TRANSCEND FL: Phase 2 Study Primary Analysis of Lisocabtagene Maraleucel as Second-Line Therapy in Patients with High-Risk Relapsed or Refractory Follicular Lymphoma

Background: Results with CD19-directed CAR T cell therapy in patients (pts) with second-line (2L) R/R follicular lymphoma (FL) and high-risk features, such as progression of disease within 24 months (POD24) from diagnosis or double refractory to anti-CD20 antibody plus alkylator, have not been previously reported. TRANSCEND FL (NCT04245839), a global, phase 2, open-label, single-arm, multicohort, pivotal study, assessed efficacy and safety of the anti-CD19 CAR T cell therapy lisocabtagene maraleucel (liso-cel) in pts with second line or later (2L+) R/R indolent NHL. Some data from the primary analysis were previously reported, including safety in 2L+ R/R FL, and focused on efficacy in third line or later R/R FL (Morschhauser F, et al. Hematol Oncol 2023;41[S2]:877‒880). Here, we report primary analysis results in the cohort of pts with 2L high-risk R/R FL.

Methods: Eligible pts in the 2L R/R FL cohort had biopsy-confirmed FL before enrollment and must have had POD24 with treatment ≤ 6 months from original FL diagnosis and/or must have had high tumor burden as defined by modified Groupe d’Etude des Lymphomes Folliculaires (mGELF) criteria. All pts received 1 prior combination systemic therapy with an anti-CD20 antibody and alkylator. Eligible pts received liso-cel (100 × 10⁶ CAR⁺ T cells) after lymphodepleting chemotherapy (LDC). Bridging therapy was allowed with reconfirmation of PET-positive disease before LDC. The primary endpoint was ORR per independent review committee (IRC) by PET/CT using Lugano 2014 criteria. Secondary endpoints included CR rate, duration of response (DOR), PFS, OS, safety, and cellular kinetics. Pharmacodynamic endpoints were exploratory.

Results: At data cutoff (January 27, 2023), 23 of 25 leukapheresed pts received liso-cel and were evaluable for safety and efficacy per IRC; 1 received nonconforming product and 1 reached CR after bridging therapy and no longer met eligibility criteria. Median (range) age was 53 y (34–69), 74% had stage III/IV disease, and 35% were high-risk per FL International Prognostic Index (FLIPI). Sixty-five percent of pts had POD24 from initiation of first-line combination chemoimmunotherapy (52% had POD24 from diagnosis), 70% met mGELF criteria (mGELF only, 48%; mGELF and POD24 from diagnosis, 22%), and 48% were double refractory to anti-CD20 antibody plus alkylator. Median (range) on-study follow-up was 18.1 months (1.0–26.8). In efficacy-evaluable pts, the ORR and CR rate were both 95.7% (95% CI, 78.1–99.9; 1-sided P < 0.0001; Table).

With a median follow-up of 16.8 months and 17.8 months, respectively, median DOR and PFS were not reached; 12-month DOR and PFS were 89.8% and 91.3%, respectively. The most common grade (gr) ≥ 3 treatment-emergent AEs (TEAE) were cytopenias; neutropenia was most frequent (52%). Cytokine release syndrome (CRS) occurred in 12 (52%) pts (no gr ≥ 3). Median (range) time to onset and resolution of CRS was 6 days (2–9) and 3 days (2–7), respectively. Neurological events (NE) occurred in 4 (17%) pts, with 1 (4%) gr 3 and no gr 4–5 (Table). Median (range) time to onset and resolution of NEs was 8.5 days (6–11) and 2.5 days (1–4), respectively. Three (13%) pts received tocilizumab/steroids for CRS/NEs. Prolonged cytopenia (gr ≥ 3 laboratory values at Day 29) occurred in 3 (13%) pts; all recovered to gr ≤ 2 by Day 90. No gr ≥ 3 infections were reported. One TEAE death occurred in the context of IRC-assessed disease progression due to gr 5 macrophage activation syndrome (MAS). Liso-cel showed rapid expansion with median (range) time to maximum transgene levels of 10 days (7–11). Persistence of liso-cel transgene was detected up to Month 12 in 5 of 18 (28%) pts. B-cell aplasia (< 3% CD19⁺ B cells in peripheral blood lymphocytes) after liso-cel infusion was rapid and maintained in ≥ 95% of pts through Month 2.

Conclusions: This is the first report of outcomes in 2L high-risk R/R FL with CD19-directed CAR T cell therapy. In this population, liso-cel achieved very high CR rates (22 of 23 pts); deep and durable remissions, with follow-up ongoing; and a favorable safety profile with low rates of severe (gr ≥ 3) CRS, NEs, and prolonged cytopenia, and no severe infections. These data support liso-cel as a potential new treatment option in pts with 2L R/R FL at high-risk for treatment failure.