Lisocabtagene maraleucel (liso-cel), a cell-based gene therapy was approved as a second-line treatmentof relapsed or refractory (rr) large B-cell lymphoma (LBCL) in adult patients by the United States (US)Food and Drug Administration (FDA).¹ Liso-cel is an autologous and chimeric antigen receptor T-cell (CAR-T)therapy that specifically directs cytotoxicity to CD19 antigen-presenting B cells.2,3 First approved inFebruary 2021, liso-cel treats certain types of LBCL, including diffuse LBCL (DLBCL), high-grade B-celllymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B.^2,3 Two new indicationshave been given to liso-cel for the LBCL treatment in patients who have refractory disease to thefirst-line immunochemotherapy, or refractory disease or relapse after the first-line immunochemotherapy^.1,3The approval of liso-cel was supported by the TRANSFORM phase 3 study, which illustrated the efficacyand safety of the therapy as a second-line treatment for rrLBCL.^1,3

While the first-line LBCL treatment with rituximab and anthracyclineimmunochemotherapy has been proven to be effective for cureor remittance in most patients, some still need to resort to thesecond-line approaches if they experience refractory disease orrelapse.³ The standard second-line treatment for rrLBCL consists ofplatinum-based salvage immunochemotherapy, high-dose chemotherapy,and autologous hematopoietic stem-cell transplantation (HSCT).³The emergence of CAR-T therapy has become a promising stepforward in developing curative treatments for rrLBCL, and thatmany clinical trials have shown that survival and response ratesincreased after the CAR-T therapy.⁴ Based on the TRANSFORMtrial, liso-cel demonstrated favorable efficacy and safety profiles asa second-line LBCL treatment, which included DLBCL, high-gradeB-cell lymphoma, primary mediastinal B-cell lymphoma, and follicularlymphoma grade 3B, contributing to its broad patient eligibility.^1,3

TRANSFORM is an ongoing pivotal, open-label phase 3 study thatcompares the efficacy and safety of liso-cel as a second-line therapy tothe current standard of care (SoC) for rrLBCL patients.³ The trial has beenconducted globally with 47 sites in the US, Europe and Japan, recruitinga total of 184 HSCT-eligible patients at 18-75 years old.³ Enrolled patientswere randomly assigned 1:1 to the liso-cel arm or the SoC arm.³ Theliso-cel group was administered 100 × 106 CAR-T cells intravenously,while the SoCgroup was delivered salvage immunochemotherapy, alsointravenously.³ Patients of the SoC arm received salvage therapy cycles ofR-DHAP (rituximab, cytosine arabinoside, cisplatin, dexamethasone),R-ICE (rituximab, ifosfamide, carboplatin, etoposide), or R-GDP (rituximab,gemcitabine, cisplatin, dexamethasone), prior to high-dose chemotherapyand autologous HSCT.³

The primary endpoint of the TRANSFORM trial was event-freesurvival (EFS) per independent review committee (IRC), with a medianfollow-up period of 6.2 months.³ The median EFS of the liso-celgroup was 10.1 months (95% CI: 6.1-not reached), a significant 4-foldincrease compared with 2.3 months (95% CI: 2.2-4.3) of the SoCgroup, indicating the clinical benefit of liso-cel over the current SoCin all analyzed subgroups.³ The key secondary endpoints relating toclinical efficacy included complete response (CR) rate, progression-freesurvival (PFS) per IRC, and overall survival (OS).³ The liso-cel group alsodemonstrated a 27% increase in CR rate and 2.5-fold in median PFS,supporting the superiority of liso-cel treatment compared with thesecond-line SoC treatment.³

The safety of liso-cel was assessed through the secondary safetyoutcomes concerning the types, frequency and the severity of adverseevents (AEs), as well as laboratory abnormalities, and hospital resourceuse.³ The most common AEs reported during the TRANSFORM trialwere neutropenia, anemia and thrombocytopenia, along with fewincidences of severe grade 3 or above cytokine release syndromeand CAR-T therapy-associated neurological events.³ AEs of any gradeaffected 48% of patients in both the liso-cel group and the SoCgroup, but no treatment-related deaths were reported in the liso-celgroup.³ Liso-cel demonstrated a manageable and established safetyprofile in rrLBCL patients during this study.³

Though the clinical efficacy and safety of liso-cel treatment in rrLBCLpatients have been proven, the TRANSFORM trial had a medianfollow-up period of only 6.2 months.³ Therefore, future studies withlonger follow-up time should be performed to ensure the satisfactoryperformance of liso-cel treatment in the long term.³ Nonetheless,the TRANSFORM trial has demonstrated that the liso-cel treatmentis a superior second-line therapy in comparison to the current SoC,supporting the FDA’s approval of it as a second-line treatment optionfor rrLBCL.^1,3