Rituximab, Lenalidomide, and Zanubrutinib (ZR2) with Sequential CAR-T Cell As First-Line Therapy for High-Risk Large B Cell Lymphoma

Introduction

CAR-T cell therapy has made a breakthrough in refractory or relapsed large b cell lymphoma (LBCL), but data as a first-line therapy is still scarce. ZUMA-12 study showed significant efficacy of CAR-T cell as first-line therapy for high-risk LBCL. However, some patients have difficulty tolerating chemotherapy prior to CAR-T cell therapy, especially elderly and frail patients. Here we report the results of rituximab, lenalidomide, and zanubrutinib (ZR²) with sequential CAR-T cell as first-line therapy for high-risk LBCL.

Methods

We conducted a single-group trial of first-line therapy in adults with newly diagnosed high-risk LBCL. High risk LBCL included high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 translocations, HGBL not otherwise specified, and DLBCL not otherwise specified with an IPI score of ≥3. Patients received two cycles of ZR² (rituximab 375 mg/m² intravenous once on day 1, lenalidomide 25 mg once per day on days 1-21, and zanubrutinib 160 mg twice daily continuously of each 28-day cycle), and those with efficacy assessment of partial response or stable disease received sequential CD19 CAR-T cell therapy. The primary endpoint was complete remission (CR) rate after CAR-T cell therapy. Here we report initial results from this study.

Results

At the cut-off date of 31 June 2024, 23 patients were enrolled. The median age was 68.5 (range 50-84) years old. All the 23 patients finished 2 cycles of ZR² which was well tolerated. Among them, 18 patients have received sequential CD19 CAR-T cell therapy. During CAR-T cell therapies, only 5 grade 1 cytokine release syndrome was observed, and no grade 2 or higher cytokine release syndrome or Immune effector cell-associated neurotoxicity syndrome was observed. The most common adverse events were hematological, which were thought to be associated with lymphodepleting chemotherapy and recovered in a short time without blood transfusion. After CD19 CAR-T cell therapy, 17/18 (94.4%) patients achieved CR. One patient with stable disease after CAR-T cell therapy received several lines of salvage chemotherapy, and finally achieved CR. After a median follow-up of 24 months, 2 patients experienced disease relapse at 6 and 16 months after CAR-T cell therapy, respectively. Both 2 patients received chemotherapy of RCHOP, and achieved CR again. As of date cut-off, all the 18 patients after CAR-T cell therapy remained in CR. The overall survival rate was 100% and the progression free survival rate at 1 year was 85.7%.

Conclusions

ZR² with sequential CAR-T cell therapy has enabled chemo-free treatment in newly diagnosed high-risk LBCL. This treatment is characterized by high CR rate, high long-term survival, and low toxicity.