Lisocabtagene Maraleucel: A Review of Indications

Before chimeric antigen receptor (CAR) T-cell therapy, standard treatment options for relapsed or refractory (R/R) B-cell lymphomas typically consisted of salvage chemotherapy with or without an autologous stem cell transplant (ASCT). Despite this, only around 30% to 40% of eligible patients with relapsed disease achieve a cure. CAR T-cell therapy has significantly improved the treatment of relapsed B-cell lymphomas and offers a longer, more durable remission in this historically difficult-to-treat patient population.¹

However, CAR T-cell therapy does not come without significant risks. One such risk is cytokine release syndrome (CRS), which results from rapid immune cell activation and can lead to symptoms ranging from mild flu-like symptoms to severe complications. Immune effector cell-associated neurotoxicity syndrome (ICANS) can also occur, presenting as confusion, seizures, or altered mental status.² While these adverse effects (AEs) can be serious, both are manageable with early recognition and intervention. The benefits of CAR T-cell therapy, such as improved disease response rates and potential for long-term remission, must be carefully weighed against these risks.

A 3D illustration of a group of stem cells. Image Credit: © pimmou - stock.adobe.com

One such therapy, lisocabtagene maraleucel (liso-cel, Breyanzi; Juno Therapeutics, Inc), is an autologous, CD19-directed CAR T-cell therapy used to treat R/R B-cell lymphomas. Liso-cel received its initial approval for adult patients with R/R diffuse large B-cell lymphoma (DLBCL) in February 2021. Since then, it has gained 5 additional indications for treatment in the B-cell lymphoma and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) space. Three of these indications were approved in 2024.³ These additional indications reflect the growing recognition of liso-cel’s efficacy and versatility in treating R/R B-cell malignancies. Before reviewing liso-cel’s newest indications from 2024, it’s important to understand the trials and data that facilitated its approval in the B-cell lymphoma space.

R/R DLBCL Indications

Liso-cel’s first indication was for the treatment of R/R large B-cell lymphomas after at least 2 lines of systemic therapy. These include diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, and grade 3B follicular lymphoma (FL). This approval was based on results of the TRANSCEND NHL trial (NCT02631044), a single-arm, open-label, multicenter study that evaluated liso-cel in 192 adult patients with R/R DLBCL, following 2 or more lines of systemic therapy. Overall response rate (ORR) served as a surrogate end point for overall survival (OS), with 73% of patients (104 out of 192) meeting this primary end point (95% CI, 67-80). Complete response (CR) rates were observed in 54% (95% CI, 47-61) of patients. In these patients who achieved a CR, median duration of response (DOR) was not reached (95% CI, 16.7 months, NR). CRS occurred in 46% of patients, with grade 3 or higher reported in 4%. Neurotoxicity occurred in 35% of patients, with grade 3 or higher occurring in 12%. Additionally, grade 3 infections occurred in 19% of patients and prolonged cytopenias were observed in 31%.⁴

Based on previous literature, it is well known that patients who relapse after first-line therapy, especially those who relapse within 1 year of initial therapy, have worse outcomes. Following its promising initial approval, liso-cel was investigated as an earlier line of therapy in the TRANSFORM study (NCT03920826). This phase 3, multicenter trial compared liso-cel with standard of care second-line therapy for primary refractory or early relapsed (<12 months) DLBCL. Eligible patients were randomized 1:1 to receive either liso-cel or standard of care treatment with platinum-based immunochemotherapy, followed by ASCT. The primary end point of median event-free survival was not reached in the investigational cohort, and was 2.4 months in the standard of care group. The CR rate was 74% in liso-cel and 43% for standard of care (P <0.0001). Median OS was not reached in the liso-cel group, and was 6.2 months for standard of care (HR, 0.724; P <0.0987).⁵ These results lead to liso-cel receiving a category 1 recommendation in the National Comprehensive Cancer Network (NCCN) guidelines for primary R/R within 12 months after initial treatment.⁶

For patients with R/R DLBCL who are not candidates for high-dose salvage chemotherapy and subsequent ASCT, treatment options are limited and often yield poor outcomes. The PILOT study investigated liso-cel as a second-line treatment option for these patients. Participants in the PILOT study (NCT03483103) were considered transplant ineligible by their physicians and met at least 1 or more frailty criteria (ie, age >70 years; performance status >2; left ventricular ejection fraction <50%; creatinine clearance <60 mL/min; diffusing capacity of the lungs for carbon monoxide <60%; or alanine aminotransferase [ALT]/ aspartate transaminase [AST] >2 times the upper limit of normal). The primary outcome of ORR was 80%, with 54% of patients achieving a CR. No new safety concerns were observed in the study, although authors observed higher incidence of grade 3 AEs compared with results from the TRANSCEND trial.⁷ These results confirmed liso-cel is a viable second-line option for patients with R/R DLBCL who are not candidates for ASCT.⁶

CLL/SLL

CLL/SLL initial therapy varies from a “watch and wait” approach in early-stage, asymptomatic disease to chemoimmunotherapy in combination with a targeted agent, such as a Bruton tyrosine kinase (BTK) inhibitor or a B-cell lymphoma 2 (BCL-2) inhibitor. Despite these treatment modalities, there remains an unmet need for effective subsequent lines of therapy, as patients often experience relapse or their disease becomes refractory. Following R/R disease, patients typically struggle to achieve durable CRs and face poorer outcomes.⁸

In March 2024, liso-cel achieved a novel approval in treatment of adult patients with R/R CLL/SLL who have received at least 2 lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. TRANSCEND CLL 004 (NCT03331198) was a phase 1/2 open-label, multicenter, single-arm study investigating liso-cel in 89 patients with R/R CLL or SLL. The primary end point of CR rate was 20% (95% CI, 11.1-31.8), with the median DOR not reached among those who achieved a CR (95% CI, 15 months-NR). ORR was 45% (95% CI, 32.3-57.5), with a median DOR of 35.3 months (95% CI, 12.4-NR). Any-grade CRS was observed in 83% of patients, with the majority being grades 1 or 2. Grade 3 CRS occurred in 9% of patients with no reported grade 4 or higher CRS events. Neurotoxicity occurred in 46% of patients, with 20% of patients experiencing grade 3. One case of grade 4 was observed.⁹ Liso-cel’s approval in CLL/SLL provides an additional treatment option with the potential for longer duration of remission in patients whose disease responds.

FL

In May 2024, liso-cel received another FDA approval for the treatment of adult patients with R/R FL who have undergone 2 or more prior lines of systemic therapy.³ This approval was based on the results of the TRANSCEND FL study (NCT04245839), a multicenter, open-label, single-arm trial that evaluated the efficacy and safety of liso-cel in patients with high-risk features. These included disease progression within 24 months of diagnosis; treatment received less than 6 months from the original diagnosis; and/or a high tumor burden, as defined by the modified Groupe d'Étude des Lymphomes Folliculaires criteria. Patients were required to have received at least 1 prior combination systemic therapy that included alkylating chemotherapy and an anti-CD20 antibody.¹⁰

Of the 25 patients who underwent leukapheresis, 23 received liso-cel and were eligible for evaluation of safety and efficacy (1 patient received a nonconforming product, and 1 achieved a CR after bridging chemotherapy). The ORR and CR rate were both 95.7% (95% CI, 78.1-99.9; P <0.0001). Median DOR and PFS were not reached, but the 12-month DOR and PFS were 89.8% and 91.3%, respectively. The most common grade 3 or higher treatment-related AEs were cytopenias, with neutropenia being the most frequently reported (52%). CRS occurred in 52% of patients (n = 12), with no instances of grade 3 or higher CRS. Neurotoxicity occurred in 17% of patients (n = 4), with 1 patient experiencing grade 3 ICANS and none reporting grade 4.¹⁰ Liso-cel demonstrated high rates of CR and evidence of long-term remission in high-risk, heavily pretreated FL, with the trial results supporting a favorable safety profile. Consequently, liso-cel was added as a third-line option for R/R FL in the latest NCCN guidelines for FL.⁶

