Major responses in MYD88 wildtype (MYD88WT) waldenstrom macroglobulinemia (WM) patients treated with bruton tyrosine kinase (BTK) inhibitor zanubrutinib (BGB-3111).

Background: BTK inhibitors have been shown to be highly active in patients with WM harboring the MYD88L265P mutation, however lower response rates and shorter survival have been reported in patients that lack such mutations (i.e MYD88WT; N Engl J Med 2015;372:1430- 1440). Zanubrutinib is a potent, specific, and irreversible oral investigational BTK inhibitor with a favorable pharmacokinetic profile resulting in complete and sustained BTK inhibition in blood and lymph nodes. Preliminary studies have identified a high response rate with 41.4% of unselected patients achieving a very good partial response [VGPR]) or better (Tam et al, IWWM-10, 2018). Zanubrutinib is currently being evaluated in several ongoing international Phase 3 studies, including two head-to head studies comparing to ibrutinib. Aim(s): Assess the safety and efficacy of zanubrutinib in WM patients with MYD88WT. Method(s): Reported here are data from an exploratory cohort of patients with treatment-na?ve (TN) or relapsed/refractory (R/R) WM in an open-label, multicenter, randomized phase 3 study. Bone marrow MYD88 and CXCR4 mutations were assessed centrally at study entry (NeoGenomics Laboratory). The MYD88 mutation assay used in this study detects all mutations in the region encompassing amino acid Ala260- Pro278, which includes the predominant mutation in WM, MYD88L265P. Mutation detection in the MYD88 amplicon includes a wildtype-allele-blocking approach resulting in enhanced sensitivity (limit of Detection [LOD] 0.5%; Int J Lab Hematol 2016;38:133-140]); compared to a standard polymerase chain reaction/bi-directional Sanger sequencing assay used to detect CXCR4 mutations (LOD 10-15%). Patients were assigned to Cohort 1 (MYD88 mutated; randomized) or Cohort 2 (MYD88WT; non-randomized) based on the MYD88 mutation assay results. All Cohort 2 patients were assigned zanubrutinib 160 mg twice daily until disease progression. Responses were assessed monthly by IgM with extramedullary disease assessment e