cell recovery. At 5 years, 11 of 16 patients had normal IgM levels, 9 of 16 had normal IgA levels, and 6 of 16 had normal IgG levels. Intravenous immunoglobulin treatment was started in 6 of 22 patients who had a response. All patients who remained in remission beyond 1 year recovered normal CD3, CD4, and CD8 T cell counts.
Secondary cancers occurred in 6 of 38 patients (16%).
No cases of replication-competent lentivirus were detected.
The University of Pennsylvania lymphoma programme investigators commented that although this was a single centre study with a relatively small number of patients, the results of 5-year follow-up indicate that alternative approaches to lymphodepletion are feasible, and cellular and humoral immunity often recover.
The study was supported by Novartis and by a grant from the Lymphoma Research Foundation.
Chong EA, Ruella, M, Schuster SJ. Five-Year Outcomes for Refractory B-Cell Lymphomas with CAR T-Cell Therapy. N Engl J Med 2021; 384:673-674