Clinical Outcomes of Patients with High-Risk Relapsed/Refractory Follicular Lymphoma Treated with Tisagenlecleucel: Phase 2 ELARA 4-Year Update

Background: Treatment strategies for patients (pts) with relapsed/refractory follicular lymphoma (r/r FL) require consideration of prior therapies and pt-related factors to identify those who are likely to benefit from available treatment options. Tisagenlecleucel is a CAR-T cell therapy approved in the United States and Europe for adults with r/r FL after ≥2 lines of prior therapy. The primary analysis of the phase 2 ELARA trial reported high response rates and a favorable safety profile in pts with high-risk r/r FL. Here we report 4-year follow-up of efficacy, safety, and pharmacokinetics findings.

Methods: Eligible pts with r/r FL (grades 1-3A) previously treated with ≥2 lines of systemic therapy (including an anti-CD20 monoclonal antibody and alkylating agent) received a single tisagenlecleucel infusion (0.6-6×10⁸ CAR+ viable T cells). Bridging therapy was permitted. Baseline clinical characteristics and circulating blood naive T cells were correlated with progression-free survival (PFS) and overall survival (OS). Cellular kinetics were determined by measurement of transgene levels by quantitative polymerase chain reaction. Minimal residual disease (MRD) levels were determined via clonoSEQ^® Next Generation Sequencing assay performed at Adaptive Biotechnologies (Seattle, WA, USA): pre-infusion tissue samples were used for the clonotype identification; MRD tracking was performed in post-infusion plasma (ctDNA) samples.

Results: As of March 27, 2024, 97 pts were infused. Ninety-four pts were evaluable for efficacy with a median follow-up of 53 months (range: 46-62). At baseline, among efficacy-evaluable pts, key pt subgroups at high-risk were identified; 72.3% of pts had FL that was refractory to ≥2 prior regimens, 66.0% had bulky disease (>7 cm or 3 lesions >3 cm), 64.9% had progression of disease within 2 years of frontline systemic therapy (POD24), 60.6% had high Follicular Lymphoma International Prognostic Index (FLIPI; ≥3), and 21.3% had high tumor burden (total metabolic tumor volume >510 mL). Median PFS was 53.3 months (95% CI: 18.2-NE) by independent review committee (IRC) among all pts; 48-mo PFS was 50.2% in all pts and 66.1% in pts with a best overall response of complete response. Among identified pt subgroups at high risk, 48-mo PFS by IRC was 45.5% (POD24), 45.5% (high FLIPI), 45.2% (bulky disease), 52.8% (double refractory), and 23.2% (high tumor burden). Median OS was not reached; 48-mo OS was 79.3% in efficacy-evaluable pts. Among identified pt subgroups at high risk, 48-mo OS was 80.8% (POD24), 73.2% (high FLIPI), 73.0% (bulky disease), 83.7% (double refractory), and 65.5% (high tumor burden). MRD data were available on 32/97 pts (33.0%); 28/32 pts (87.5%) achieved MRD negativity at any time point. MRD-negative status was achieved in 82.8% (24/29) of evaluable pts at day 28, 77.8% (14/18) at month 3, 72.7% (16/22) at month 6, and 82.4% (14/17) at month 12, respectively. CAR transgene persistence (T_last; time to last quantifiable transgene level) was observed for up to 1680 days; median T_last was 210 days (range: 13-1680). No new safety signals have been reported since the last data cut. Second primary malignancies (defined as any new cancer occurring post infusion regardless of tisagenlecleucel relationship) were reported in 6 (6.2%) pts and included basal cell carcinoma (n=2), squamous cell carcinoma (n=2), acute myeloid leukemia (n=1), bladder transitional cell carcinoma (n=1), Bowen’s disease (n=1), malignant melanoma (n=1), metastatic squamous cell carcinoma (n=1), and myelodysplastic syndrome (n=1). As of the data cutoff, 19 pts have died during the study: 8 due to progressive disease, 10 due to AEs (1 pt each; acute myeloid leukemia, bladder transitional cell carcinoma, cardiac arrest, CRS, encephalitis, gastrointestinal hemorrhage, infection, metastatic squamous cell carcinoma, pneumonia, sepsis), and 1 from euthanasia.

Conclusions: Updated long-term follow-up from the ELARA trial continues to demonstrate robust durable responses >4 years post infusion, alongside a favorable safety profile. Correlative analyses suggest that most baseline high-risk disease characteristics (double-refractory disease, bulky disease, POD24, and high FLIPI) are not associated with inferior efficacy following tisagenlecleucel infusion in pts with r/r FL. Furthermore, high frequencies of MRD-negative status were achieved in a subset of evaluable pts.