The role of lisocabtagene maraleucel for relapsed/refractory follicular lymphoma: a commentary

Introduction

Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin’s lymphoma (NHL) and comprises around 22% of all cases that are newly diagnosed (1,2). There are around 5 per 100,000 new cases each year and presents typically at a median age of 60 years (3). The pathogenesis and architecture of FL has been described extensively (4). Around 90% of FLs include the t(14;18) translocation, which results in BCL2 overexpression, leading to increased cell survival and uncontrolled proliferation of cells (5,6). FLs also commonly express CD10, CD19, CD20, BCL-6, monoclonal immunoglobulin light chain, and are typically negative for CD23 and CD5 (6).

Patients usually present with asymptomatic lymphadenopathy that waxes and wanes and can be present for many years. About 70% of patients the disease will involve the bone marrow, while less than 20% of patients will experience B symptoms (6). FL typically follows an indolent course, allowing many patients to adopt a watch-and-wait approach rather than immediately initiating treatment (7). At some point, a proportion of patients will develop symptomatic disease and treatment will be required, which typically consist in an alkylating based regimen in combination with anti-CD20 monoclonal antibodies and that results in high response rates (3,6,7). Despite effectiveness of first line regimens, FL patients are expected to relapse at some point during their course of the disease. Early relapse, especially within 24 months from initial therapy, is the most important prognostic factor that impacts survival and occurs in about 20% of patients (8,9).

In the relapse/refractory (R/R) FL setting, there are several treatment options, including autologous hematopoietic cell transplantation (HCT) in eligible patients. While these are effective approaches, patients still relapse. Beyond second line therapies, options were traditionally more limited, with shorter duration of remissions and higher lymphoma related mortality (10,11). Currently, several options have emerged and approved for routine use in R/R FL after two lines of therapy, including bispecific antibodies (BiAbs), 2^nd generation anti CD20 monoclonal antibodies plus zanubrutinib, the EZH2 inhibitor tazemetostat, lenalidomide and rituximab (R²), and chimeric antigen receptor T-cell therapy (CAR-T). These have all shown great efficacy in heavily pretreated R/R FL (12).

The role of CAR-T cell therapy in FL

Chimeric antigen receptors (CARs) are a synthetic protein that consists of an extracellular ligand-binding domain, a transmembrane domain, a spacer domain that connects the two, in addition to one or more cytoplasmic domains. T cells that display CARs have shown great efficacy at treating malignancy, specifically hematologic malignancies (13). These CAR-T cells can recognize, bind, and cause destruction of lymphoma cells that express the target antigen (14).

In addition to lisocabtagene maraleucel (Liso-cel) there are currently two additional CAR-T products approved for R/R FL as a third line therapy: axicabtagene ciloleucel (Axi-cel) and tisagenlecleucel (Tisa-cel).

The ZUMA-5 clinical trial led to the approval of Axi-cel for R/R FL after 2 lines of therapy. The primary analysis included 124 patients with R/R FL and demonstrated an overall response rate (ORR) and complete response (CR) rate of 94% and 79%, respectively. At 3-year follow up, the median progression-free survival (PFS) and overall survival (OS) were 40.2 months and not reached, respectively (15,16). Similarly, the ELARA trial reported high efficacy rates in similar patient population (3^rd line setting R/R FL) with an ORR and CR rates of 86% and 69%, respectively. The estimated 24-month PFS and OS were 57.7% and 87.7%, respectively (Figure 1) (17,18).

Figure 1 Comparison between ZUMA-5, ELARA, TRANSCEND-FL, GO29781, and EPCORE-NHL-1. ^†, the EPCORE-NHL-1 study only reports the ICANS rate (all grades/grade ≥3: 6%/0%); NE rates are not available. For comparison, ICANS rates are also available for the ELARA study (all grades/≥ grade 3: 4%/1%) and the GO29781 study (all grades/≥ grade 3: 1%/0%). The different studies were not compared head-to-head and are presented for descriptive purposes only. AE, adverse event; Axi-cel, axicabtagene ciloleucel; CR, complete response; CRS, cytokine release syndrome; d, day; FLIPI, follicular lymphoma international prognostic index; GELF, Groupe d’Etude des Lymphomes Folliculaires; HCT, hematopoietic cell transplantation; ICANS, immune effector cell-associated neurotoxicity syndrome; Liso-cel, lisocabtagene maraleucel; LP, leukapheresis; NA, not available; NE, neurological event; NR, not reached; ORR, overall response rate; PFS, progression-free survival; POD24, progression of disease within 24 months; Tisa-cel, tisagenlecleucel.

