SUMMARY: The American Cancer Society estimates that in 2026, about 79,320 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,970 individuals will die of this disease.
Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure, and genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR). These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen.
CD19-directed Chimeric Antigen Receptor (CAR) T-cell therapy has transformed the treatment landscape for patients with relapsed or refractory B-cell Non-Hodgkin Lymphoma. Despite durable responses in a substantial proportion of patients treated with these therapies, it remains unresolved whether a single CAR T-cell infusion can provide lifelong disease control for heavily pretreated lymphoma.
A 10-year follow-up of patients treated with CTL019, now known as Tisagenlecleucel (KYMRIAH®), provides some of the longest available evidence addressing this question.
Study Design: A 10-Year Evaluation of Tisagenlecleucel
The analysis included 38 patients who received Tisagenlecleucel at the University of Pennsylvania as part of a single-center Phase 2 clinical trial. The cohort included 24 patients with LBCL (Large B-Cell Lymphoma) and 14 with FL (Follicular Lymphoma). All patients had relapsed or refractory B-cell Non-Hodgkin Lymphoma and received autologous T cells genetically modified to express a CD19-directed CAR incorporating a 4-1BB costimulatory domain.
The median follow-up was 10.1 years, with follow-up extending to 11.5 years in some patients. The data cutoff was October 1, 2025. To specifically evaluate the possibility of long-term disease eradication, the investigators defined patients who remained in continuous Complete Remission for at least 5.5 years after infusion, with no additional lymphoma therapy or maintenance treatment, as having a long-term response. This threshold was selected because the last observed relapse in the cohort occurred 5.4 years after CAR T-cell infusion.
Relapses Were Concentrated Early, With No Relapses Beyond 5.4 Years
The long-term results revealed that most treatment failures occurred early after CAR T-cell infusion, particularly within the first year. However, no lymphoma relapses were observed beyond 5.4 years.
At 10 years, lymphoma-free survival was:
- 32% among patients with LBCL
- 47% among patients with FL
Ten-year Progression-Free Survival was 17% and 29%, respectively, while Overall Survival was 17% and 50%.
These findings suggest that patients who remain in remission for several years after CAR T-cell therapy may have a very low risk of subsequent lymphoma relapse. In heavily pretreated patients historically considered to have incurable disease, the results support the possibility that CAR T-cell therapy can produce long-term remission, and potentially cure, in a subset of patients.
In this study, no relapses occurred beyond 5.4 years, and patients with FL experienced no relapses beyond 2.7 years.
CAR T-Cell Persistence May Contribute to Long-Term Disease Control
Patients who achieved long-term remission appeared to have higher levels of persistent CAR T cells during the first 2 years after infusion than those who did not achieve prolonged disease control. This observation suggests that, for 4-1BB–based CAR T-cell products, sustained CAR T-cell persistence may be particularly important for maintaining long-term tumor control.
The findings also support continued investigation of CAR T-cell persistence as a potential biomarker of durable response.
Immune Recovery May Remain Incomplete
Long-term remission did not necessarily equate to complete immune recovery. Among patients with long-term responses, 58% had normalized T-cell counts at last follow-up, with CD4+ and CD8+ T-cell reconstitution observed in approximately 50% and 92% of patients, respectively.
B-cell aplasia persisted in 44% of patients with long-term responses, and 42% continued to receive intravenous immunoglobulin at 10 years. These findings highlight the need for ongoing monitoring of immune recovery, infection risk, and the potential need for immunoglobulin replacement even among patients who remain lymphoma-free for many years.
Persistent grade 2 or 3 neutropenia was uncommon, occurring in 5% of patients, and no late anemia or thrombocytopenia was observed.
Second Primary Cancers and Late Mortality Require Long-Term Surveillance
Nine patients developed a second primary cancer, corresponding to a 10-year cumulative incidence of 21%. No CAR T-cell–related lymphomas were observed.
The risk of second malignancies may reflect the extended follow-up period and the extensive prior exposure to cytotoxic therapy in this heavily pretreated population. The findings underscore the importance of long-term cancer surveillance and raise the possibility that earlier use of CAR T-cell therapy could eventually reduce cumulative exposure to genotoxic chemotherapy in selected patients.
The 10-year cumulative incidence of non–relapse-related mortality was 18%, decreasing to 14% when COVID-19–related deaths were excluded. These findings further emphasize the importance of comprehensive survivorship care beyond lymphoma surveillance alone.
Clinical Implications
This decade-long follow-up provides some of the strongest evidence that CD19-directed CAR T-cell therapy can produce exceptionally durable remissions in relapsed or refractory B-Cell Lymphoma. The absence of relapses beyond 5.4 years suggests that patients who achieve sustained remission may have a very low risk of later disease recurrence, supporting the possibility of cure in a subset of patients.
At the same time, long-term survivors may experience persistent B-cell aplasia, hypogammaglobulinemia, and other late health risks. Continued monitoring of immune function, infection risk, second primary cancers, and other late complications will therefore remain an essential component of long-term care.
Take-Home Message
A single infusion of Tisagenlecleucel produced decade-long lymphoma-free survival in approximately one third of patients with LBCL and nearly one half of those with FL. With no relapses observed beyond 5.4 years, these findings support the potential for long-term disease eradication, and possibly cure, in some patients with heavily pretreated B-Cell Lymphoma.
Ten-Year Outcomes after CAR T-Cell Therapy for B-Cell Lymphomas. Ruella M, Paruzzo L, Chong ER, et al. N Engl J Med 2026;394:2440-2448
