JULIET 5-Year Data Solidifies Tisa-Cel as Curative in R/R LBCL

Five-year follow-up data from the global, phase 2 JULIET (NCT02445248)trial, which evaluated the chimeric antigen receptor (CAR)T-cell therapy tisagenlecleucel (tisa-cel; Kymriah) in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), showed potential for inducing durable, long-term remissions and a favorable safety profile.^1,2

The 5-year analysis demonstrates sustained efficacy, with a significant portion of patients achieving durable responses.1 The overall response rate was 53% (n = 61/115). The best overall response (BOR) of complete response (CR) was 39.1% (n = 45/115). Of the total patients, 19 who initially had a partial response later converted to CR. The majority of these conversions (78.9%) occurred within 6 months of infusion, with the latest conversion happening between 24- and 36-months post-infusion. Among 30 patients still in follow-up at 60 months, 26 had achieved CR as their BOR. Of those, 22 (84.6%) remained in CR at the 60-month mark.

The median duration of response was not evaluable (NE) in the total patient population and was not reached among the responders (n = 61). Of the total patients, 60-month relapse-free probability was NE and was 60.5% in the responders group (95% CI, 46.3%–72%). The median overall survival (OS) of the total patients was 11.1 months (95% CI, 6.6–23.9), and 76.5 months in the responders group (95% CI, 37.8–NE). The 60-month OS probability between the 2 groups was 31.7% (95% CI, 23.1%–40.6%) vs 55.8% (95% CI, 41.9%–67.7%). The 60-month progression-free survival (PFS) probability was 28% (95% CI, 19.5%–37.8%) vs NE between the 2 groups. The median disease-specific survival was 21.2 months (95% CI, 10.1–NE) vs NE between the 2 groups.

Safety Profile

The analysis confirmed a favorable and manageable long-term safety profile for tisa-cel, with no new or unexpected late safety issues emerging after 5 years.

Among 35 patients evaluable for safety >3 years after infusion, 14 (40%) experienced late-onset adverse events. In terms of secondary malignancies, 15 events were reported in 13 patients (11.3%). No secondary T-cell malignancies were reported.

No replication-competent lentivirus (RCL) was detected at any point, and there was no evidence of CAR-transgene or RCL-mediated cell transformation.

Of the total patients, 76 deaths were reported. Disease progression was the most common cause of death (78%). The majority of deaths (92%) occurred within 36 months of infusion. Of the total deaths, 4 occurred > 3 years post-infusion were not related to disease relapse and were caused by myelodysplastic syndrome (n = 2), bacterial sepsis (n = 1), and respiratory failure (n = 1).

Biomarker Analysis

The study identified several baseline characteristics and biomarkers significantly associated with clinical response and long-term survival. These findings may help refine patient selection for therapy. 

Patients associated with achieving a response had R/R disease, 1 (vs 2 or more) bridging regimens, lactate dehydrogenase (LDH) level ≤ upper limit of normal (ULN), and C-reactive protein (CRP) level <15 mg/L. Patients who achieved long-term OS had LDH ≤ ULN and/or CRP <15 mg/L.

Patients with Myc-negative (Myc–) tumors had significantly longer PFS and OS compared to those with Myc-positive (Myc+) tumors. The median PFS was 6.2 months (Myc–) vs 2.5 months (Myc+). The median OS was 21 months (Myc–) vs 7.8 months (Myc+).Higher infiltration of T cells (CD3+ >3%) in the tumor was associated with longer PFS and OS.Higher levels of exhausted T cells (LAG3+CD3+ >20%) were linked to poorer outcomes, including shorter PFS and OS.

Long-term persistence of the CART cells was observed in both responders and nonresponders, indicating the durability of the cellular product after infusion.The tisa-cel transgene was detected in peripheral blood for up to 1830 days in responders. The transgene was detected for up to 1480 days in nonresponders.

Patients could enroll in the PAVO study (NCT02445222) for an additional 10 years of follow-up after completing the initial 5 years in JULIET.

The study authors conclude that the JULIET trial was "foundational in establishing CAR –T-cell therapy as a curative standard-of-care option for patients with R/R LBCL in the third-line setting." The results confirm the long-term survival benefit without new safety signals, solidifying the role of tisa-cel as a "transformative therapy" for this difficult-to-treat patient population.

“These findings continue to demonstrate the long-term survival benefit of tisagenlecleucel without new safety signals in [R/R] LBCL,” concluded Maziarz et al, authors of the study. “The results support the role of tisagenlecleucel as a transformative therapy for [R/R] LBCL and provide critical evidence for long-term risk-benefit assessment. The JULIET trial has been foundational in establishing CAR –T-cell therapy as a curative standard-of-care option for patients with [R/R] LBCL in the third-line setting and provided valuable safety and scientific insights and knowledge that advanced the field, expanding the potential for CAR-T cell therapy to multiple new applications.”

REFERENCES

1.Maziarz R, Bishop M, Tam C et al. Five-year analysis of the JULIET trial of tisagenlecleucel in patients with relapsed/refractory large B-cell lymphoma. J Clin Oncol. doi: 10.1200/JCO-25-00507.

2.Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients (JULIET). ClincialTrials.gov. Updated April 18, 2024. Accessed November 20, 2025. https://clinicaltrials.gov/study/NCT02445248