Long-Term Clinical Outcomes and Correlative Efficacy Analyses in Patients (Pts) with Relapsed/Refractory Follicular Lymphoma (r/r FL) Treated with Tisagenlecleucel in the Elara Trial

Background: Tisagenlecleucel is the first CAR-T cell therapy approved in the United States and European Union for r/r FL in the third-line or later setting. In the primary analysis of the single-arm, open-label, Phase II ELARA trial, tisagenlecleucel demonstrated high response rates and an excellent safety profile in adult pts with high-risk r/r FL. Herein, we report >2-year follow-up data on the continued durability of response (DOR), longer-term safety, as well as biomarker and pharmacokinetic analyses from the ELARA trial. Methods: Eligible pts had r/r FL (grades 1-3A) following ≥2 lines of therapy that included an anti-CD20 antibody and an alkylating agent or had relapsed after autologous stem cell transplant (SCT). Bridging chemotherapy was permitted. Following lymphodepleting (LD) chemotherapy, pts received single-dose tisagenlecleucel (0.6-6×108 CAR+ viable T cells). Baseline clinical factors, tumor microenvironment (TME) assessment, blood soluble factors, and circulating blood cells were correlated with clinical response and progression-free survival (PFS). Cellular kinetics were determined by measurement of transgene levels by quantitative polymerase chain reaction. Results: Among 94 pts evaluable for efficacy [median follow-up of 28.9 months (mo)], complete response rate was 68% (95% CI, 57.7-77.3) and overall response rate was 86.2% (95% CI, 77.5-92.4). Median PFS was not reached (NR); the estimated 24 mo-PFS post infusion was 57.4% (95% CI, 46.2, 67.0; Figure). The estimated 24 mo-DOR and OS post infusion were 64.6% (77.8% for pts with CR) and 87.7% (95% CI, 78.3, 93.2), respectively. No new safety signals were reported. Neurological events (NEs) were reported in 12 (12.3%) pts including 1 pt with probable progressive multifocal leukoencephalopathy who had prior grade 4 immune effector cell-associated neurotoxicity syndrome. Three new deaths (total 13 deaths) occurred during this longer-term follow-up period [progressive disease (PD), n=1; serious adverse events (SAEs), n=2, urothelial bladder carcinoma and post allogeneic SCT (alloSCT) complications]. No new deaths were treatment related. A total of 23 (24%) pts received at least one subsequent therapy post infusion. Of these, 4 pts received alloSCT, and one pt received only localized radiotherapy. Persistence of the CAR transgene was observed for up to 925 days (median, 210 days; range, 13 to 925 days). Eight pts had SARS-COV-2 infection at the time of data cut-off. Among all parameters tested, elevated tumor burden [TB; total metabolic tumor volume (TMTV) ≥240 cm3] at baseline (pre-LD chemotherapy), progression of disease within 2 years of initial chemoimmunotherapy (POD24), and >4 nodal areas at inclusion were clinical factors that correlated significantly with lower efficacy. Furthermore, baseline serum IL-10 and TNF-α levels were highly correlated with TB (Spearman correlation = 0.80 and 0.86, respectively (both P<0.001), with higher levels significantly associated with non-response/relapse and shorter PFS. Additionally, baseline TME was characterized by fluorescence immunohistochemistry, and an increase in LAG3+ exhausted T cells (≥3% of total T cells) was the only factor that significantly associated with shorter PFS (median PFS, 5.9 mo vs NR, P=0.0017). Also, decreased CD8+ cytotoxic T cells and increased CD19+ B cells in peripheral blood at baseline were associated with poor outcome. POD24, >4 nodal areas at inclusion, baseline TB, and tumor infiltrated LAG3+CD3+ cells remained significant in multivariate Cox models for PFS analysis. Cellular kinetics shows that the mean in vivo maximal expansion (Cmax) in pts with no POD24 was higher compared with pts with POD24. Pts with high TB, based on TMTV at baseline, had a shorter DOR relative to pts with low TB. Conclusions: Updated long-term data from the ELARA trial demonstrated robust durable responses >2 years post infusion, with a continued favorable safety profile. Correlative analyses suggest that high-risk disease characteristics (elevated TB at baseline, POD24, >4 nodal areas at inclusion), exhausted T cells in the TME, and increased IL-10 and TNF-α levels are associated with worse long-term outcomes following tisagenlecleucel in pts with r/r FL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal