Research Guide: Relapsed/Refractory Diffuse Large B-Cell Lymphoma - A Breakthrough in CD20 CAR-T Preemptive Therapy

Relapsed/Refractory Diffuse Large B-Cell Lymphoma (r/r DLBCL) is a highly aggressive hematologic malignancy. In recent years, CD19 Chimeric Antigen Receptor T-cell (CD19 CAR-T) therapy has brought revolutionary breakthroughs in the treatment of r/r DLBCL patients. However, not all patients achieve durable complete remission. Previous studies have shown that patients who only achieve partial response (PR) after CD19 CAR-T therapy have a significantly higher early relapse rate; once the disease progresses, the median overall survival is even less than 6 months. Therefore, there is an urgent need for a treatment strategy that can deepen the response and prolong survival in this high-risk population.

The widespread expression of the CD20 antigen on the surface of B-cells makes it a target for CAR-T therapy in B-cell malignancies. CD20 CAR-T therapy has shown encouraging efficacy in patients with r/r B-cell non-Hodgkin lymphoma after failure of CD19 CAR-T therapy. Recently, the team of Directors Ke Xiaoyan and Hu Kai from the Department of Lymphoma and Myeloma at Beijing Gobroad Hospital published a study titled "CD20 CAR-T Therapy Preemptively Treats Patients with Relapsed/Refractory DLBCL in Partial Remission after CD19 CAR-T" in the journal Transplant and Cellular Therapy. This study focused on the clinical efficacy and safety of CD20 CAR-T as a "preemptive" consolidation therapy for r/r DLBCL patients in PR after CD19 CAR-T treatment.

Study Results

The study enrolled 19 adult patients with r/r DLBCL who achieved only a part

ial response (PR) after CD19 CAR-T therapy between 2019 and 2022, and subsequently received CD20 CAR-T cell infusion. Sixteen patients (84.2%) successfully achieved a complete response (CR). This high response rate is significantly superior to the previously reported efficacy of CD20 CAR-T used as salvage therapy.

During a median follow-up of up to 29.4 months, the median progression-free survival (PFS) reached 27.0 months (95% CI, 14.6 to Not Reached [NR]), meaning most patients maintained a disease-free state long-term after treatment. Specifically, the 12-month and 24-month PFS rates were as high as 78.9% and 57.0%, respectively, fully demonstrating the durable efficacy of CD20 CAR-T as consolidation therapy. Meanwhile, the median overall survival (OS) was not reached. The 12-month and 24-month OS rates were 94.7% and 78.6%, respectively, indicating a favorable long-term survival outlook for the patients.

In terms of safety, CD20 CAR-T therapy demonstrated good tolerability. No Grade 3 or higher Cytokine Release Syndrome (CRS) or Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) were observed in the study, indicating a significant advantage of this therapy in controlling severe adverse reactions. Although some patients experienced Grade 3 or higher hematologic adverse events, such as neutropenia (79%), leukopenia (78.9%), and thrombocytopenia (47.2%), most of these adverse events resolved within 1 month after treatment and did not seriously impact the overall prognosis of the patients.

Simultaneously, the study showed that CD20 CAR-T cells effectively expanded in vivo, with a median time to peak of 11 days and a median persistence time of 28 days. In a subgroup analysis of patients with TP53 gene mutations, 6 out of 7 TP53-mutated patients (85.7%) achieved CR, and neither median PFS nor OS was reached, suggesting that CD20 CAR-T is also effective for refractory DLBCL patients with TP53 mutations. Among patients without TP53 mutations, 6 (75.0%) achieved CR, with a median PFS of 21.3 months, further confirming the broad applicability of CD20 CAR-T.

Summary and Outlook

Director Hu Kai: The breakthrough of this study lies in being the first to systematically evaluate CD20 CAR-T as a preemptive consolidation strategy for r/r DLBCL patients in partial response (PR) after CD19 CAR-T therapy. This innovative approach not only fills a gap in clinical practice but also provides an unprecedented treatment option for this high-risk patient population, holding significant clinical importance.

The remarkable efficacy demonstrated by the results is noteworthy. Not only was the safety profile favorable, but the high complete response rate of 84% and the median progression-free survival of 27 months also represent a significant improvement compared to previous reports of CD20 CAR-T used as salvage therapy.

This excellent performance may be attributed to the synergistic effect of multiple factors. First, effectively addressing target antigen heterogeneity is key. After CD19 CAR-T therapy, some tumor cells may escape by downregulating CD19 expression, forming antigenically heterogeneous clones. Sequential use of CD20-targeted CAR-T therapy can effectively clear these escape clones, prolong the persistence of CAR-T cells in vivo, and deepen the response. Second, the strategy of early intervention is crucial. This study administered preemptive CD20 CAR-T therapy before patients showed obvious clinical relapse. This early intervention helps to more thoroughly eliminate minimal residual disease (MRD), securing a longer disease-free survival for patients.

Furthermore, the reduction in tumor burden and improvement in the tumor microenvironment also play positive roles. Achieving partial response after CD19 CAR-T therapy means the patient's tumor burden has already been reduced, and immunosuppressive signals in the tumor microenvironment may also be weakened. This favorable internal environment creates better conditions for the subsequent expansion and anti-tumor function of CD20 CAR-T cells. Additionally, standardized management was also integral to the success of this study.

Director Ke Xiaoyan: The Department of Lymphoma and Myeloma at Beijing Gobroad Hospital has accumulated extensive clinical experience in CAR-T therapy. Standardized bridging therapy, lymphodepletion regimens, and strict infection prevention measures together form a safe and efficient treatment system, positively impacting the overall prognosis of patients.