From December 7 to 10, 2024, the 66th American Society of Hematology (ASH) Annual Meeting took place in San Diego, USA, where global experts gathered to discuss the latest advancements in hematology. Among the key findings presented, Abstract 607 highlighted real-world safety data on CD19 CAR-T therapy, specifically Tisagenlecleucel, offering new insights into its clinical application for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL).To provide an in-depth analysis of these findings, Hematology Frontier invited Dr. Zhitao Ying from the Cancer Hospital Chinese Academy of Medical Sciences, to discuss the latest progress in CAR-T therapy and its implications for clinical practice.Study title：
Tisagenlecleucel for the Management of Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma: An Interim Report of the European Post-Authorisation Safety Study Conducted by EBMT” (Abstract 607)
Dr. Zhitao Ying emphasized that Tisagenlecleucel is a second-generation CAR-T cell therapy targeting CD19, featuring a 4-1BB costimulatory domain. It was the first CAR-T therapy globally approved for clinical use, receiving FDA approval in May 2018 and EMA approval in August 2018 for the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). The recently published real-world study from Europe further validates the efficacy and safety of Tisagenlecleucel in a non-trial setting.
Key Takeaways from the Real-World Data
Professor Ying noted two important insights from this study.
First, the JULIET trial, which served as the registration trial for Tisagenlecleucel in r/r DLBCL, reported a best overall response rate (ORR) of 53.0% and a complete response (CR) rate of 39%. With a median follow-up of 40.3 months, the trial found a median progression-free survival (PFS) of 2.9 months and a median overall survival (OS) of 11.1 months. The real-world data in this study align closely with the JULIET trial results, reporting a best ORR of 62%, a CR rate of 42%, and a median duration of response (mDOR) of 15 months.
However, despite its pioneering role in CAR-T therapy, Tisagenlecleucel faces challenges compared to Axicabtagene ciloleucel (Axi-cel) and Lisocabtagene maraleucel (Liso-cel). Due to the longer cell manufacturing time (median 54 days), Tisagenlecleucel has not demonstrated a significant advantage in short-term efficacy or long-term survival over competing products. This issue was particularly evident in the BELINDA study, where Tisagenlecleucel failed as a second-line treatment for aggressive lymphoma, highlighting the importance of rapid CAR-T production and optimized treatment sequencing.
Toxicity and Future Considerations in CAR-T Therapy for r/r DLBCL
Dr. Zhitao Ying highlighted that cytokine release syndrome (CRS) and neurotoxicity remain the most common adverse events associated with CAR-T therapy. In the JULIET trial, the incidence of grade 3-4 CRS was 22%, while severe neurotoxicity occurred in 12% of patients. However, in this real-world study, the rates of both grade 3-4 CRS and neurotoxicity significantly decreased to 8.6%.
This decline in toxicity rates can be attributed to two main factors. First, as CAR-T therapy becomes more widely used, clinicians have gained greater experience in managing associated toxicities, leading to improved supportive care strategies. Second, different grading criteria were used in clinical trials and real-world studies, with the JULIET trial utilizing the University of Pennsylvania grading scale, while the real-world study followed ASTCT (American Society for Transplantation and Cellular Therapy) guidelines, which may classify toxicities differently.
Another emerging concern is the increased incidence of secondary hematologic malignancies following CAR-T treatment. In this real-world study, seven patients developed myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN). At this year’s ASH meeting, researchers explored the potential mechanisms behind these secondary malignancies, suggesting a possible link to defects in DNA damage repair pathways (Abstract 653).
The Future of CAR-T Therapy: Challenges and Opportunities
CAR-T therapy represents a breakthrough in hematologic cancer treatment, fundamentally reshaping the approach to r/r DLBCL. Both clinical trials and real-world data reaffirm its efficacy and safety, yet significant challenges remain, including long manufacturing times, high costs, and uncertainties regarding long-term durability of response.
Recent years have witnessed remarkable advances in novel therapies for r/r DLBCL, including bispecific antibodies, antibody-drug conjugates (ADCs), and other targeted immunotherapies. A promising direction for the future is to explore combination strategies, integrating CAR-T therapy with these novel agents to enhance treatment efficacy, improve durability of response, and expand therapeutic options for patients with relapsed/refractory disease. Such an approach could potentially overcome current limitations of CAR-T therapy and bring new hope to patients with limited treatment options.
Conclusion
This real-world study reaffirms the clinical value of CAR-T therapy in r/r DLBCL and provides key insights for optimizing future CAR-T treatments. Despite existing challenges such as long manufacturing times and high costs, continuous advancements in medical research and drug development are expected to enhance CAR-T therapy by improving efficacy and reducing toxicity.
With ongoing innovations, the future of CAR-T therapy is likely to become more personalized and precise, offering improved survival outcomes and better quality of life for patients with hematologic malignancies. As the field progresses, the integration of next-generation CAR-T therapies and novel combination approaches may further expand treatment possibilities, bridging the gap between innovation and clinical accessibility.
Dr. Zhitao Ying
Cancer Hospital Chinese Academy of Medical Sciences Chief Physician, MD Director of the Lymphoma/Head and Neck Oncology Department
- Vice Chairman, Cell Immunotherapy Committee, China Health Promotion Foundation
- Standing Member, Youth Expert Committee, Chinese Society of Clinical Oncology (CSCO)
- Standing Member, Cancer Heterogeneity and Personalized Therapy Committee, Chinese Anti-Cancer Association
- Youth Member, Hematologic Oncology Committee, Chinese Anti-Cancer Association
- Member, Geriatric Hematology Lymphoma Group, Chinese Geriatrics Society
- Member, Clinical Research and Drug Evaluation Committee, Chinese Geriatrics Society
- 11th Youth Member, Chinese Society of Oncology
- Associate Editor, JCO-Blood Chinese Edition (Cell and Immunotherapy Section)
- Editorial Board Member, Blood and Genomics
Expertise: Diagnosis and treatment of malignant lymphoma, cellular immunotherapy.
