Zanubrutinib Combined With BR in the First-line Treatment of Waldenström's Macroglobulinemia

A Multicenter Study on the First-line Treatment of Waldenström's Macroglobulinemia With Zanubrutinib in Combination With Rituximab and Bendamustine

Current retrospective studies have demonstrated that achieving deep remission following treatment for Waldenström's macroglobulinemia (WM) correlates with prolonged survival. While the bendamustine-rituximab (BR) regimen or single-agent zanubrutinib are currently recommended as first-line therapies, neither achieves optimal deep remission. Additionally, prolonged zanubrutinib monotherapy may lead to cumulative adverse effects. Therefore, this study aims to evaluate the efficacy and safety of the bendamustine-rituximab-zanubrutinib combination regimen as a first-line treatment option for MYD88-mutated WM patients.

Inclusion Criteria:

1. Previously untreated symptomatic Waldenström macroglobulinemia (WM) meeting IWWM-7 diagnostic criteria:

   1. Presence of monoclonal IgM-type immunoglobulin in serum
   2. Bone marrow infiltration by plasmacytoid lymphocytes or bone marrow biopsy showing small lymphocytes/plasma cells/plasmacytoid lymphocytes (any quantity) in the intertrabecular space
   3. Exclusion of other non-Hodgkin lymphoma subtypes
   4. Typical immunophenotype: CD5-/CD10-/CD19⁺/CD20⁺/CD23-/CD79b⁺ /sIgM⁺/CD138- clonal B-cells. Variant phenotypes may show CD5/CD10/CD23 /CD38 positivity or coexistence of clonal B-cells and plasma cells.

2. MYD88 L265P mutation is detected in peripheral blood or bone marrow.

3. Serum monoclonal IgM ≥5 g/L.

Exclusion Criteria:

1. Co-morbidity of uncontrolled infection or autoimmune disease
2. Co-morbidity of other active malignancy
3. Co-morbidity of uncontrolled heart disease
4. Co-morbidity of severe digestive system disorders precluding oral medication
5. Seropositive for human immunodeficiency virus
6. Hepatitis B virus (HBV)-DNA > 1000 copies/mL
7. Seropositive for hepatitis C (except in the setting of a sustained virologic response)
8. Neutrophil <1×10E9/L, platelet < 75×10E9/L, alanine transaminase (ALT) or aspertate aminotransferase (AST) > 2.5 × upper limit of normal (ULN), total bilirubin > 1.5 × ULN，eGFR < 30 mL/min, or receiving renal replacement therapy.