Clinical Outcomes of Patients with Relapsed/Refractory Follicular Lymphoma Treated with Tisagenlecleucel: Phase 2 Elara 3-Year Follow-up

Background Primary analysis of the Phase II ELARA trial (median follow-up: 17 mo) reported high response rates and a favorable safety profile in heavily pretreated patients (pts) with relapsed/refractory follicular lymphoma (r/r FL). Here we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after a median follow-up of more than 3 y. Methods Pts with r/r FL (grades 1-3A) and ≥2 prior lines of systemic therapy (including an anti-CD20 monoclonal antibody [mAb] and alkylating agent) received a single tisagenlecleucel infusion (0.6-6 × 108 CAR+ viable T cells). Bridging therapy was allowed. Baseline clinical characteristics and circulating blood naive T cells were correlated with clinical response. Cellular kinetics were assessed using qPCR. Results As of March 29, 2023, 97 pts were infused and had a median follow-up of 41 mo (range, 34.2-49.7). At baseline, 68% of pts were double refractory to anti-CD20 mAb and alkylating agent, 65% had bulky disease (>7 cm or 3 lesions >3 cm), and 63% had POD24. Among 94 pts evaluable for efficacy, BOR of CR rate by independent review committee assessment was 68% (95% CI, 57.7-77.3%) and overall response rate (CR + partial response) 86% (95% CI, 77.5-92.4%). Median PFS was 37 mo; 36-mo PFS was 53% in all pts and 69% in pts with a BOR of CR. In the POD24 subgroup, 36-mo PFS was 50% (n=61) compared with 59% for pts without POD24 (n=33; Fig.). CAR transgene persistence was observed for up to 1290 days. Pts without POD24 had higher median in vivo CAR expansion and longer persistence than pts with POD24. Median DOR was not reached; 64% of responding pts had ongoing response at the time of the 36-mo analysis. Among pts with a BOR of CR, 73% had an ongoing response at the time of the 36-mo analysis. High baseline levels of circulating CD8+ naive T cells (>2.14% of total T cells) were associated with prolonged PFS and DOR. Median OS and median time to next treatment were not reached. The OS rate at 36 mo was 82%; probability of starting a new treatment at 36 mo was 35%. In the POD24 subgroup, 36-mo OS rate was 83% compared with 81% in pts without POD24 (Fig.). No new safety signals were reported. The most common grade ≥3 AEs were neutropenia (43%) and anemia (19%). The most common serious AEs were cytokine release syndrome (20% [Lee grading]), pneumonia (11%), and febrile neutropenia (8%). To date 18 pts have died during the study (progressive disease, n=8; AE, n=9; euthanasia, n=1). Conclusions Pts with r/r FL maintained a high rate of durable responses more than 3 y after tisagenlecleucel infusion, including pts in high-risk subgroups such as POD24. Tisagenlecleucel's safety profile remains favorable with no new safety signals during extended follow-up. Correlative analyses suggest higher baseline levels of CD8+ naive T cells (>2.14%) are associated with improved long-term clinical outcomes.