Clinical outcomes of tisagenlecleucel in patients with relapsed/refractory follicular lymphoma (r/r FL): Phase 2 ELARA 5-year update

Tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has been approved in the United States and Europe for adults with r/r FL after ≥2 lines of prior therapy based on the phase 2 ELARA trial (NCT03568461) in 2022. With a median follow-up (mFU) of 53 months, 4- year progression-free survival (PFS) was 50.2% along with a favorable safety profile (Thieblemont C, ASH 2024). Here, the authors report the final analysis from the ELARA trial after mFU of >5 years. Eligible patients (pts) with r/r FL (grade 1-3A) previously treated with ≥2 lines of systemic therapy (including an anti-CD20 monoclonal antibody and alkylating agent) received a single tisagenlecleucel infusion (0.6-6 × 10 8 CAR+ viable T cells). Bridging therapy was permitted. Here, a longterm efficacy and safety analysis, including duration of response (DOR), PFS, and overall survival (OS) in all pts and in pts with high-risk disease characteristics along with safety analysis are reporte d. Cellular kinetics were determined by the measurement of transgene levels by quantitative polymerase chain reaction.

As of May 28, 2025, mFU was 61.0 months (range: 3.1–67.0 months) in all infused pts (N=97). All pts were evaluable for safety and 94 pts for efficacy. At baseline, pts with high-risk disease characteristics included 60% with high Follicular Lymphoma International Prognostic Index score (FLIPI) of ≥3, 62% with progression of disease within 2 years of frontline systemic therapy (POD24), 64% with bulky disease (>7 cm or 3 lesions >3 cm), 68% with double refractory to prior CD20 antibody and alkylating agent, and 21% with high tumor burden (total metabolic tumor volume >510 mL). The ORR (86.2%) and CR (68.1%) remained consistent with previous data in overall pts and high-risk disease characteristics subgroups (Dreyling M, Blood 2024). The median DOR was not reached (95% confidence internal [CI]: 35.8–NE), the 4-year estimated DOR in all responders was 61% (95% CI, 48.8–71.1) and 71.2% (95% CI, 57.7–81.1) in pts achieving CR. The median PFS was 53.2 months (95% CI,18.2–NE) with an estimated 5-year PFS of 46% (95% CI, 35.0–56.3) in the overall population and 59.8% (95% CI, 46.2–71.1) in pts with CR. In pts with highrisk disease characteristics, 5-year estimated PFS was 35.5% (high FLIPI), 41.1% (POD24), 45.1% (bulky disease), 50.5% (double refractory). In pts with high tumor burden, 5-year PFS was not estimable due to small subgroup size. At this final analysis, median OS was not reached; with an estimated 5-year OS of 74.1% (95% CI, 63.0–82.3). Among identified high‑risk pts, estimated 5-year OS was 64.4% (high FLIPI), 74.6% (POD24), 71.1% (bulky disease), 79.8% (double refractory), and 65.5% (high tumor burden). CAR transgene persistence (Tlast ; time to last quantifiable transgene level) was observed up to 60.9 months; the median Tlast was 8.6 months (range: 0.6–60.9 months). The long-term follow-up analysis demonstrates a favorable safety profile of tisagenlecleucel. More than 1 year after tisagenlecleucel infusion, blood and lymphatic system disorders were reported in 11 (13.1%) pts (neutropenia [6.0%], anemia [4.8%], and thrombocytopenia [3.6%]), infection and infestations reported in 34 (40.5%) pts (COVID-19 [17.9%] and pneumonia [11.9%]). Adverse events reported >4 year after tisagenlecleucel infusion will be presented at congress. Second primary malignancies (defined as any new cancer occurring post infusion regardless of tisagenlecleucel relationship) were reported in 7 (7.2%) pts, including 2 events each of basal cell carcinoma, myelodysplastic syndrome, squamous cell carcinoma of skin, and 1 event each of acute myeloid leukemia, bladder transitional cell carcinoma, Bowen's disease, malignant melanoma, and metastatic squamous cell carcinoma. In total, 22 pts died during the study, causes of death includes disease progression (n=8), AEs (n=13, majorly infections), and euthanasia.

