The 29th Annual Meeting of the European Hematology Association (EHA) was grandly held in Madrid, Spain, from June 13 to 16, 2024. As the largest international conference in the field of hematology in Europe, it annually attracts experts and scholars from around the world to share and discuss innovative ideas and the latest scientific and clinical research findings in hematology. At this year's conference, several studies from Professor Jia Wei's team at Tongji Hospital, Huazhong University of Science and Technology, were selected for poster or electronic poster presentations. This report highlights two studies in the field of aggressive B-cell lymphoma (P2090 and P1164), aiming to provide references for improving the long-term survival and optimizing treatment options for relapsed/refractory B-cell lymphoma.

1. Serum Eosinophil Chemokine Predicts Long-Term Survival in Patients with Refractory Aggressive B-Cell Lymphoma Treated with CD19 CAR-T Therapy

Background

Non-Hodgkin lymphoma (NHL) is a common and life-threatening malignancy in China. Recent clinical trials of chimeric antigen receptor T-cell (CAR-T) therapy have significantly improved the prognosis of B-cell tumors. Third-generation CAR-T targeting CD19 is a crucial treatment for refractory/relapsed lymphomas, particularly B-cell tumors. However, challenges such as poor efficacy and post-treatment relapse remain. Therefore, early identification of non-responders or patients at high risk of relapse through clinical characteristics and biomarkers is critical. Understanding the timing and susceptibility factors of relapse can further enhance the efficacy of CD19 CAR-T therapy.

Objective

To predict the duration of CAR-T therapy and long-term prognosis of patients based on cytokine profiles.

Methods

We enrolled 44 patients diagnosed with refractory or relapsed aggressive B-cell lymphoma from December 2017 to November 2022. These patients received commercial CD19 CAR-T products or participated in clinical trials involving CD19 CAR-T therapy. A total of 88 serum samples were collected on day 0 (before infusion) and on day 7 or 14 post-infusion. Serum samples were tested using meso scale discovery and Luminex methods. A P-value below 0.05 was considered statistically significant.

Results

This study recruited 44 patients with B-cell malignancies who received CAR-T therapy. The median follow-up time was 21.5 months (3.2 to 72.9 months). At three months post-infusion, 38 patients achieved remission, with 31 patients maintaining remission after one year. Post-infusion, levels of GM-CSF, IFN-γ, IL-2 Ra, IL-3, IP-10, IL-10, and SCGF-b significantly increased in all patients, while MCP-1, IL-7, and IL-15 levels decreased. At three months post-infusion, CTACK levels were significantly higher in the non-remission group (PD/death) compared to the remission group (CR/PR), suggesting that CTACK can promote T-cell aggregation in the skin. The cutoff value for CTACK was determined to be 215.4 pg/ml based on the ROC curve. Patients were divided into high and low CTACK level groups, indicating that CTACK can predict three-month prognosis. Based on progression-free survival (PFS) of more than one year, patients were divided into two groups. Eotaxin and SCF were found to be associated with one-year survival prognosis. Eotaxin and SCF were identified as predictors of one-year survival based on ROC curve and survival analysis. SCF plays a key role in the proliferation and survival of mast cells, indirectly promoting the recruitment of effector T cells to inflammatory sites. In multivariate Cox regression analysis, Eotaxin was an independent risk factor for long-term survival (P=0.033). Eotaxin can promote eosinophil infiltration, suggesting that eosinophils may enhance the aggregation of CAR-T and T cells.

Conclusion

Our study indicates that CTACK levels at three months have the potential to predict prognosis in patients receiving CD19 CAR-T therapy, while Eotaxin and SCF levels are associated with one-year prognosis post-treatment. High levels of Eotaxin were identified as an independent risk factor for long-term prognosis in multivariate analysis. Insufficient expansion or dysfunction of CAR-T or T cells may induce the release of these three cytokines, enhancing the aggregation and cytotoxicity of CAR-T cells and T cells against tumor cells, which is detrimental to long-term prognosis.

2. Superior Efficacy of Dual-Targeted CD19/20 CAR-T Therapy in Treating Relapsed/Refractory B-Cell Lymphoma: A Preliminary Multi-Center Interim Report

Background

CD19 CAR-T therapy has shown significant efficacy in patients with B-cell lymphoma and B-cell acute lymphoblastic leukemia. However, its effectiveness is limited due to CD19 antigen loss or downregulation. In phase 1–2 CD19 CAR-T clinical trials, the median progression-free survival was only 5.9 months. Studies have found that dual-targeted CAR-T therapy, such as CD19/22, can reduce the risk of disease recurrence, demonstrating excellent efficacy in B-cell malignancies. CD20 is widely expressed on malignant B cells, and CD20 monoclonal antibodies have become the standard treatment for diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia. These findings prompted us to explore the potential advantages of dual-targeted CD19/20 CAR-T therapy. Therefore, we treated relapsed/refractory B-cell lymphoma patients from three centers with second-generation CAR-T targeting CD19/20.

Objective

To develop dual-targeted CD19/20 CAR-T and evaluate their safety and efficacy in treating relapsed/refractory B-cell lymphoma patients.

Methods

From July 2022 to December 2023, 16 patients with relapsed/refractory B-cell lymphoma (DLBCL, n=11; BCL, n=1; MZL, n=2; BL, n=2) received dual-targeted CD19/20 CAR-T therapy (210^6/kg, n=3; 310^6/kg, n=2; 410^6/kg, n=2; 510^6/kg, n=7; 6*10^6/kg, n=2). These patients were from Tongji Hospital, Bethune Hospital of Shanxi, and the Fourth Hospital of Hebei Medical University.

Results

Among the 16 patients who received dual-targeted CD19/20 CAR-T infusions, the median age was 49 years (range: 30–70 years), with 14 patients having stage III/IV disease. The peak CAR-T expansion mainly occurred 1–2 weeks post-infusion (Figure A). One patient died on day 19 post-infusion due to rapid disease progression. The remaining 15 patients were evaluated for efficacy at 1, 3, 6, 12, 18, and 24 months post-infusion according to the Lugano 2014 criteria, with a median follow-up of 7.9 months (as of February 1, 2024). Among patients who achieved CR, the median peak CAR-T copies were 10^3.6/ug gDNA (95% CI: 10^2.8–10^4.4/ug gDNA), while in non-CR patients, the median peak CAR-T copies were 10^3.4/ug gDNA (95% CI: 10^2.9–10^4.7/ug gDNA); this difference did not reach statistical significance, possibly due to the small patient number (Figure B). Dual-targeted CD19/20 CAR-T was safe, with 6/16 (37.5%) patients experiencing grade 1–2 cytokine release syndrome (CRS), and 10/16 (62.5%) patients not experiencing CRS. No patients experienced grade 3–4 CRS. One patient developed neurotoxicity (ICE score=9, ICANS score=1). The objective response rate (ORR) was 93%, with 53% of patients achieving complete remission (CR) and 40% achieving partial remission (PR) (Figures C, D). The median overall survival and median progression-free survival in CR patients were not reached, with an estimated 12-month progression-free survival rate of 85.7% (95% CI: 33.4–97.9%) (Figures E, F). CR patients had an estimated 12-month progression-free survival rate of 85.7% (95% CI: 33.4–97.9%) and PR patients had 64.3% (95% CI: 29.1–85.4%).

Conclusion

In summary, our study indicates that dual-targeted CD19/20 CAR-T therapy is safe and effective for treating relapsed/refractory B-cell lymphoma, with 85.7% of patients achieving complete remission having durable responses. It may become a promising immunotherapy targeting lymphoma cells in the future.