PF487 MAJOR RESPONSES IN MYD88 WILDTYPE (MYD88WT) WALDENSTRÖM MACROGLOBULINEMIA (WM) PATIENTS TREATED WITH BRUTON TYROSINE KINASE (BTK) INHIBITOR ZANUBRUTINIB (BGB‐3111)
Authors: M. Dimopoulos, S. Opat, H.‐P. Lee, G. Cull, S. D'Sa, R. Owen, A. Tedeschi, R. García Sanz, M. Varettoni, C. Buske, V. LeBlond, W.Y. Chan, J. Schneider, M. Osman, A. Cohen, J. Huang, C.S. Tam
Journal: HemaSphere (2019)

Background: BTK inhibitors have been shown to be highly active in patients with WM harboring the MYD88 L265P mutation, however lower response rates and shorter survival have been reported in patients that lack such mutations (i.e MYD88 WT ; 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. Aims: Assess the safety and efficacy of zanubrutinib in WM patients with MYD88 WT . Methods: Reported here are data from an exploratory cohort of patients with treatment‐naïve (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 Ala 260 ‐ Pro 278 , which includes the predominant mutation in WM, MYD88 L265P . 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 ( MYD88 WT ; 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 every 3 months, according to response criteria in the NCCN WM guidelines and modified Owen criteria ( Br J Haematol 2013;160:171–176). Results: A total of 26 MYD88 WT WM patients (5 TN, 21 R/R) were enrolled into Cohort 2; 23 CXCR4 WT , 1 CXCR4 WHIM and 2 with unknown CXCR4 WHIM mutation status. The median duration of follow‐up (cut‐off 30Nov2018) was 9.5 months (range, 2.3–18.8). The overall response rate was 76.9% (20/26), with a major response rate of 53.8% (14/26) including 15.4% (4/26) with VGPR; one patient achieved normalized IgM and was negative by immunofixation (CR by IgM) but extramedullary disease persisted. Median time to first major response was 2.9 months (range, 1.9–7.4). Median PFS has not been reached. Most frequent adverse events (AEs in ≥15%) were diarrhea (19.2%, grade 3: 7.7%); constipation, contusion, muscle spasm, and upper respiratory tract infection (each 15.4%). Serious AEs occurred in 8 patients (30.8%), all single cases except for pyrexia (n = 2, 7.7%). No fatal events or atrial fibrillation were reported. Major hemorrhage was reported in 2 patients (7.7%). Zanubrutinib discontinuations occurred due to AE (n = 1, 3.8%), and disease progression (n = 4, 15.4%). Summary/Conclusion: Zanubrutinib was generally well tolerated and demonstrated single‐agent major response activity (including VGPR) in over 50% of patients with MYD88 WT WM. The depth and durability of response in patients with MYD88 WT WM will be further assessed in this ongoing Phase 3 study. image