After a median follow-up of >5 years, tisagenlecleucel continues to demonstrate durable responses and prolonged survival in pts with r/r FL including in pts with high-risk disease characteristics. No new safety signals were reported. More than 75% of patients were alive, and approximately half remained progression-free at this final analysis, indicating the curative potential of tisagenlecleucel in r/r FL.

Health-related quality of life trajectories of patients with aggressive B-cell lymphomas treated with CAR T-cell therapy: results from a prospective observational study

Chimeric antigen receptor (CAR) T-cell therapy has substantially improved survival for patients with aggressive B-Cell lymphomas and a wealth of efficacy and safety data are now available. However, limited evidence exists regarding health-related quality of life (HRQoL) trajectories of these patients, and this is particularly true for those treated outside controlled clinical trial settings. Objective The primary objective of this analysis was to prospectively assess HRQoL profiles of patients with aggressive B-Cell lymphomas treated with CAR T-Cell therapy up to 12 months. A secondary objective was to explore short term HRQoL improvements by treatment response. This was a multicenter prospective, observational GIMEMA study including patients across 13 centers in Italy. Eligible patients were ≥18 years old with a confirmed diagnosis of aggressive B-cell lymphomas, scheduled to undergo CAR T-cell therapy and with a baseline HRQoL assessment completed. HRQoL and fatigue were assessed with the well-validated EORTC QLQ-C30 and the QLQ-NHL-HG29 and the FACIT-F, respectively. The PROMIS Ability to Participate in Social Roles and the Activities (social function) and the PROMIS Cognitive Function were also used. Mean score changes were estimated using a linear mixedeffects model with repeated measures and analyzed with a growth curve analysis. Mean score trajectories were modeled with fixed effects of the following covariates: age, sex, time of visit and random error to account for the within subject’s design. For the purpose of this analysis, the authors reported data up to 12 months. The “time of visit” variable was considered as continuous, to study if there was a distinguishable temporal trend of the scale over time. A sensitivity analysis was conducted to assess whether HRQoL compliance over time was associated with any baseline characteristics or CRS/ICANS reported at day+10 after infusion. An exploratory analysis was also conducted to quantify the proportion of responders and non-responders reporting early (from 1 month to 3 months post-infusion) HRQoL clinically meaningful improvements. Responders were defined as patients who achieved a complete or partial remission at 3 months.

Overall, 170 patients were enrolled between June 2022 and February 2024. The median age was 61.1 years and 31.2% were female. HRQoL compliance was 100% and 87% at baseline and 1 months, 75% at 3 and 6 months, and 69% at 9 and 12 months. One-month post-infusion, EORTC QLQ-C30 scales showed statistically and clinically meaningful deteriorations in the following scales: physical (Δ=11.7; p=<.001) and role (Δ=9.4; p=<.001) functioning, fatigue (Δ=12.4; p=<.001). Likewise, also fatigue by the FACIT-F (Δ=4.3; p= <.001) showed a statistically and clinically meaningful deterioration. Interestingly, no decline in cognitive functioning was observed. However, after one-month post infusion, substantial improvements wereobserved in 13 out of the 15 scales of the EORTC QLQ-C30. Amongst functional aspects, the scale with greater improvement up to 12 months was role functioning (Δ=22.3; p=<.001), while amongst symptoms, fatigue (Δ=19.6; p=<.001) had the greatest improvement over time.  Differences over time across scales of the QLQ-NHL-HG29 were not substantial. No associations were found between HRQoL compliancecompletion over time and baseline characteristics or early (day+10) CRS or ICANS supporting the reliability of our longitudinal model estimates.  The percentage of patients with early clinically meaningful improvements in selected HRQoL domains was generally higher in responding patients. For example, clinically meaningful improvements in physical functioning (EORTC QLQ-C30) were observed in 71.8% and 28.6% of responders and non-responders, respectively. Likewise, the percentage of patients with a clinically meaningful improvement in social function (PROMIS) was higher in responders (60%) relative to non-responders (33.3%). Substantial HRQoL impairments are observed one-month post CAR T-cell infusion, however, this was not the case for cognitive functioning. However, starting from one-month post infusion, marked changes were observed up to 12 months with clinically meaningful improvements in key health domains, including fatigue. Also, our data suggests that patients who achieve an early response may report greater improvements in HRQoL compared to non-responders.

