Systematic review and meta-analysis: CAR-T vs bispecific antibody as third or later-line therapy for follicular lymphoma

Blood Cancer Journal ARTICLE www.nature.com/bcj OPEN Systematic review and meta-analysis: CAR-T vs bispecific antibody as third or later-line therapy for follicular lymphoma ✉ Lawrence Cheng Kiat Ng 1,2,6 , Xiu Hue Lee1,2,6, Yan Chin Tan1,2, Kye Ling Wong1,2, Johnny Chung Yue Chow1, Victor Wei Teik Ling3,4, 3,4 Edwin Wei Sheng Thong , Esther Hian Li Chan3,4, Wee Lee Chan 3,5, Miny Samuel3,4,7 and Michelle Li Mei Poon3,4,7 1234567890();,: © The Author(s) 2025 There is currently no clear consensus on the standard of care for relapsed or refractory follicular lymphoma (FL) beyond third-line therapy, where both anti-CD19 CAR-T-cell therapy (CAR-T) and CD3×CD20 bispecific antibodies (BsAbs) have demonstrated efficacy. This study aimed to examine their efficacy and toxicity profiles. Relevant studies published between January 2010 and June 2025 were identified through major databases. Of 3960 records screened, 12 studies met the inclusion criteria—7 involving CAR-T and 5 involving BsAbs. The pooled overall response rate (ORR) and complete response rate (CRR) were 93% and 82% for CAR-T, compared with 82% and 67% for BsAbs (p = 0.0002 and p = 0.005, respectively). Among patients with POD24, the CRR was 75% for CAR-T and 69% for BsAbs (p = 0.56). This translated into improved progression-free survival (PFS) with CAR-T: 6-month, 1-year and 3-year PFS rates were 85%, 74% and 54%, respectively, compared with 74%, 62%, and 42% for BsAbs (p = 0.006, p = 0.002 and p = 0.009, respectively). A trend toward higher 3-year overall survival (OS) was observed with CAR-T (80%) versus BsAbs (73%) (p = 0.48). Grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred more frequently with CAR-T (8% vs. 0%, p = 0.04), whereas grade ≥3 infections were numerically higher with BsAbs (17% vs. 9%, p = 0.31). One-year non-relapse mortality (NRM) was similar between groups at 3%. Overall, CAR-T demonstrated potentially higher efficacy in this non-comparative metaanalysis, while the two therapies exhibited noticeable differences in toxicity profiles. Blood Cancer Journal (2026)16:17 ; https://doi.org/10.1038/s41408-025-01439-x INTRODUCTION Follicular lymphoma (FL) has an incidence of 20–25% worldwide and is the most common subtype of indolent B-cell lymphoma [1]. Despite its indolent nature, 15–20% of FL assume a more aggressive disease progression, particularly those with progression of disease within 24 months (POD24). This subpopulation of FL typically requires multiple lines of therapies, including autologous stem cell transplant [2]. Unfortunately, both progression-free survival (PFS) and overall survival (OS) decline markedly with each subsequent line of treatment. This was demonstrated by Batlevi et al., who reported a stepwise reduction in median PFS and OS with each progressive line of chemotherapy [3]. At the same time, a multicentre study from the USA reported considerable variability in the types of therapies used in third-line or later, with 2-year PFS of 40% and lymphoma remained the main cause of death (17% in 5 years) after a median follow-up of 71 months [4]. Both studies highlight the limitations of conventional immunochemotherapies in achieving and maintaining disease control. The treatment paradigm of relapsed or refractory (R/R) FL has shifted remarkably since the introduction of chimeric antigen receptor T-cell therapy (CAR-T), as well as bispecific antibody (BsAb), all of which have successfully demonstrated an unprecedentedly high metabolic complete response rate (CRR) in the third line (3L) or beyond (3L+) setting [5–10]. However, based on their single-arm Phase 2 trials, these treatment modalities have been associated with significant adverse events, particularly neurological toxicities such as immune effector cellassociated neurotoxicity syndrome (ICANS), cytokine-release syndrome (CRS) and infective complications. In the absence of Phase 3 randomised controlled trials comparing these two T-cell-mediated therapies, the clinical decision-making process in the 3L or beyond R/R FL setting remains challenging. While awaiting the availability of more Phase 3 clinical trials data [11], our group conducted this systematic review and comparative meta-analysis of all currently available Phase 1/2 CAR-T and BsAb trials in R/R FL as 3L+ treatment with the aim of comparing their relative strengths and weaknesses, focusing on their efficacy and safety profiles. MATERIALS AND METHODS Search strategy and study selection criteria This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Review and MetaAnalysis Protocols (PRISMA-P) [12] and the Meta-Analysis Of Observational 1 Department of Haematology, Singapore General Hospital, Singapore, Singapore. 2Duke-NUS Medical School, Singapore, Singapore. 3Department of Haematology-Oncology, National University Cancer Institute, National University Hospital, Singapore, Singapore. 4Yong Loo Lin School of Medicine, Singapore, Singapore. 5Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore. 6These authors contributed equally: Lawrence Cheng Kiat Ng, Xiu Hue Lee. 7These authors jointly supervised this work: Miny Samuel, Michelle Li Mei Poon. ✉email: Received: 4 August 2025 Revised: 18 November 2025 Accepted: 12 December 2025 L.C.K. Ng et al. 2 Table 1. List of key eligibility criteria for studies to be included. Criteria Included Excluded Population ▪ Adult (≥18 years) subjects with Follicular lymphoma ▪ Patients had received ≥2 prior lines of therapy. ▪ Children with follicular lymphoma ▪ Subjects with other types of NHL Interventions ▪ CAR-T treatment ▪ Dual targeting CAR-T or non-CD19 Targeting CAR-T Comparison ▪ CD20-CD3 Bispecific treatment ▪ Dual targeting bispecifics or non-CD20CD3 bispecifics Study design ▪ Prospective interventional clinical trials that determined a therapeutic dose and evaluated the efficacy of CD20×CD3 bispecific monoclonal antibodies or CAR-Tcell therapy for R/R FL will be selected for the meta-analysis ▪ Long-term follow-up studies. ▪ Preclinical studies ▪ Phase 1 studies at the dose escalation phase ▪ Prognostic studies ▪ Retrospective studies ▪ Case reports ▪ Commentaries and letters (publication type) ▪ Consensus reports ▪ Nonsystematic reviews Language ▪ All languages ▪ None Date ▪ Jan 2010 to June 2025 ▪ Studies published prior to Jan 2010 Studies in Epidemiology guidelines [13] and registered on the PROSPERO database (Prospero no: CRD42024608398). A comprehensive systematic search of Medline/PubMed, Embase and the Cochrane Library was conducted. To achieve maximum sensitivity for the search strategy, combinations of free text and medical subject heading were used e.g. For patient population, ‘lymphoma, follicular’[Mesh] OR ‘lymphoma, b-cell’[MeSH Terms], relapsed refractory [MeSH Terms] AND for intervention, ‘chimeric t cell receptor’ [MeSH Terms] OR ‘CAR-T’, (...truncated)