The drug: Liso-cel

Liso-cel is a patient-derived, CD19-directed CAR-T-cell product, consisting of CD8⁺ and CD4⁺ components (14). During Liso-cel manufacturing, a patient’s T cells are first recovered through leukapheresis. These cells are subsequently activated, transduced, and expanded. Once a sufficient number of cells have been produced, these cells are infused back into the patient (13,14).

Liso-cel has demonstrated substantial efficacy in treating relapsed/refractory B-cell lymphomas. The pivotal TRANSCEND-NHL-001 study evaluated patients with relapsed or refractory large-B cell lymphoma (LBCL) that received Liso-cel in the third line setting as single infusions and demonstrated an ORR, CR and PFS of 73%, 53% and 6.8 months, respectively. These findings resulted in the first food and drug administration (FDA) approval of Liso-cel for R/R LBCL after 2 lines of systemic therapy (19). Following this trial, Liso-cel was studied as second line therapy in transplant eligible DLBCL in the phase III clinical trial TRANSFORM that compared CAR-T versus standard of care platinum-based chemotherapy. The study met its primary endpoint of event-free survival (EFS); 10.1 versus 2.3 months with SOC therapy, demonstrating a trend of survival improvement (20). These outcomes resulted in the subsequent approval in DLBCL refractory or relapsing to frontline therapy within 12 months. Liso-cel gained subsequent approvals as second line transplant-ineligible DLBCL, refractory mantle cell lymphoma (MCL) and refractory chronic lymphocytic leukemia (CLL) (21-23).

The TRANSCEND-FL clinical trial

The TRANSCEND-FL clinical trial evaluated the therapeutic outcomes of patients with R/R FL and R/R marginal zone lymphoma. For the FL cohorts, patients were required to have undergone at least 1 or more prior therapies including an alkylating + CD20 monoclonal antibody-based therapy. The FL cohorts consisted of 3 or more lines of therapy (3L) or as a second line treatment (2L). Notably, this study was the first to date to report outcomes of Liso-cel therapy in the 2L FL population. This study also evaluated several different subgroups including those with progression of disease within 24 months (POD24), double refractory disease, high tumor burden, high risk follicular lymphoma international prognostic index (FLIPI), and those who received bridging therapy (24).

The study enrolled and apheresed 139 patients with 130 infused with Liso-cel, 124 patients were efficacy evaluable (101 patients for 3L+ FL, 23 with 2L FL). The median time from leukapheresis to product availability was 29 days. Liso-cel was successfully manufactured in 133 out of 139 patients (96%). Five patients received infusion of a non-conforming Liso-cel product. The median age was 60 years (range, 23–80 years). Among key characteristics, 86% had Ann Arbor stage III/IV disease, 53% had high-risk FLIPI score, 45% were considered POD24, 56% met modified Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria, 62% were double refractory (refractory to both anti-CD20 and alkylating agent), and 38% received bridging therapy.

Liso-cel demonstrated an excellent activity in heavily treated in 3L+ R/R FL with ORR of 97% and CR of 94%. In 2L FL patients, the ORR was 96% with all responders achieving CR. With a median follow-up of 17.6 months, the median duration of response (DOR) and PFS were not reached at the time of last follow up in the primary analysis. In the subgroup analysis, ORR, CR rate, DOR and 12-month PFS estimate remained statistically high across all subgroups, including those with high risk disease features (POD24, double refractory, etc.).

