A phase II study of patients with heavily pretreated B-cell non-Hodgkin lymphoma (NHL) reports decade-long remissions in approximately one-third of patients with large B-cell lymphomas (LBCL) and in nearly half of patients with follicular lymphoma (FL), following a single infusion of the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, tisagenlecleucel.
CAR T-cell therapy involves genetic engineering of autologous T cells to express synthetic receptors that enable antigen-specific tumour recognition independently of major histocompatibility complex, which allows the engineered cells to overcome key mechanisms of immune evasion and to exert potent cytotoxic activity against tumour cells. Clinical application of CAR T-cell therapies targeting B-cell lineage antigens has demonstrated remarkable efficacy in heavily pretreated patients with B-cell NHL, establishing CAR T-cell therapy as a critical therapeutic option for relapsed or refractory (R/R) disease. [Front Immunol 2026;17:1820425]
“CAR T-cell therapies have transformed the treatment of R/R B-cell NHL. However, the durability of remissions beyond 5 years and the curative potential of CAR T-cell therapy remain unclear,” wrote the researchers from the University of Pennsylvania, US. “Here, we report the 10-year follow-up of patients with refractory or multiply relapsed B-cell NHL who had been treated with tisagenlecleucel in a single-centre, phase II clinical trial.” [N Engl J Med 2026;394:2440-2448]
The researchers evaluated long-term survival, immune reconstitution, and toxic effects in 38 patients with R/R B-cell NHL (LBCL: n=24; median age, 55 years; female, 29 percent; median lines of prior therapy, 5) (FL: n=14; median age, 59 years; female, 50 percent; median lines of prior therapy, 5) who had received a single infusion of tisagenlecleucel.
Long-term survival
At a median follow-up of 10.1 years (range, 7.9–11.5 years), no patients experienced a relapse beyond 5.4 years, with no relapses among FL patients beyond 2.7 years. “Our findings support the hypothesis that patients with a long-term response to CAR T-cell therapy may be cured – including patients with heavily pretreated LBLC or FL, who are generally considered to have incurable disease,” commented the researchers.
At 10 years, lymphoma-free survival rate was 32 percent among patients with LBCL and 47 percent among those with FL. “These 10-year data confirm that early survival curve plateaus may predict durable remissions, which is unlike the results seen with chemoimmunotherapy or bispecific antibody therapies, which are more frequently characterized by late relapses, especially in patients with FL,” remarked the researchers. [Blood Cancer J 2020;10:74; Blood 2025;145:708-719; Blood 2025;146:2177-2188]
Of the 12 patients with long-term response, six had FL, three had transformed FL, two had diffuse LBCL and one had T-cell histiocyte-rich LBCL. The median age was 57 years, and 75 percent of long-term responders were female. The median number of previous therapies was four.
Immune reconstitution and B-cell aplasia
CAR-transgene DNA levels from day 28 through the first 2 years after the infusion appeared to be higher among patients with vs without a long-term response. “Thus, the magnitude of CAR T-cell persistence over time, rather than early peak expansion – a key driver of durable responses in CD28-costimulated CAR T-cells – may be critical for long-term outcome with 4-1BB–based CAR T-cell products,” suggested the researchers.
By 10 years of follow-up, six evaluable patients with a long-term response had broad immune reconstitution, with a numerically higher terminally differentiated effector memory T-cell count than 131 persons in a healthy matched cohort. All patients recovered CD4+ T-cell counts >200 cells/mL over time, suggesting that CD4+ recovery may eventually reach a threshold sufficient to mitigate the risk of infection.
However, as of data cut-off, 44 percent of evaluable patients with a long-term response had persistent B-cell aplasia, necessitating ongoing intravenous immune globulin as infection prophylaxis in 42 percent of patients.
Long-term safety
At 10 years, no chronic anaemia or thrombocytopenia was observed, and 95 percent of patients had stable neutrophil recovery. However, the remaining two patients had ongoing grade 2/3 neutropenia at the last follow-up.
