Zanubrutinib in Combination with R-CHOP for Previously Untreated Ｍcd Type of Diffuse Large B-Cell Lymphoma (DLBCL)

Introduction:

Patients with coexisting MYD88L265P and CD79B mutations (MCD subtype) of diffuse large B-cell lymphoma (DLBCL) exhibit poor outcomes with R-CHOP therapy, highlighting the urgent need for alternative treatment strategies. Numerous studies have demonstrated that MCD type of DLBCL is profoundly reliant on the B-cell receptor signaling pathway, and blocking Bruton's tyrosine kinase (BTK) can effectively disrupt this pathway, thereby eliciting an anti-lymphoma effect. The present study aimed to investigate the efficacy and safety of zanubrutinib in combination with R-CHOP in previously untreated DLBCL patients harboring both MYD88L265P and CD79B mutations. Herein, we present the preliminary findings of this investigation.

Methods：

Previously untreated patients with coexisting MYD88L265P and CD79B mutations diffuse large B-cell lymphoma (MCD subtype of DLBCL), aged 18 to 70 years, with an ECOG performance status of 0 to 3, were enrolled in this study. Patients were administered with zanubrutinib (160 mg orally twice daily [BID]) plus R-CHOP chemotherapy（ZR-CHOP） for four consecutive 21-day cycles. Patients achieving complete remission (CR) after four cycles received an additional two cycles of ZR-CHOP, followed by two cycles of rituximab monotherapy. In contrast, patients assessed with a partial response (PR) after four cycles were prescribed an extended course of four additional ZR-CHOP cycles. The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints encompassed the overall response rate (ORR)，overall survival（OS） and safety.

Results：

Twenty-three patients with newly diagnosed MCD subtype of diffuse large B-cell lymphoma were enrolled until July 1, 2024. The median age was 59.5 years (range: 33-76 years). Twelve patients (52%) were assessed as stage III to IV according to the Ann Arbor staging system. Seventeen patients (73.9%) presented with extranodal involvement. Ten patients (43.5%) had an International Prognostic Index (IPI) score of 2 or higher. The cell of origin was germinal center B-cell (GCB) in 5 patients (21.7%) and non-GCB in 18 patients (78.3%).

At the data cut-off date of July 1, 2024, all 23 patients received at least one cycle of R-CHOP plus zanubrutinib. Fifteen patients had received 6 cycles of treatment, and 3 patients received 8 cycles. Among the 22 evaluable patients, ORR was 90.9%, with 19 patients (86.4%) achieving CR. One patient (4.5%) died due to progressive disease (PD), and another patient (4.5%) withdrew from the trial after completing 3 cycles due to disease progression. Among the 17 evaluable patients with the non-GCB subtype, 14 achieved CR, and 1 achieved PR.

The median follow-up time was 15.7 months (ranging from 4 to 28 months). The median PFS and OS had not been reached at the time of analysis. The estimated 1-year PFS rate was 90.2%, and the estimated 1-year OS rate was 94.1%. The ZR-CHOP regimen was generally well-tolerated.

Conclusions：

Zanubrutinib in combination with the R-CHOP is effective and well-tolerated for previously untreated MCD subtype of Diffuse Large B-Cell Lymphoma.