As reported in a letter to the editor in The New England Journal of Medicine by Elise A. Chong, MD, and colleagues, long-term follow-up of a single-center trial of tisagenlecleucel showed maintained responses in a high proportion of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma.
In the trial, initially reported in 2017, 24 patients with DLBCL and 14 with follicular lymphoma received tisagenlecleucel infusion after various lymphodepletion regimens.
Key Findings
The median follow-up was 60.7 months. Among 24 patients with DLBCL, an objective response was observed in 14 (58%), with complete response in 11 (46%). Median duration of response was 61.4 months (95% confidence interval [CI] = 3.2 months–not estimable), with 60% of responders (95% CI = 27%–82%) maintaining a response at 5 years.
The median progression-free survival was 5.8 months (95% CI = 1.6–64.2 months). At 5 years, 31% of patients (95% CI = 14%–51%) remained progression-free.
“Although this was a single-center trial 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.”— Elise A. Chong, MD, and colleagues
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Among 14 patients with follicular lymphoma, an objective response was observed in 11 (79%), with complete response in 10 (71%). The median duration of response has not been reached (95% CI = 9.5 months–not estimable), with 60% of responders (95% CI = 25%–83%) maintaining a response at 5 years. Median progression-free survival was 26.2 months (95% CI = 2.8 months–not estimable). At 5 years, 43% of patients (95% CI = 18%–66%) remained free of disease progression. The use of different lymphodepletion regimens did not affect clinical outcomes.
Among patients with complete remission beyond 1 year, the CAR19 transgene was continuously detectable throughout the follow-up period in 6 (50%) of 12 patients on quantitative polymerase chain reaction assay (median duration = 39.4 months, range = 22.5–57.3 months); the transgene could not be detected in 4 patients (33%) between 32.7 and 47.8 months, and the remaining patients had transgene levels that alternated between detectable and undetectable.
Among 18 patients who experienced relapse within 1 year, 1 (6%) had transgene loss. Among five patients with relapse at beyond 1 year, three had undetectable transgene levels (relapses at 32, 35, and 64 months). Among all patients with disease relapse or progression, 1 (8%) of 12 had loss of CD19 expression on tumor cells on flow cytometry despite transgene persistence. No patient with relapse after 1 year had loss of CD19 expression.
The median time from infusion to resolution of all cytopenias was 56 days (interquartile range [IQR] = 27–139 days). Recovery of B cells was observed within 2 years in 11 (69%) of 16 patients in complete remission for more than 1 year, with 9 (82%) of the 11 having detectable CAR19 transgene at B-cell recovery. At 5 years, 11 (69%) of 16 patients had normal IgM levels, 9 (56%) had normal IgA levels, and 6 (38%) had normal IgG levels. Intravenous immunoglobulin treatment was started in 6 (27%) of 22 patients with a response.
All patients with remission for beyond 1 year recovered normal CD3, CD4, and CD8 T-cell counts (median time to recovery of CD3 T cells = 4.6 months, IQR = 3.9–4.9 months). Secondary cancers occurred in 6 (16%) of 38 patients.
The investigators stated, “We observed that most responses at 1 year were sustained at 5 years; however, some late relapses may occur. Although this was a single-center trial 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. No unexpected late safety concerns emerged in our trial.”
Disclosure: For full disclosures of the study authors, visit nejm.org.
