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.

Aim: 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.

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： As of June 24, 2025, a total of 43 previously untreated patients with the MCD subtype of diffuse large B-cell lymphoma were enrolled. The median age was 60.5 years (range: 33-76 years). Twenty-two patients (51%) were assessed as stage III to IV according to the Ann Arbor staging system. Extranodal involvement was observed in 79% of cases (n=34), while 53.5% (n=23) exhibited an International Prognostic Index (IPI) score ≥2. Immunohistochemical subtyping revealed germinal center B-cell (GCB) origin in 6 patients (14%) and non-GCB origin in 37 patients (86%).

All 43 enrolled patients received ≥1 cycle of R-CHOP plus Zanubrutinib. Among them, 32 (74.4%) completed protocol therapy, 7 remained on treatment, and 4 discontinued. In the evaluable patients (n=40), ORR was 92.5%, with 35 patients (87.5%) achieving CR. In the non-GCB subgroup (n=34 evaluable), objective responses comprised 31 CR (91.2%) and 1 PR.

The median follow-up time was 16 months (rang from 3 to 35months). The median PFS and OS had not been reached at the time of analysis. The estimated 2-year PFS rate was 95%, and the estimated 2-year OS rate was 97.4%. The ZR-CHOP regimen was generally well-tolerated. The most common AEs (all grades) included neutropenia (58.1%), pulmonary infection (14%), anemia (9.3%) and thrombocytopenia (7%). Grade 3 or 4 adverse events occurred in 37.2% of patients, with neutropenia alone accounting for the majority of these cases.

Conclusions： Zanubrutinib in combination with the R-CHOP is effective and safe for treating previously untreated MCD subtype of Diffuse Large B-Cell Lymphoma.

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2025
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