While no cases of CAR T-cell–related lymphomas were observed, the 10-year cumulative incidence of second primary cancer was 21 percent, which exceeds the 6 percent incidence that was previously reported in a large meta-analysis. This possibly reflects the longer observation period or extensive pretreatment (or both) in the study cohort. [Clin Cancer Res 2024;30:4690-4700]
“The 10-year incidence of second primary cancer … aligns closely with data from a Danish registry of patients with lymphoma treated with high-dose chemotherapy and autologous transplantation – a finding that underscores the hypothesis that previous exposure to chemotherapy may be a primary driver or at least a cofactor of long-term risk of second primary cancers,” wrote the researchers. [Lancet Haematol 2023;10:e838-e848]
“If early exposure to cytotoxic chemotherapy is playing a role in the incidence of second cancers, an argument could be made for moving CAR T-cell therapy earlier in the line of therapies to reduce the risk of second cancer by reducing the cumulative exposure to genotoxic chemotherapy,” they added.
The 10-year cumulative incidence of non–relapse-related death was 18 percent, which was comparable to a matched lymphoma population (20 percent). [https://seer.cancer.gov/data-software/documentation/seerstat/nov2024/] Causes of non–relapse-related death included second cancers (8 percent), COVID-19 (5 percent), cardiac arrest related to anthracycline-induced cardiomyopathy (3 percent), and respiratory failure (3 percent).
Greater selectivity in the future?
Persistent cytopenias, prolonged B-cell aplasia, and hypogammaglobulinaemia may increase the risk of infection for years after CAR T-cell therapy infusion. Delayed recovery of T cells and persistent B-cell aplasia, which are risk factors for infection after the receipt of CAR T-cell therapy, represent a major cause of non–relapse-related death. [Nat Rev Clin Oncol 2023;20:359-371; Nat Med 2024;30:2667-2678]
One strategy under investigation attempts to refine the specific recognition and targeting of malignant as opposed to all B cells, which occurs with targeting of pan-B cell markers such as CD19. A recently published preclinical study evaluated a novel CAR T-cell therapy designed to selectively target malignant haematopoietic stem/progenitor cells with mutant calreticulin (mutCALR) in myeloproliferative neoplasms (MPNs), while sparing healthy cells, including B cells. [Sci Transl Med 2026;18:eadz3553]
The therapy exploits a unique neoepitope generated by frameshift mutations in the calreticulin gene, which leads to formation of a complex with the thrombopoietin receptor (TpoR) on the surface of malignant cells that is responsible for oncogenic cytokine receptor signalling. The engineered CAR T cells use a single-chain variable fragment (scFv) that specifically recognizes mutant C-terminus of calreticulin, ensuring that only mutCALR+ and TpoR+ cells are targeted. Healthy cells, including wild-type B cells and other haematopoietic cells, do not express this neoepitope and are therefore not recognized or attacked by the CAR T cells.
In co-culture experiments, CAR T cells efficiently depleted mutCALR+ cells even when these were a minority among healthy cells, with up to 96.7 percent clearance of malignant cells and minimal impact on wild-type populations. No activation or cytotoxicity was observed against wild-type cells, including those expressing TpoR but lacking the mutant calreticulin. Single-cell RNA sequencing in human bone marrow organoid models confirmed that apoptosis was selectively induced in mutCALR+ malignant cells, with no enrichment of apoptosis pathways in wild-type cells.
While this approach offers a promising, cancer-specific therapy for patients with high-risk MPNs, it also sets a precedent for highly selective cellular therapies in the broader field of haematologic malignancies, which may eventually address the clinical challenge of persistent B-cell aplasia in R/R B-cell NHL patients treated with CAR T-cell therapy.
Conclusion
While limited by single-centre design and a modest sample size, 10-year data establish that CD19-directed CAR T-cell therapy can lead to exceptionally long remissions and possibly cure some patients with R/R NHL.