The safety of Liso-cel was evaluated, focusing on treatment-emergent adverse events (TEAEs). The most frequently observed complications included cytopenias, particularly neutropenia, along with anemia and thrombocytopenia. Cytokine release syndrome (CRS) occurred in 75 patients (58% total, 59% 3L+, and 52% 2L), though most CRS events were grade 1 with only one patient experiencing grade 3 events and no grade 4 or 5 events. Neurological events (NEs) were also evaluated and occurred in 15% of patients (15% 3L+, 17% 2L). NEs mainly occurred as grade 1 events, with three as grade 3, and no grade 4 or 5 events.

Discussion

Liso-cel has demonstrated significant efficacy in patients with relapsed or refractory FL, as well as a treatment for second-line disease, particularly in patients who exhibit high-risk features. The safety profile of Liso-cel is comparable to that of other previously approved CAR-T cell products. Moreover, TRANSCEND-FL is the first to explore the use of CAR-T as an earlier therapeutic option in relapsed or refractory disease.

In the current era of FL therapy landscape, there have been notable advances in treatment options, such as BiAbs and CAR-T cell therapy for patients with relapsed or refractory disease, contributing to improved clinical outcomes in these populations. Liso-cel is among those innovative therapies and proves to be a viable treatment option with strong efficacy and a favorable safety profile.

A first challenge is to choose among the three approved CAR-T products. Cross-comparison of trials will be difficult, given different patient populations and design (i.e., lack of bridging chemotherapy with ZUMA-5). However, they are all very effective with high rates of responses and long DORs.

The ORR and CR of Liso-cel were consistent with other CAR-T products, including Axi-cel and Tisa-cel, as well as BiAbs mosunetuzumab and epcoritamab (see Figure 1). The ORR and CR of Liso-cel were 97% and 94% respectively, while the ORR for the other therapies ranged from 80–94% and CR ranged from 60–79%.

The safety outcomes of Liso-cel are also consistent with prior studies for 2L as well as 3L+ R/R FL. Liso-cel was associated with 1% CRS and 2% NE grade 3 or greater events. Through this, Liso-cel showed a similar safety profile to Tisa-cel and the BiAbs, with Tisa-cel and epcoritamab both demonstrating 0% CRS, and mosunetuzumab with 2% CRS. Tisa-cel had 1% NE grade ≥3 events while epcoritamab demonstrated 0% grade ≥3 events, and mosunetuzumab reported 3% NE grade ≥3 events.

Notably, Axi-cel was associated with grade ≥3 CRS and grade ≥3 NE of 6% and 15%, respectively, reinforcing the notion that Liso-cel demonstrates a more advantageous safety profile than Axi-cel. The rates of severe infections and prolonged cytopenias were also found to be numerically lower in Liso-cel treated patients when compared to Axi-cel treated patients. However, the toxicity profile in the ELARA trial seems to be similar with what it was reported with Liso-cel.

Another noteworthy difference in this study is that the follow-up period is shorter with Liso-cel than that reported in studies for other CAR-T products. The median follow-up time reported in the TRANSCEND-FL trial was 18.9 months compared to the Axi-cel trial and Tisa-cel in which the follow-up time is longer (between 3 and 4 years). For an indolent lymphoma, a longer follow-up time is a better indicator of durable response and safety.

In comparison to currently approved BiAb products, CAR-T therapies offer advantages including a single administration and enhanced efficacy. However, these treatments necessitate patients to be referred to specialized CAR-T centers for the monitoring of potential side effects, including CRS and neurotoxicity.

BiAbs, however, have a better potential for use in less specialized centers, provided the development and implementation of adequate training and establishment of specific protocols. This would allow for increased access to advanced treatment options for late-stage disease in patients unable to receive treatment in a CAR-T capable center.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-18/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-18/coif). J.C.C. reports receiving consulting fees from GenMab, Kite/Gilead, Novartis, BMS, AdiCet, Autolus, Genentech, Crispr, AstraZeneca; payments or honoraria from Lilly and GenMab; and participating on the Data Safety Monitoring Board or Advisory Board of Atara. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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