Editor's Note: The efficacy of CAR-T therapy in B-cell lymphoma is increasingly recognized, and its real-world application is expanding. However, patients with high tumor burden face a high incidence of cytokine release syndrome (CRS) and poor outcomes, leading to high treatment-related mortality. There is an urgent need for effective bridging therapies to reduce CRS incidence and improve remission rates in relapsed/refractory B-cell lymphoma patients. From June 13-16, 2024, the 29th European Hematology Association (EHA) Annual Meeting will take place. Dr.  Rui Liu, head of the research team of Professors Xiaoyan Ke and Kai Hu from Beijing Gaobo Hospital, will present a poster titled “VENETOCLAX AND BTK INHIBITORS BASED CHEMOTHERAPY IS A POTENTIAL EFFECTIVE CAR-T BRIDGING THERAPY IN R/R B-NHL,” offering new insights into bridging therapies before CAR-T for relapsed/refractory B-cell lymphoma.

Research Highlights – Difficult Exploration, Illuminating Hope

Professor Kai Hu mentioned that to improve the efficacy of CAR-T cell therapy for relapsed/refractory B-cell lymphoma and reduce treatment-related mortality, the search for “effective CAR-T bridging therapies” has been challenging, but there is hope for breakthroughs.

Our center evaluated the efficacy of a “Venetoclax±BTKi”-based chemotherapy regimen as a bridging therapy before CAR-T cell therapy for relapsed/refractory B-cell lymphoma. The study included 63 patients, with 46% male and a median age of 51 years (range 20-80 years). The breakdown was as follows: DLBCL (n=38), HGBL (n=7), SCNSL (n=4), tFL (n=4), FL (n=3), Richter (n=3), PMBL (n=2), and BL (n=2). A total of 92% (58/63) of patients were in stages III-IV. Second-generation gene sequencing was performed on 84% (53/63) of patients to analyze their genetic subtypes, including MCD subtype (n=14), P53 subtype (n=23), BN2 subtype (n=1), EZB-MYC+ (n=2), EZB-MYC- (n=8), ST2 subtype (n=4), and N1 subtype (n=1). The median number of previous chemotherapy cycles was 8 (range 2-20). Additionally, 8% (5/63) of patients had previously undergone autologous stem cell transplantation, 8% (5/63) had received radiotherapy, and 6% (4/63) had received CAR-T cell therapy. Of the patients, 41% (26/63) received Venetoclax monotherapy combined with other chemotherapy as bridging therapy, while 59% (37/63) received Venetoclax combined with a BTK inhibitor and other chemotherapy. Venetoclax was administered at doses of 10 mg-100 mg QD, and BTK inhibitors (mainly Zanubrutinib, with some Ibrutinib and Orelabrutinib) were used at a dose of 160 mg BID. The median time between bridging therapy and CAR-T cell infusion was 20 days (range 5-82 days).

The overall objective response rate (ORR) was 24% (15/63), and the complete response rate (CRR) was 6% (4/63). If considering SD+ (defined as efficacy greater than disease stabilization but less than partial response) as an effective indicator, the response rate was 59% (37/63). The MCD subtype had the highest response rate at 71% (10/14), followed by the P53 subtype at 56% (13/23), and the EZB subtype at 50% (5/10). Three months after CAR-T therapy, the ORR was 48% (30/63), and the CRR was 32% (20/63). Adverse events included anemia (98%), neutropenia (92%), and thrombocytopenia (71%).

The median follow-up time was 39.33 months, with a median overall survival (OS) of 11.90 months. The estimated 1-year OS rate was 49.5%, and the 2-year OS rate was 42.6%. There was no statistically significant difference in OS between Venetoclax monotherapy and Venetoclax combined with BTK inhibitors (P=0.976). Patients with a history of failed autologous transplantation (P=0.021, HR=0.059) and those with a history of failed CAR-T cell therapy (P=0.008, HR=11.714) affected OS rates.

The Venetoclax and BTKi-based bridging therapy is effective and safe. The MCD subtype showed the best efficacy and is recommended as a bridging therapy before CAR-T. Further prospective studies with larger samples are planned.

Summary and Outlook

Professor Xiaoyan Ke mentioned that the initial study results indicate that the Venetoclax and BTKi-based bridging therapy is effective, especially for patients with the MCD subtype, and may be a viable option for bridging therapy before CAR-T.

Based on the initial results, we have conducted further clinical observations and studies, hoping to find more suitable and effective treatments through continuous exploration, ultimately saving more patients and helping them regain health and embrace a new life.