The prognostic value of patient-reported fatigue for survival in patients with aggressive B-cell lymphomas treated with CAR T-cell therapy

Chimeric antigen receptor (CAR) T-cell therapy is a valuable treatment option for patients with aggressive B-cell lymphomas. Predicting survival is critical to better identify patients at risk and some pre-infusion clinical and laboratory prognostic factors have already been identified. However, very limited evidence exists on the potential prognostic value of patient reported health status data. The primary objective of this analysis was to investigate the prognostic value of pre-infusion (baseline) patient-reported fatigue for overall survival (OS). A secondary objective was to describe baseline health related quality of life (HRQoL) profile by fatigue severity. This analysis is based on data from a prospective observational study assessing HRQoL and fatigue of adult patients with aggressive B-cell lymphomas scheduled to receive CAR T-cell therapy. At baseline, HRQoL profile was assessed with the EORTC QLQ-C30 and the QLQ-NHL-HG29. Fatigue was assessed with the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Univariate and multivariate Cox regression analyses were performed to identify factors associated with OS. The initial univariate model included the following baseline variables: sex, age, diagnosis, ECOG PS, presence of comorbidities, number of prior lines of therapy, disease status, bulky disease, systemic B symptoms, prior stem cell transplantation, extranodal involvement, Ann Arbor stage, time from baseline HRQoL assessment to infusion, as well as FACIT-F scores. Type of CAR T-cell product was also included as covariate. A bootstrap resampling procedure was run on 5000 models to assess the prognostic importance of each variable. For this analysis patients were categorized into lower (LF) and higher fatigue (HF) groups based on the median FACIT-F score. The median follow-up (FUP) time was reported, and OS curves were estimated using the Kaplan-Meier method, stratified by fatigue groups, and compared using the log-rank test. Current analysis is based on 169/170 patients with a valid baseline FACIT-F questionnaire. The median age of patients was 61 years (interquartile range [IQR]: 51–68), and 31.4% were female. The median FUP time for the overall cohort was 23 months and 40 (23.7%) died during the FUP period. Most deaths (69%) were due to disease progression, followed by infections (18%), secondary malignancies (5%), and other causes (8%). In the univariate analysis, age (HR 1.04, 95% CI 1.01–1.07, p=.013), and fatigue (HR 0.83, 95% CI 0.75– 0.91, p<.001) were significantly associated with OS. Ann Arbor Stage (p=.06), diagnosis using DLBCL as reference category (PMBCL: p=.07; MCL: p=.52) and disease status (p=.09) showed trends toward association with OS but did not reach statistical significance.

The final multivariate model retained three baseline variables: sex, age, and FACIT-F score. In this model only age and fatigue remained significantly associated with OS with a HR of 1.03 (95% CI 1.00–1.06, p=.036) and a HR 0.86, (95% CI 0.78–0.94, p<.001), respectively. This latter data translates into a 14% decrease in the hazard of death for every 3-points increases (clinically meaningful improvement) in the FACIT-F scores. According to the bootstrap analysis, the inclusion frequencies for the variables retained in the final multivariate model were: fatigue (91%), age (59%), and sex (28%). The HF group showed a more rapid decline in survival probability (p=.018) over time compared to the LF group. The estimated OS of the overall population at 12 months was 80% (95% CI: 74–86%). The 12-month estimated OS was 87% (95% CI: 80–95%) and 73% (95% CI: 64–83%) in the LF and HF, respectively. Patients in the HF group reported a markedly worse baseline HRQoL profile compared to those with LF. To illustrate, large clinically important differences were observed with regard to key EORTC QLQ-C30 scales, that is, role functioning (Δ = 32), global quality of life (Δ = 20.5), social functioning (Δ = 19.4), and dyspnea (Δ = 17.3). Marked differences were also observed in key scales of the QLQ-NHL-HG29 questionnaire.

These findings point to the importance of systematically assessing patient-reported fatigue before CAR Tcell infusion in the setting of aggressive B-Cell Lymphomas, as it provides independent prognostic information for survival. Assessment of fatigue may help to early identify most vulnerable individuals who are at greater risk and in need of special attention.