Efficacy and safety of tisagenlecleucel (Tisa-cel) in adult patients (Pts) with relapsed/refractory follicular lymphoma (r/r FL): Primary analysis of the phase 2 Elara trial.
Authors: Schuster Stephen J. , Dickinson Michael J. , Dreyling Martin H. , Martínez Joaquín , Kolstad Arne , Butler Jason Paul , Ghosh Monalisa , Popplewell Leslie , Chavez Julio C. , Bachy Emmanuel , Kato Koji , Harigae Hideo , Kersten Marie José , Andreadis Charalambos , Riedell Peter A. , Abdelhady Ahmed M. , Zia Aiesha , Morisse Mony Chenda , Fowler Nathan Hale , Thieblemont Catherine 
Published: June 2021

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Background: Most pts with r/r FL experience multiple relapses and progressively worse clinical outcomes with each line of therapy, underlining a need for novel therapies. Tisa-cel has demonstrated durable responses and manageable safety in adult pts with r/r diffuse large B-cell lymphoma. Here we report the primary analysis of ELARA, an international, single-arm phase 2 trial of tisa-cel in adult pts with r/r FL. Methods: Eligible pts (≥18 y) had r/r FL (grades [Gr] 1-3A) after ≥2 lines of therapy or had failed autologous stem cell transplant. Bridging therapy was permitted followed by disease assessment prior to tisa-cel infusion. Pts received tisa-cel (0.6-6×108 CAR+ viable T cells) after lymphodepleting chemotherapy. The primary endpoint was complete response rate (CRR) by central review per Lugano 2014 criteria. Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and cellular kinetics. Predefined primary analysis occurred when ≥90 treated pts had ≥6 mo of follow-up. Results: As of September 28, 2020, 98 pts were enrolled and 97 received tisa-cel (median follow-up, 10.6 mo). At study entry, median age among treated pts was 57 y (range, 29-73), 85% had stage III-IV disease, 60% had a FLIPI score ≥3, 65% had bulky disease, and 42% had LDH > upper limit of normal. The median number of prior therapies was 4 (range, 2-13); 78% of pts were refractory to their last treatment (76% to any ≥2 prior regimens) and 60% progressed within 2 y of initial anti-CD20–containing treatment. Of 94 pts evaluable for efficacy, the CRR was 66% (95% CI, 56-75) and the ORR was 86% (95% CI, 78-92). CRRs/ORRs were comparable among key high-risk subgroups. Estimated DOR (CR) and PFS rates at 6 mo were 94% (95% CI, 82-98) and 76% (95% CI, 65-84), respectively. Of 97 pts evaluable for safety, 65% experienced Gr ≥3 adverse events within 8 weeks post-infusion, most commonly neutropenia (28%) and anemia (13%). Any-grade cytokine release syndrome (per Lee scale) occurred in 49% of pts (Gr ≥3, 0%). Any-grade neurological events (per CTCAE v4.03) occurred in 9% of pts (Gr 3, 0%; Gr 4, 1 pt and recovered). Three pts died from progressive disease. Cellular kinetic parameters for tisa-cel were estimated using transgene levels (by qPCR) in peripheral blood. Cmax and AUC0-28d were similar between responders (CR or partial response) and non-responders (stable or progressive disease). Maximum transgene levels were reached by a median of 10 days in responders and 12.9 days in non-responders; transgene persistence was detected up to 370 days and 187 days, respectively. Conclusions: These data demonstrate the efficacy and acceptable safety of tisa-cel in pts with r/r FL, including high-risk pts after multiple lines of prior therapy, and suggest that tisa-cel may be a promising therapy for pts with r/r FL. Clinical trial information: NCT03568461.