Efficacy and Safety of Tisagenlecleucel in Adult Patients with Relapsed/Refractory Follicular Lymphoma: Interim Analysis of the Phase 2 Elara Trial

Background: Follicular lymphoma (FL) remains an incurable disease for most patients (pts), characterized by a relapsing and remitting pattern. For pts with relapsed/refractory (r/r) FL, treatment outcomes typically worsen with each subsequent line of therapy, highlighting an unmet need. Tisagenlecleucel (tisa-cel) has demonstrated clinical benefits and manageable safety in pediatric and young adult pts with r/r B-cell acute lymphoblastic leukemia and adult pts with r/r diffuse large B-cell lymphoma. In a prior phase (Ph) 2a study of 14 pts with r/r FL, 71% achieved durable complete remission with tisa-cel (Chong et al. ICML 2019). Here we present a planned interim analysis of ELARA, a Ph 2, international trial of tisa-cel in adults with r/r FL.

Methods: Adults with histologically confirmed FL (grades [Gr] 1-3A) being r/r within 6 mo after second-/later-line therapy (including an anti-CD20 monoclonal antibody with an alkylating agent) or relapsed after autologous hematopoietic stem cell transplant (autoHSCT), and with ECOG performance score of 0-1 were eligible. Pts with histologic transformation, prior allogeneic HSCT, or active CNS involvement were excluded. All pts received lymphodepleting chemotherapy followed by tisa-cel infusion of 0.6-6×10⁸ CAR-T cells (bridging therapy prior to infusion was permitted). Disease was reassessed prior to infusion for all pts who received bridging therapy to establish a new baseline. After infusion, disease assessments were performed every 3 mo. The primary endpoint was complete response rate (CRR) based on best response by central review (Lugano 2014 criteria). Pts evaluable for efficacy had measurable disease at infusion and ≥6 mo follow-up from infusion or discontinued early. Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

Results: As of May 26, 2020, 122 pts were screened, 98 were enrolled, 97 received tisa-cel (median follow-up, 6.5 mo), and 52 were evaluable for efficacy (median follow-up, 9.9 mo). At study entry, median age among treated pts was 57 y (range, 29-73), 66% of pts were male, 84% had stage III-IV disease, and 60% had a FLIPI score ≥3. The median number of prior lines of therapy was 4 (range, 2-13), including prior autoHSCT in 36%; 77% were refractory to the last prior treatment (75% ≥2 prior regimens), and 60% had disease progression within 2 y of initial anti-CD20–containing treatment. Overall, 43% of pts received bridging therapy; 18% were treated as outpatient. Of the first 52 pts evaluable for efficacy, CRR was 65.4% (34/52; 99.5% CI, 45.1-82.4) in the intent-to-treat (ITT) population and 71.1% (33/46; 99.5% CI, 56.5-84.0) in the per-protocol (PP) population; ORR was 82.7% (43/52; 95% CI, 69.7-91.8) in the ITT population and 84.8% (39/46; 95% CI, 71.1-93.7) in the PP population. In pts with best response of CR, probability of response lasting ≥6 mo was 89.7% (84.4% for all responding pts [CR+PR]). CRR and ORR were consistent across key prognostic subgroups and per investigator assessment. Median DOR, PFS, OS, and time to next antilymphoma treatment were not reached. Of 97 pts evaluable for safety, 69% experienced Gr ≥3 adverse events, most commonly neutropenia (Gr 3, 13%; Gr 4, 15%); 48% of pts had cytokine release syndrome related to tisa-cel (CRS; Gr 1, 29%; Gr 2, 20%; Gr ≥3, 0%; per Lee scale). To treat CRS, 15% of pts required tocilizumab and 3% required steroids. Any grade serious neurologic events (NEs; per CTCAE v4.03) occurred in 10% of pts; 2% had Gr ≥3 and all recovered (1 pt developed Gr 4 immune-effector cell neurotoxicity syndrome related to tisa-cel concomitant with possible HHV6 encephalitis; 1 pt developed Gr 3 delirium unrelated to tisa-cel after progression of disease and start of salvage therapy). Median time to CRS and serious NEs onset were 4 and 8.5 d, respectively, with respective median time to resolution of 4 and 2 d. Three pts died from progressive disease; no deaths were treatment-related.

Conclusions: Preliminary data from ELARA suggest that tisa-cel is effective in extensively treated r/r FL, resulting in high CRRs and ORRs, including in high-risk pts. The overall safety profile is favorable, with no severe CRS and very low NE reported, requiring limited anticytokine therapy.