Mantle Cell Lymphoma

Also in May 2024, the FDA approved liso-cel for the treatment of R/R mantle cell lymphoma (MCL) after at least 2 prior lines of therapy, based on the MCL cohort of the TRANSCEND NHL 001 trial.³ Patients were eligible for liso-cel after receiving 2 or more lines of therapy, which included a BTK inhibitor, an alkylating agent, and a CD20-targeted agent. Historically, patients with MCL who progress on BTK inhibitors have poor outcomes with subsequent treatment options. While recent literature has supported the use of CAR T-cell therapy, specifically brexucabtagene autoleucel (Tecartus; Kite Pharma, Inc), this has demonstrated high rates of treatment-related toxicity.¹¹

In the MCL cohort of the TRANSCEND NHL 001 trial, 104 patients underwent leukapheresis, and liso-cel was infused into 88 of them. The ORR was 83.1% (95% CI, 73.3-90.5), with a CR rate of 72.3% (95% CI, 61.4-81.6) and a median DOR of 15.7 months (95% CI, 6.2-24.0). The most commonly observed grade 3 or higher treatment-related AE was pancytopenia, with neutropenia being the most frequently reported (56%). CRS occurred in 61% of patients, with only 1% classified as grade 3 or higher. Neurological events (NEs) were reported in 31% of patients, with 9% being grade 3 or higher. Liso-cel demonstrated a high CR rate, durable remission, and a low incidence of serious grade 3 or higher CRS, NEs, and infections in patients with heavily pretreated MCL.¹¹

Discussion and Conclusions

The expanded indications of CAR T-cell therapy, particularly with liso-cel’s new indications, have transformed the treatment landscape of R/R B-cell malignancies. Liso-cel's ability to achieve high response rates and durable remissions offers a promising option for patients who have exhausted traditional subsequent therapies. Data from various clinical trials demonstrate not only its efficacy, but also a manageable safety profile, even in heavily pretreated populations. As we continue to grow in our understanding of CAR T-cell therapy, ongoing research and clinical trials are germane in optimizing treatment strategies and addressing the unmet needs of patients facing these challenging conditions. This is especially relevant regarding potentially moving CAR T to a sooner line of therapy in patients who progress in less than 12 months from initial treatment, as demonstrated with liso-cel’s DLBCL indication as a second-line option. Ultimately, liso-cel’s new indications represent a significant advancement, providing hope for improved outcomes in a patient population that historically has limited options.

REFERENCES

1. Sehn LH, Salles G. Diffuse large B-cell lymphoma. N Engl J Med. 2021;384(9):842-858. doi:10.1056/NEJMra2027612

2. Testa U, Leone G, Pelosi E, Castelli G, Hohaus S. CAR-T cell therapy in large B cell lymphoma. Mediterr J Hematol Infect Dis. 2023;15(1):e2023066. doi:10.4084/MJHID.2023.066

3. Breyanzi. Prescribing information. Bristol Myers Squibb; May 2024. Accessed November 18, 2024. https://packageinserts.bms.com/pi/pi_breyanzi.pdf

4. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0

5. Abramson JS, Solomon SR, Arnason JE, et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of phase 3 TRANSFORM study. Blood. 2023;141(14):1675-1684. doi:10.1182/blood.2022018730

6. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 3.2024. Accessed November 18, 2024. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf

7. Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Lancet Oncol. 2022;23(8):1066-1077. doi:10.1016/S1470-2045(22)00339-4

8. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2025. Accessed November 18, 2024. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf

9. Siddiqi T, Maloney DG, Kenderian S, et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet. 2023;402(10402):641-654. doi:10.1016/S0140-6736(23)01052-8

10. Morschhauser F, Dahiya S, Palomba ML, et al. TRANSCEND FL: phase 2 study results of lisocabtagene maraleucel (liso-cel) in patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL). Hematol Oncol. 2023;41:877-880. doi:10.1002/hon.3196_LBA4

11. Wang M, Siddiqi T, Gordon LI, et al. Lisocabtagene maraleucel in relapsed/refractory mantle cell lymphoma: primary analysis of the mantle cell lymphoma cohort from TRANSCEND NHL 001, a phase I multicenter seamless design study. J Clin Oncol. 2024;42(10):1146-1157. doi:10.1200/JCO.23.02214