In recent years, cell immunotherapy, with Chimeric Antigen Receptor T-cell (CAR T) therapy as a representative, has made significant strides in the field of hematologic malignancies. It has profoundly altered the treatment landscape for blood cancers, with several products gaining clinical approval. Especially in the past year, CAR T therapy for lymphoma has achieved remarkable milestones.
The ZUMA-1 study is the earliest clinical trial evaluating the CAR T product Axi-cel for the treatment of relapsed/refractory large B-cell lymphoma (R/R LBCL), reporting six-year survival data in 2023. With a median follow-up of 63.1 months, the 5-year lymphoma-related event-free survival rate (LREFS) was 33.5%, and the 5-year LREFS rate for complete responders (CR) was 56.8%. Real-world data from the U.S. Lymphoma CAR T Consortium's 5-year follow-up showed a median follow-up of 58 months, with a median overall survival (OS) of 28 months, a 5-year OS rate of 37%, and a 5-year disease-specific survival rate (DSS) of 51.1%.
The TRANSCEND NHL 001 study assessed another CAR T product, Liso-cel, in R/R LBCL. Two-year follow-up data reported in 2023 showed a median follow-up of 19.9 months, with objective response rate (ORR) and CR rates of 73% and 53%, respectively. The 2-year median duration of response (DOR), progression-free survival (PFS) rate, and OS rate were 49.5%, 40.6%, and 50.5%, respectively.
The RELIANCE study, a domestic clinical trial evaluating the CAR T product Relma-cel for R/R LBCL, reported 2-year follow-up results in 2023. With a median follow-up of 17.9 months, ORR and CR rates were 77.59% and 53.45%, respectively, and 1-year and 2-year OS rates were 75% and 69.3%. Therefore, both international and domestic CAR T therapies for R/R LBCL demonstrate long-term benefits for some relapsed and refractory patients.
There is increasing evidence supporting CAR T treatment in the second-line setting. The ZUMA-7 study, a global multicenter randomized controlled clinical trial, investigated Axi-cel versus standard-of-care (SOC) as salvage therapy with autologous stem cell transplantation for early relapsed/refractory LBCL after first-line treatment. 2023 follow-up data demonstrated OS benefits for patients in the CAR T treatment group.
The TRANSFORM study, another global multicenter, randomized phase III trial, evaluated the efficacy and safety of Liso-cel versus SOC in the second-line treatment of R/R DLBCL patients. With a median follow-up of 17.5 months, the median event-free survival (EFS) was not reached and 2.4 months for Liso-cel and SOC groups, respectively. Median PFS was not reached and 6.2 months, and median OS was not reached and 29.9 months. These studies further support CAR T as an option for primary refractory and early relapsed patients.
In clinical practice, approximately 50% of LBCL patients are not suitable for high-dose chemotherapy with autologous stem cell transplantation after first-line treatment, leading to poor prognosis. Data from 2023 on CAR T therapy in the second-line setting for these patients have been updated. The PILOT study evaluated Liso-cel in second-line treatment for R/R LBCL patients ineligible for transplantation, with a median follow-up of 18.2 months, showing an 80% ORR and a median DOR of 23.3 months. CR patients had an unreached median DOR, a 72.1% PFS rate at 18 months, and a 59% OS rate for all patients. The ALYCANTE study also assessed the efficacy of Axi-cel in this patient population, with a best response rate and CR rate of 92.5% and 80%, respectively. Therefore, CAR T cell therapy offers more curative possibilities for second-line LBCL patients ineligible for transplantation.
Given the significant benefits of CAR T treatment in R/R LBCL patients, the ZUMA-12 study explores the use of CAR T therapy even earlier in LBCL patients. This study enrolled LBCL patients with high-risk factors who tested positive on PET assessment after completing 2 cycles of immunotherapy. With a median follow-up of ≥40 months, patients treated with Axi-cel showed a high sustained response rate, an 87% ORR, and 3-year PFS and OS rates of 84.4%. Thus, Axi-cel may benefit high-risk LBCL patients who have received less treatment in the past.
