Fixed-duration zanubrutinib, bendamustine, rituximab achieves high response rates for Waldenström macroglobulinemia in first report from phase 2 trial

In the phase 2 ZeBRa trial, patients with symptomatic, treatment-naive Waldenström Macroglobulinemia who received fixed-duration zanubrutinib, bendamustine, and rituximab therapy showed high rates of overall and major response, according to a presentation at the 23rd Annual Meeting and Exposition of the International Myeloma Society in Glasgow, Scotland.

CR/VGPR rates were also not impacted by the presence of CXCR4 or TP53 mutations, wrote the study’s lead author, Andrew P. Branagan, MD, PhD, of Mass General Brigham Cancer Institute in Boston.

The presentation covered 52 patients with more than one response assessment. The cohort had a median age of 71 years (range, 42-87), median serum immunoglobulin M of 3,006 mg/dL, and median hemoglobin of 10.6 g/dL. In addition, 96% of the patients had MYD88 L265P mutation, 50% had bone marrow involvement, 34% had CXCR4 mutation, and 12.7% had TP53 mutation.

After a median follow-up of 7.5 months (95% CI, 4.8-9.9; range, 1-17.5), the rate of CR was 7.7%, VGPR was 36.5%, partial response was 40.4%, minor response was 11.5%, and stable disease was 3.8%. The rate of CR/VGPR was 44.2% (95% CI, 30.5-58.7), major response rate was 84.6% (95% CI, 71.9-93.1), and the overall response rate was 96.2% (95% CI, 86.8-99.5). Among patients with MYD88–positive disease, the rate of CR/VGPR was 43.8% for CXCR4–wild-type and 50% for CXCR4–mutated patients, respectively. The CR/VGPR rate was 42.9% for patients with TP53 mutation and 46.3% for patients without.

While survival and safety follow-up are ongoing, the initial findings support the continued investigation of frontline zanubrutinib, bendamustine, and rituximab therapy for patients with Waldenström macroglobulinemia, Dr. Branagan and colleagues wrote.

Reference
Branagan AP, Sarosiek SP, Lei MM, et al. Fixed-Duration Zanubrutinib, Bendamustine, and Rituximab in Symptomatic, Treatment-Naive Waldenström Macroglobulinemia: First Report of the Multicenter Phase 2 ZeBRa Trial (WM-NET2). Abstract LB-33. Presented at the 23rd Annual Meeting and Exposition of the International Myeloma Society; September 23-26, 2026; Glasgow.