Curing relapsed/refractory indolent non-Hodgkin lymphoma (R/R iNHL) has become a possibility, especially for patients with high-risk features. Follicular lymphoma (FL) is a common subtype of NHL, accounting for 8.1% to 23.5% of NHL patients in China. In recent years, despite the significant efficacy of rituximab combined with chemotherapy, FL incidence has been continuously increasing, with 30%-40% of patients experiencing primary refractory or early relapse. CAR T therapy has emerged as an effective treatment for R/R iNHL.
The ZUMA-5 study assessed the efficacy and safety of Axi-cel in R/R iNHL patients. Four-year follow-up results demonstrated persistent effectiveness and long-term survival in these patients, indicating the potential for cure.
The ELARA study evaluated the efficacy and safety of Tisa-cel in R/R FL patients. With a median follow-up of 30 months, the median PFS was 37 months. The 3-year PFS rate for all patients was 53%, and for CR patients, it was 69%. Extended follow-up results from the ELARA study indicated high response rates and sustained remission with good safety in R/R FL patients who had received multiple lines of treatment. Persistent anti-tumor activity was also observed in patients with high-risk clinical features.
The TRANSCEND FL study showed that Liso-cel treatment in patients with third-line and above achieved ORR and CR rates of 97% and 94%, respectively, with 1-year PFS and OS rates of 80.7% and 92.1%. Importantly, Liso-cel demonstrated even better survival data in second-line FL patients (POD24), with 1-year PFS and OS rates of 91.3% and 95.7%. This study revealed that Liso-cel exhibits high response rates and good safety features in R/R FL patients, with greater benefits observed in early-line use. Therefore, for patients with relapsed/refractory indolent non-Hodgkin lymphoma (R/R iNHL), especially follicular lymphoma (FL) patients, there can be benefits from CAR T-cell therapy, with the potential for partial patients to achieve cure.
Emerging Therapeutic Options for Mantle Cell Lymphoma
Brexu-cel (KTE-X19) has been approved for treating patients with relapsed/refractory mantle cell lymphoma (R/R MCL). In the pivotal ZUMA-2 clinical study, with a median follow-up of 35.6 months, the overall response rate (ORR) and complete response (CR) rate were 91% and 68%, respectively. The median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were 28.2 months, 25.8 months, and 46.6 months, respectively. This represents the longest follow-up in clinical studies for CAR T-cell therapy in MCL, suggesting that KTE-X19 can provide sustained long-term relief. Patients tolerated toxicities well, and even those with high-risk features benefited from the treatment.
The MCL cohort analysis in the TRANSCEND NHL001 study evaluated the efficacy and safety of Liso-cel in patients with high-risk disease characteristics. The overall ORR and CR rates were 83% and 72%, respectively, with a median PFS of 15.3 months and OS of 18.2 months. Subgroup analyses demonstrated consistent PFS, OS, and safety outcomes across all subsets, with a significant improvement in quality of life. These findings support CAR T-cell therapy as a potential new treatment option for R/R MCL, especially for patients with limited treatment choices.
Relma-cel, a CD19-targeting CAR T product, has received domestic approval for treating third-line and above patients with large B-cell lymphoma (LBCL) and FL. Recent data shows sustained high efficacy in R/R MCL patients, raising expectations for obtaining approval for MCL indication domestically.
Looking back over the past year, while CAR T therapy has made some achievements in the lymphoma field, there are still many unresolved issues, such as further improving efficacy, achieving similar outcomes in T-cell lymphoma treatment, and selecting options after CAR T treatment failure. With deeper basic research and ongoing clinical efforts, the future of CAR T therapy holds promise.
(Authors are affiliated with Beijing Tongren Hospital, Capital Medical University, and the Cancer Hospital, Chinese Academy of Medical Sciences.)
